instruction
stringlengths 34
186
| input
stringlengths 2.02k
93.8k
| output
stringlengths 2
418
| meta_questiontype
stringclasses 6
values | meta_inputlicense
stringclasses 6
values | meta_pmid
stringlengths 8
8
| meta_safetyreportid
int64 9.51M
21M
| meta_articlepubdate
stringlengths 4
10
|
|---|---|---|---|---|---|---|---|
What was the dosage of drug 'PREDNISOLONE'? | Treatment of adult Burkitt lymphoma with the CALGB 1002 protocol: a single center experience in Jordan.
The treatment of adult Burkitt lymphoma with pediatric-based chemotherapy protocols usually results in high cure rates, although with significant toxicity. We report our experience with the Cancer and Leukemia Group B1002 (CALGB 1002) protocol.
The files of adult patients diagnosed with Burkitt lymphoma and treated with the CALGB 1002 protocol at King Hussein Cancer Center between 2008 and 2017 were reviewed. Baseline demographics, clinical laboratory features, treatment details, and responses were collected. The correlations between clinical and laboratory variables with event-free survival (EFS) and overall survival (OS) were determined by univariate and multivariate analyses using backward stepwise Cox regression models. EFS and OS were plotted using Kaplan-Meier curves.
This study included 19 patients with a median age of 33 years (range, 19-65). Eleven (58%) and two (10.5%) patients had advanced-stage and central nervous system disease, respectively. Among 106 administered cycles, the median interval between cycles was 23 days (range, 19-84 days). Sixteen patients (84%) achieved a complete response. After a median follow-up of 40.8 months, the 3-year EFS and OS rates were 78.95%. Patients with a low-risk International Prognostic Index (IPI) had better survival than those with intermediate-or high-risk IPI. Grade III-IV hematological toxicities occurred in 88% of patients, while 73% had grade III-IV mucositis.
In adult Burkitt lymphoma, the CALGB 1002 protocol provides high cure rates and can be administered promptly, but is associated with significant toxicity. Risk-adapted approaches and other, less toxic, chemotherapeutic regimens should be considered.
pmcINTRODUCTION
Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by a high proliferation rate (Ki 67 of approximately 100%) and deregulation of the MYC gene. It is more common in the pediatric age group, peaking around 10 years of age, but accounts for only about 1% of all NHL in adults [1-3].
Clinically, BL often presents with rapidly enlarging masses and extranodal site involvement, especially the bone marrow and central nervous system (CNS). Owing to its rapid growth, early diagnosis and prompt treatment initiation are important [4].
The treatment of BL in adults is challenging because of the lack of randomized trials to define the best initial regimen. Most first-line regimens are adopted from intensive pediatric protocols and include a combination of anthracycline, alkylator, vincristine, etoposide, and agents to treat and prevent CNS disease [5].
Cancer and Leukemia Group B (CALGB) developed an intensive regimen (CALGB 9251) that initially included multi-agent chemotherapy with prophylactic cranial radiotherapy and 12 doses of intrathecal chemotherapy (ITC) [6]. As 61% of patients in the first cohort developed severe neurological toxicity, in the second cohort, prophylactic cranial radiotherapy was administered only to patients with bone marrow involvement, and only seven ITC doses were administered. The 5-year overall survival (OS) rate was 52%. In a follow-up study (CALGB 1002), the addition of rituximab resulted in improvements of 4-year event-free survival (EFS) and OS to 78% and 74%, respectively [7].
The CALGB 1002 protocol was used for the treatment of most BL cases in our center. Our study aimed to describe the characteristics and outcomes of adult BL patients treated with the CALGB 1002 protocol.
MATERIALS AND METHODS
We retrospectively analyzed the medical records of adult patients diagnosed with BL and treated with the CALGB 1002 regimen at the Medical Oncology Department, King Hussein Cancer Center in Jordan between January 2008 and December 2017.
The following variables were retrieved from patient charts and electronic medical records: age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, initial lactate dehydrogenase (LDH) level, stage on time of diagnosis, and extra-nodal sites involved. In addition, treatment details including the timing of chemotherapy administration, ITC, hematological and non-hematological toxicities, response, and relapse were also obtained.
The details of the treatment protocol are provided in Table 1.
Staging was performed according to the Lugano staging system based on computed tomography (CT) scans [8]. Bulky disease was defined as tumor bulk >10 cm in the transverse or coronal diameters. The International Prognostic Index (IPI) was calculated as initially described using age, performance status, LDH level, stage, and number of extranodal sites [9]. The patients were considered to have low risk if they met all of the following criteria: Lugano stage I–II, normal LDH, ECOG performance status of 0–1, and tumor mass <10 cm [10]. Patients who did not fulfill the criteria for low-risk disease were considered to have high-risk disease.
Response evaluation was performed based on the modified Cheson lymphoma response criteria [11]. Toxicity grading was done using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [12].
EFS was calculated from the time of diagnosis until the time of death, progression, or relapse, while OS was calculated from the time of diagnosis until death from any cause or the date of the last follow-up.
The correlations of different clinical and laboratory variables with EFS and OS were determined by univariate and multivariate analyses using the backward stepwise Cox regression model. The EFS and OS were calculated and plotted using the Kaplan–Meier method.
RESULTS
Patient characteristics
This study included 19 patients, 12 (63%) of whom were male. The median age was 33 years (range, 19–65 yr). Eleven patients (58%) had advanced-stage disease (stage III or IV), and 14 (73.6%) had extranodal involvement. CNS involvement was found in two patients (10.5%). Bone marrow involvement was also found in two patients (10.5%), and 13 patients (68%) had high-risk disease. The detailed patient characteristics are shown in Table 2.
Treatment and response
The median time from diagnosis to treatment initiation was 11 days (range, 8–56 days). A total of 106 cycles were administered, with the median interval between cycles of 23 days (range, 19–84 days). All patients were administered a median of six doses of ITC (range, 2–6). Three patients (15.8%) received craniospinal radiotherapy.
Sixteen patients (84%) achieved a complete response (CR), while the other three patients failed to achieve a CR (one had a partial response: one died of chemotherapy-related sepsis before having a response evaluation, and one developed disease progression).
After a median follow-up of 36 months, the 3-year EFS and OS rates were both 78.9% (Figs. 1, 2).
Four patients (21.1%) died: two from disease progression and two from chemotherapy-related complications.
Stratification of the patients according to IPI showed a significant difference in 3-year OS rates between patients with low IPI and those with intermediate or high IPI (100% vs. 60%, P=0.038) (Fig. 3). In contrast, the 3-year OS rates did not differ significantly between patients with low- and high-risk disease (100% vs. 69%, P=0.147) (Fig. 4).
Univariate analysis showed that abnormal LDH, intermediate or high IPI, and bulky disease were correlated with worse OS. However, none of these factors was significant in the multivariate analysis (Table 3).
Toxicity
Hematological toxicities, including grade III–IV neutropenia and thrombocytopenia, were both found in 88% of patients, while febrile neutropenia occurred in 89% of patients. The most important grade III–IV non-hematological toxicities were mucositis, which occurred in 13 patients (72%). Two patients (10.5%) from chemotherapy-related toxicities, one after the second cycle and the second after the fifth cycle.
DISCUSSION
We reported our experience with the treatment of BL with a uniform chemotherapy protocol. To our knowledge, only one study has previously reported real-life experiences with the CALGB protocol in BL [13]. Comparison to the original study by Rizzieri et al. [7], our patients had more favorable features including younger median age (33 vs. 43 yr) and fewer patients with initial bone marrow involvement (10.5% vs. 28%), B symptoms (26% vs. 48%), and high-intermediate or high IPI scores (32% vs. 47%). However, the EFS and OS rates were almost comparable, which might be explained by the smaller sample size and relatively higher treatment-related mortality (10.5% vs. 6.6%).
Interestingly, as observed in most BL trials, all of our patients who achieved CR after completion of treatment continued to be disease-free until the last follow-up.
Several features of the CALGB 1002 protocol contribute to its high efficacy, including the use of non-cross-resistant chemotherapeutic agents, lack of treatment delays (as demonstrated in our study), and aggressive CNS prophylaxis [14]. However, the major disadvantage of the CALGB 1002 protocol is the lack of a risk-stratified approach. This may result in unnecessary exposure of low-risk patients to toxic treatments. Most trials stratify patients according to their initial features as well as their interim response to treatment. The features used to define “high risk” included one of the following: elevated LDH, ECOG performance status ≥2, and bulky disease (7–10 cm). Although using
Risk-stratified treatment was also tested in 113 patients treated with a dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) protocol [16]. The low-risk patients were administered two cycles, and a third cycle if PET-CT scans showed no evidence of disease. Patients who did not achieve complete remission after the second cycle and all high-risk patients were administered six cycles. The 4-year EFS rates were 100% and 82.1% in the low- and high-risk groups, respectively.
Similar to the results of many BL studies [7, 17, 18] our study findings confirmed the significantly inferior outcomes of patients with intermediate and high IPI compared to those of patients with lower IPI scores (3-yr EFS: 60% vs. 100%). The best management of BL with high-intermediate and high IPI remains unclear. A recent phase II UK-NCI trial showed that the use of rituximab with CODOX-M/IVAC was associated with more favorable outcomes [2-yr progression-free survival (PFS) of 77.2% and OS of 80.7%] [19]. In addition, in a multicenter trial that reported the outcomes of patients treated with dose-adjusted EPOCH-R, the outcomes were favorable regardless of IPI [16].
The use of pediatric-inspired protocols in adult BL is associated with substantial hematological and non-hematological toxicities, with treatment-related mortality occurring in 5–10% of patients [7, 10, 20-22]. The use of dose-adjusted EPOCH-R was associated with favorable outcomes (4-yr EFS and OS of 84.5% and 87%, respectively) with much lower toxicities. However, patients with CNS involvement were at high risk for treatment failure, with an EFS of only 40% [15]. Moreover, a recent multicenter cohort study showed that CNS relapse was more common in dose-adjusted EPOCH-R than in CODOX-MI/VAC and Hyper-CVAD (13% vs. 4% and 3%, respectively) [23]. Incorporation of high-dose methotrexate with dose-adjusted EPOCH-R has been successfully attempted [24, 25] and may help to improve the outcomes of patients with CNS involvement and decrease the rate of CNS relapse.
Our study has important limitations, including its retrospective nature and the small number of patients observed in most of the BL studies.
In conclusion, despite its substantial toxicities, CALGB 1002 could be administered promptly, resulting in high cure rates among patients with BL. Adoption of risk-adapted approaches, as well as the use of less intensive chemotherapeutic protocols, would direct future progress in the treatment of BL.
Fig. 1 Overall survival.
Fig. 2 Event-free survival.
Fig. 3 Overall survival in patients with low- and high-risk disease (P=0.138).
Fig. 4 Overall survival according to low versus high International Prognostic Index (IPI) values (P=0.038).
Table 1 Cancer and Leukemia Group B1002 (CALGB 1002) protocol.
Cycle 1
Drug Dose Days
Cyclophosphamide 200 mg/m2 1–5
Prednisolone 60 mg/m2 1–7
Cycles 2, 4, and 6
Drug Dose Days
Ifosfamide 800 mg/m2 1–5
Mesna 200 mg/m2 1 to 5 (At h 0, 4, and 8 after ifosfamide)
Methotrexate 1,500 mg/m2 1
Leucovorin 25 mg/m2 36 h after starting methotrexate infusion,
then 10 mg/m2 until methotrexate level <0.05 μmol/L
Vincristine 2 mg 1
Cytarabine 1,000 mg/m2 4–5
Etoposide 80 mg/m2 4–5
Intrathecal
Methotrexate 15 mg 1
Cytarabine 40 mg
Hydrocortisone 50 mg
Rituximab Cycle 2:
50 mg/m2, then 8
375 mg/m2 10
Cycles 4 and 6:
375 mg/m2 8
Filgrastim 5 mcg/kg Starting on day 7
Cycles 3, 5 and 7
Drug Dose Days
Cyclophosphamide 200 mg/m2 1–5
Methotrexate 1,500 mg/m2 1
Leucovorin 25 mg/m2 36 h after starting methotrexate infusion, then
10 mg/m2 until methotrexate level <0.05 μmol/L
Vincristine 2 mg 1
Doxorubicin 25 mg/m2 4–5
Dexamethasone 10 mg/m2 4–5
Intrathecal
Methotrexate 15 mg 1
Cytarabine 40 mg
Hydrocortisone 50 mg
Rituximab 375 mg/m2 8
Filgrastim 5 mcg/kg Starting on day 7
Table 2 Patient characteristics.
Variable (N=19) N (%)
Age Median: 33 (19–65)
Age >60 yr 1 (5.3)
Male 12 (63)
Stage
I–II 8 (42.1)
III–IV 11(58)
ECOG performance status
0–1 15 (78.9)
2 or more 4 (21.1)
High LDH 10 (52.6)
Extranodal involvement 14 (73.6)
Number of extranodal sites
1 7 (36.8)
>1 7 (36.8)
Bone marrow involvement 2 (10.5)
CNS involvement 2 (10.5)
Bulky disease 5 (26.3)
B symptoms 5 (26.3)
Risk classification
Low 6 (31.5)
High 13 (68.5)
International Prognostic Index
Low (0–1) 9 (47.3)
Low-intermediate (2) 4 (21.1)
High-intermediate (3) 3 (15.8)
High (4–5) 3 (15.8)
B symptoms: fever (>38°C), weight loss (>10% over 6 mo), and drenching night sweats.
Abbreviations: CNS, central nervous system; LDH, lactate dehydrogenase.
Table 3 Univariate and multivariate analysis.
Variable Univariate analysis (P) OR Multivariate analysis (P)
Age at diagnosis >60 yr 0.62
Ann Arbor stage III–IV 0.06
Serum LDH level >1×normal 0.04 70.66 0.97
>1 extranodal site 0.55
Bone marrow involvement 0.68
CNS involvement 0.68
International Prognostic Index 0.04 70.66 0.97
B symptoms 0.30
Bulky disease 0.01 11.37 0.49
Abbreviations: CNS, central nervous system; LDH, lactate dehydrogenase; OR, odds ratio.
Authors’ Disclosures of Potential Conflicts of Interest
No potential conflicts of interest relevant to this article were reported. | 60 MILLIGRAM/SQ. METER, CYCLICAL (CYCLE 1: ON DAYS 1-7) | DrugDosageText | CC BY-NC | 34880141 | 20,994,380 | 2021-12-09 |
What was the outcome of reaction 'Sepsis'? | Treatment of adult Burkitt lymphoma with the CALGB 1002 protocol: a single center experience in Jordan.
The treatment of adult Burkitt lymphoma with pediatric-based chemotherapy protocols usually results in high cure rates, although with significant toxicity. We report our experience with the Cancer and Leukemia Group B1002 (CALGB 1002) protocol.
The files of adult patients diagnosed with Burkitt lymphoma and treated with the CALGB 1002 protocol at King Hussein Cancer Center between 2008 and 2017 were reviewed. Baseline demographics, clinical laboratory features, treatment details, and responses were collected. The correlations between clinical and laboratory variables with event-free survival (EFS) and overall survival (OS) were determined by univariate and multivariate analyses using backward stepwise Cox regression models. EFS and OS were plotted using Kaplan-Meier curves.
This study included 19 patients with a median age of 33 years (range, 19-65). Eleven (58%) and two (10.5%) patients had advanced-stage and central nervous system disease, respectively. Among 106 administered cycles, the median interval between cycles was 23 days (range, 19-84 days). Sixteen patients (84%) achieved a complete response. After a median follow-up of 40.8 months, the 3-year EFS and OS rates were 78.95%. Patients with a low-risk International Prognostic Index (IPI) had better survival than those with intermediate-or high-risk IPI. Grade III-IV hematological toxicities occurred in 88% of patients, while 73% had grade III-IV mucositis.
In adult Burkitt lymphoma, the CALGB 1002 protocol provides high cure rates and can be administered promptly, but is associated with significant toxicity. Risk-adapted approaches and other, less toxic, chemotherapeutic regimens should be considered.
pmcINTRODUCTION
Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by a high proliferation rate (Ki 67 of approximately 100%) and deregulation of the MYC gene. It is more common in the pediatric age group, peaking around 10 years of age, but accounts for only about 1% of all NHL in adults [1-3].
Clinically, BL often presents with rapidly enlarging masses and extranodal site involvement, especially the bone marrow and central nervous system (CNS). Owing to its rapid growth, early diagnosis and prompt treatment initiation are important [4].
The treatment of BL in adults is challenging because of the lack of randomized trials to define the best initial regimen. Most first-line regimens are adopted from intensive pediatric protocols and include a combination of anthracycline, alkylator, vincristine, etoposide, and agents to treat and prevent CNS disease [5].
Cancer and Leukemia Group B (CALGB) developed an intensive regimen (CALGB 9251) that initially included multi-agent chemotherapy with prophylactic cranial radiotherapy and 12 doses of intrathecal chemotherapy (ITC) [6]. As 61% of patients in the first cohort developed severe neurological toxicity, in the second cohort, prophylactic cranial radiotherapy was administered only to patients with bone marrow involvement, and only seven ITC doses were administered. The 5-year overall survival (OS) rate was 52%. In a follow-up study (CALGB 1002), the addition of rituximab resulted in improvements of 4-year event-free survival (EFS) and OS to 78% and 74%, respectively [7].
The CALGB 1002 protocol was used for the treatment of most BL cases in our center. Our study aimed to describe the characteristics and outcomes of adult BL patients treated with the CALGB 1002 protocol.
MATERIALS AND METHODS
We retrospectively analyzed the medical records of adult patients diagnosed with BL and treated with the CALGB 1002 regimen at the Medical Oncology Department, King Hussein Cancer Center in Jordan between January 2008 and December 2017.
The following variables were retrieved from patient charts and electronic medical records: age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, initial lactate dehydrogenase (LDH) level, stage on time of diagnosis, and extra-nodal sites involved. In addition, treatment details including the timing of chemotherapy administration, ITC, hematological and non-hematological toxicities, response, and relapse were also obtained.
The details of the treatment protocol are provided in Table 1.
Staging was performed according to the Lugano staging system based on computed tomography (CT) scans [8]. Bulky disease was defined as tumor bulk >10 cm in the transverse or coronal diameters. The International Prognostic Index (IPI) was calculated as initially described using age, performance status, LDH level, stage, and number of extranodal sites [9]. The patients were considered to have low risk if they met all of the following criteria: Lugano stage I–II, normal LDH, ECOG performance status of 0–1, and tumor mass <10 cm [10]. Patients who did not fulfill the criteria for low-risk disease were considered to have high-risk disease.
Response evaluation was performed based on the modified Cheson lymphoma response criteria [11]. Toxicity grading was done using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [12].
EFS was calculated from the time of diagnosis until the time of death, progression, or relapse, while OS was calculated from the time of diagnosis until death from any cause or the date of the last follow-up.
The correlations of different clinical and laboratory variables with EFS and OS were determined by univariate and multivariate analyses using the backward stepwise Cox regression model. The EFS and OS were calculated and plotted using the Kaplan–Meier method.
RESULTS
Patient characteristics
This study included 19 patients, 12 (63%) of whom were male. The median age was 33 years (range, 19–65 yr). Eleven patients (58%) had advanced-stage disease (stage III or IV), and 14 (73.6%) had extranodal involvement. CNS involvement was found in two patients (10.5%). Bone marrow involvement was also found in two patients (10.5%), and 13 patients (68%) had high-risk disease. The detailed patient characteristics are shown in Table 2.
Treatment and response
The median time from diagnosis to treatment initiation was 11 days (range, 8–56 days). A total of 106 cycles were administered, with the median interval between cycles of 23 days (range, 19–84 days). All patients were administered a median of six doses of ITC (range, 2–6). Three patients (15.8%) received craniospinal radiotherapy.
Sixteen patients (84%) achieved a complete response (CR), while the other three patients failed to achieve a CR (one had a partial response: one died of chemotherapy-related sepsis before having a response evaluation, and one developed disease progression).
After a median follow-up of 36 months, the 3-year EFS and OS rates were both 78.9% (Figs. 1, 2).
Four patients (21.1%) died: two from disease progression and two from chemotherapy-related complications.
Stratification of the patients according to IPI showed a significant difference in 3-year OS rates between patients with low IPI and those with intermediate or high IPI (100% vs. 60%, P=0.038) (Fig. 3). In contrast, the 3-year OS rates did not differ significantly between patients with low- and high-risk disease (100% vs. 69%, P=0.147) (Fig. 4).
Univariate analysis showed that abnormal LDH, intermediate or high IPI, and bulky disease were correlated with worse OS. However, none of these factors was significant in the multivariate analysis (Table 3).
Toxicity
Hematological toxicities, including grade III–IV neutropenia and thrombocytopenia, were both found in 88% of patients, while febrile neutropenia occurred in 89% of patients. The most important grade III–IV non-hematological toxicities were mucositis, which occurred in 13 patients (72%). Two patients (10.5%) from chemotherapy-related toxicities, one after the second cycle and the second after the fifth cycle.
DISCUSSION
We reported our experience with the treatment of BL with a uniform chemotherapy protocol. To our knowledge, only one study has previously reported real-life experiences with the CALGB protocol in BL [13]. Comparison to the original study by Rizzieri et al. [7], our patients had more favorable features including younger median age (33 vs. 43 yr) and fewer patients with initial bone marrow involvement (10.5% vs. 28%), B symptoms (26% vs. 48%), and high-intermediate or high IPI scores (32% vs. 47%). However, the EFS and OS rates were almost comparable, which might be explained by the smaller sample size and relatively higher treatment-related mortality (10.5% vs. 6.6%).
Interestingly, as observed in most BL trials, all of our patients who achieved CR after completion of treatment continued to be disease-free until the last follow-up.
Several features of the CALGB 1002 protocol contribute to its high efficacy, including the use of non-cross-resistant chemotherapeutic agents, lack of treatment delays (as demonstrated in our study), and aggressive CNS prophylaxis [14]. However, the major disadvantage of the CALGB 1002 protocol is the lack of a risk-stratified approach. This may result in unnecessary exposure of low-risk patients to toxic treatments. Most trials stratify patients according to their initial features as well as their interim response to treatment. The features used to define “high risk” included one of the following: elevated LDH, ECOG performance status ≥2, and bulky disease (7–10 cm). Although using
Risk-stratified treatment was also tested in 113 patients treated with a dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) protocol [16]. The low-risk patients were administered two cycles, and a third cycle if PET-CT scans showed no evidence of disease. Patients who did not achieve complete remission after the second cycle and all high-risk patients were administered six cycles. The 4-year EFS rates were 100% and 82.1% in the low- and high-risk groups, respectively.
Similar to the results of many BL studies [7, 17, 18] our study findings confirmed the significantly inferior outcomes of patients with intermediate and high IPI compared to those of patients with lower IPI scores (3-yr EFS: 60% vs. 100%). The best management of BL with high-intermediate and high IPI remains unclear. A recent phase II UK-NCI trial showed that the use of rituximab with CODOX-M/IVAC was associated with more favorable outcomes [2-yr progression-free survival (PFS) of 77.2% and OS of 80.7%] [19]. In addition, in a multicenter trial that reported the outcomes of patients treated with dose-adjusted EPOCH-R, the outcomes were favorable regardless of IPI [16].
The use of pediatric-inspired protocols in adult BL is associated with substantial hematological and non-hematological toxicities, with treatment-related mortality occurring in 5–10% of patients [7, 10, 20-22]. The use of dose-adjusted EPOCH-R was associated with favorable outcomes (4-yr EFS and OS of 84.5% and 87%, respectively) with much lower toxicities. However, patients with CNS involvement were at high risk for treatment failure, with an EFS of only 40% [15]. Moreover, a recent multicenter cohort study showed that CNS relapse was more common in dose-adjusted EPOCH-R than in CODOX-MI/VAC and Hyper-CVAD (13% vs. 4% and 3%, respectively) [23]. Incorporation of high-dose methotrexate with dose-adjusted EPOCH-R has been successfully attempted [24, 25] and may help to improve the outcomes of patients with CNS involvement and decrease the rate of CNS relapse.
Our study has important limitations, including its retrospective nature and the small number of patients observed in most of the BL studies.
In conclusion, despite its substantial toxicities, CALGB 1002 could be administered promptly, resulting in high cure rates among patients with BL. Adoption of risk-adapted approaches, as well as the use of less intensive chemotherapeutic protocols, would direct future progress in the treatment of BL.
Fig. 1 Overall survival.
Fig. 2 Event-free survival.
Fig. 3 Overall survival in patients with low- and high-risk disease (P=0.138).
Fig. 4 Overall survival according to low versus high International Prognostic Index (IPI) values (P=0.038).
Table 1 Cancer and Leukemia Group B1002 (CALGB 1002) protocol.
Cycle 1
Drug Dose Days
Cyclophosphamide 200 mg/m2 1–5
Prednisolone 60 mg/m2 1–7
Cycles 2, 4, and 6
Drug Dose Days
Ifosfamide 800 mg/m2 1–5
Mesna 200 mg/m2 1 to 5 (At h 0, 4, and 8 after ifosfamide)
Methotrexate 1,500 mg/m2 1
Leucovorin 25 mg/m2 36 h after starting methotrexate infusion,
then 10 mg/m2 until methotrexate level <0.05 μmol/L
Vincristine 2 mg 1
Cytarabine 1,000 mg/m2 4–5
Etoposide 80 mg/m2 4–5
Intrathecal
Methotrexate 15 mg 1
Cytarabine 40 mg
Hydrocortisone 50 mg
Rituximab Cycle 2:
50 mg/m2, then 8
375 mg/m2 10
Cycles 4 and 6:
375 mg/m2 8
Filgrastim 5 mcg/kg Starting on day 7
Cycles 3, 5 and 7
Drug Dose Days
Cyclophosphamide 200 mg/m2 1–5
Methotrexate 1,500 mg/m2 1
Leucovorin 25 mg/m2 36 h after starting methotrexate infusion, then
10 mg/m2 until methotrexate level <0.05 μmol/L
Vincristine 2 mg 1
Doxorubicin 25 mg/m2 4–5
Dexamethasone 10 mg/m2 4–5
Intrathecal
Methotrexate 15 mg 1
Cytarabine 40 mg
Hydrocortisone 50 mg
Rituximab 375 mg/m2 8
Filgrastim 5 mcg/kg Starting on day 7
Table 2 Patient characteristics.
Variable (N=19) N (%)
Age Median: 33 (19–65)
Age >60 yr 1 (5.3)
Male 12 (63)
Stage
I–II 8 (42.1)
III–IV 11(58)
ECOG performance status
0–1 15 (78.9)
2 or more 4 (21.1)
High LDH 10 (52.6)
Extranodal involvement 14 (73.6)
Number of extranodal sites
1 7 (36.8)
>1 7 (36.8)
Bone marrow involvement 2 (10.5)
CNS involvement 2 (10.5)
Bulky disease 5 (26.3)
B symptoms 5 (26.3)
Risk classification
Low 6 (31.5)
High 13 (68.5)
International Prognostic Index
Low (0–1) 9 (47.3)
Low-intermediate (2) 4 (21.1)
High-intermediate (3) 3 (15.8)
High (4–5) 3 (15.8)
B symptoms: fever (>38°C), weight loss (>10% over 6 mo), and drenching night sweats.
Abbreviations: CNS, central nervous system; LDH, lactate dehydrogenase.
Table 3 Univariate and multivariate analysis.
Variable Univariate analysis (P) OR Multivariate analysis (P)
Age at diagnosis >60 yr 0.62
Ann Arbor stage III–IV 0.06
Serum LDH level >1×normal 0.04 70.66 0.97
>1 extranodal site 0.55
Bone marrow involvement 0.68
CNS involvement 0.68
International Prognostic Index 0.04 70.66 0.97
B symptoms 0.30
Bulky disease 0.01 11.37 0.49
Abbreviations: CNS, central nervous system; LDH, lactate dehydrogenase; OR, odds ratio.
Authors’ Disclosures of Potential Conflicts of Interest
No potential conflicts of interest relevant to this article were reported. | Fatal | ReactionOutcome | CC BY-NC | 34880141 | 20,994,380 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anticoagulation drug level below therapeutic'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | ASPIRIN, HEPARIN SODIUM, NITROFURANTOIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,230,998 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Contraindicated product administered'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN, ASPIRIN, NITROFURANTOIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,496,858 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Device related thrombosis'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN, ASPIRIN, NITROFURANTOIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,474,689 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Food interaction'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | ASPIRIN, HEPARIN SODIUM, NITROFURANTOIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,230,998 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastric disorder'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN, ASPIRIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,216,094 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal haemorrhage'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN, ASPIRIN, NITROFURANTOIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,496,858 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematuria'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,227,121 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhagic erosive gastritis'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,227,121 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional product use issue'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,227,121 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Labelled drug-drug interaction medication error'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN, ASPIRIN, NITROFURANTOIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,496,858 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombosis in device'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN, ASPIRIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,216,094 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | ASPIRIN, HEPARIN SODIUM, NITROFURANTOIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,230,998 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Upper gastrointestinal haemorrhage'. | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | APIXABAN, ASPIRIN | DrugsGivenReaction | CC BY-NC-ND | 34880201 | 20,216,094 | 2021-12-09 |
What is the weight of the patient? | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | 144 kg. | Weight | CC BY-NC-ND | 34880201 | 20,216,094 | 2021-12-09 |
What was the administration route of drug 'APIXABAN'? | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 34880201 | 20,216,094 | 2021-12-09 |
What was the outcome of reaction 'Anticoagulation drug level above therapeutic'? | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | Recovered | ReactionOutcome | CC BY-NC-ND | 34880201 | 20,230,998 | 2021-12-09 |
What was the outcome of reaction 'Anticoagulation drug level below therapeutic'? | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | Recovered | ReactionOutcome | CC BY-NC-ND | 34880201 | 20,230,998 | 2021-12-09 |
What was the outcome of reaction 'Device related thrombosis'? | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | Recovered | ReactionOutcome | CC BY-NC-ND | 34880201 | 20,474,689 | 2021-12-09 |
What was the outcome of reaction 'Drug interaction'? | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | Recovered | ReactionOutcome | CC BY-NC-ND | 34880201 | 20,474,689 | 2021-12-09 |
What was the outcome of reaction 'Gastric disorder'? | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | Recovered | ReactionOutcome | CC BY-NC-ND | 34880201 | 20,216,094 | 2021-12-09 |
What was the outcome of reaction 'Thrombosis in device'? | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | Recovered | ReactionOutcome | CC BY-NC-ND | 34880201 | 20,216,094 | 2021-12-09 |
What was the outcome of reaction 'Upper gastrointestinal haemorrhage'? | Left Ventricular Assist Device Pump Thrombosis in a Patient Treated with Apixaban.
BACKGROUND Direct oral anticoagulants (DOAC) are currently the preferred agents for long-term anticoagulation in the appropriate patient with venous thromboembolism, non-valvular atrial fibrillation, and left ventricular thrombi because of their ease of use, fixed dosing, lack of need for routine monitoring, and limited dietary and drug interactions. However, warfarin is still the agent of choice for preventing thromboembolic events in patients with left ventricular assist devices (LVAD). In this case report, we explore the outcome of using apixaban in a patient with an LVAD. CASE REPORT A 56-year-old woman with morbid obesity and stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, who was on long-term anticoagulation with apixaban after failure of warfarin therapy, presented to the Emergency Department with 2 months of worsening fatigue, dark urine, and 1 day of low-flow alarms from her HVAD. Laboratory and radiographic data were consistent with a diagnosis of pump thrombosis. She underwent pump exchange and was started on a heparin drip. Genetic testing for warfarin resistance was negative. Detailed history-taking revealed that the failure to maintain a therapeutic international normalized ratio (INR) was likely due to dietary factors. She was re-challenged with warfarin, and a therapeutic INR level was reached shortly after initiation. She was later discharged on a stable dose of warfarin and remained in a good clinical state without any major adverse events at the 1-year follow-up. CONCLUSIONS Apixaban can be associated with an increased risk of thrombosis in patients with HVADs and should be used with caution and only in select patients.
pmcBackground
Anticoagulation is essential for maintaining functional left ventricular assist devices (LVAD) and preventing thromboembolic events. The 2013 International Society of Heart and Lung Transplantation Guidelines issued a level B evidence recommendation for the use of vitamin K antagonists (VKA) as the agents of choice for anticoagulation, with a goal international normalized ratio (INR) individualized to each device manufacturer [1]. One of the main challenges with VKA is maintaining therapeutic INR, and failure to do so can predispose patients to bleeding and thromboembolic complications. One meta-analysis of 5 studies showed that patients with continuous-flow LVADs had a time in therapeutic range (TTR) of only 46.6% [2]. The many challenges with VKA led to an interest in using direct oral anticoagulants (DOAC) as an alternative option because of their ease of use and limited dietary interactions, despite the lack of solid safety data in LVAD patients [3]. Here, we present a case of a patient who developed an LVAD pump thrombosis while taking apixaban.
Case Report
A 56-year-old woman with stage D congestive heart failure status after HeartWare ventricular assist device (HVAD) placement 2 years prior, presented to the Emergency Department with 2 months of worsening fatigue, dark cola-colored urine, and 1 day of low-flow alarms from her HVAD. Her past medical history was significant for class III obesity (weighing 144 kg with a body mass index [BMI] of 44 kg/m2), non-insulin-dependent diabetes mellitus, chronic kidney disease (CKD) stage IIIb with an estimated glomerular filtration rate (eGFR) of 44, obstructive sleep apnea, and stage 1B endometrial cancer status after total abdominal hysterectomy with no evidence of active disease. Since the HVAD placement, she was maintained on a daily high-dose aspirin 325 mg and warfarin with a goal INR between 2.0 and 3.0. At first, she maintained consistently therapeutic INR levels with a stable warfarin dose of 15 mg daily. Five months after warfarin initiation, she was prescribed a course of nitrofurantoin for a urinary tract infection (UTI), resulting in a supra-therapeutic INR level of 8 that required temporary discontinuation of warfarin. After successful treatment of the UTI, she was re-started on her prior maintenance dose of 15 mg, but her INR level remained subtherapeutic despite adherence to warfarin and no medication changes. Antithrombin III level was low at 62 (range: 80–120), while protein C and S levels were not checked. Two months after up-titration of warfarin to doses as high as 25 mg daily without achieving goal INR, a decision was made to switch her anticoagulation to apixaban 5 mg twice daily because of inadequate TTR and presumed warfarin resistance. The patient was maintained on apixaban for over 1 year without any serious adverse events except for a minor episode of upper gastrointestinal bleeding secondary to erosive gastropathy requiring cessation of anticoagulation for 2 days. Two months prior to the current encounter, she noticed intermittent cola-colored urine and worsening fatigue. She denied chest pain, palpitations, new pedal edema, or dyspnea. One day prior to the encounter, she noticed low-flow alarms from her HVAD, which prompted her to present to the Emergency Department. Her workup was significant for a greater than 50% rise in lactate dehydrogenase up to 606 (range: 140–280) and plasma-free hemoglobin of 30 (range: 5–15) while serum creatinine remained at baseline. Apixaban was held, and the patient was started on bivalirudin drip. HVAD interrogation showed a reduced average flow of 0.5 L/min, and power of 2.3 Watts at a speed of 2500 rpm. Computed tomography (CT) imaging of the chest was negative for pulmonary embolism and did not show definitive outflow cannula thrombosis or significant stenosis. Due to high clinical suspicion of thrombosis, a transesophageal echocardiogram was performed, which showed a lack of Doppler flow through the HVAD, confirming a diagnosis of pump thrombosis. The patient underwent pump exchange with excellent post-exchange flow rates, and was started on a heparin drip. Genetic testing for warfarin resistance gene mutation (VKORC1) was negative. The difficulty in achieving and maintaining therapeutic INR with warfarin in the past was attributed to consuming a diet rich in vitamin K; therefore, a decision was made to re-challenge with warfarin while bridging with heparin. Therapeutic INR was achieved within 3 days of starting warfarin, and she was discharged after extensive counseling on dietary restrictions and drug-drug interactions. One month following discharge, a repeat echocardiogram and device interrogation showed an adequately functioning HVAD with a stable and therapeutic INR. No major complications occured at 1-year follow-up.
Discussion
Durable mechanical circulatory support (MCS) devices such as LVADs have been shown to improve heart failure outcomes when used as destination therapy compared to medical therapy alone in severe refractory disease [4]. Long-term anticoagulation is used to mitigate the increased risk of thrombotic events associated with the implantation of these devices, including that of ischemic stroke and device thrombosis. The current evidence suggests that VKA offers the best outcomes and the lowest risk of thromboembolic events in this patient population [5]. On this basis, the International Society of Heart and Lung Transplantation issued a level B evidence recommendation for the use of VKA as the method of choice for anticoagulation in their 2013 guidelines, with a goal INR individualized to each device manufacturer [1].
HeartWare, the manufacturer for this patient’s ventricular assist device, specifically recommend aspirin 325 mg daily and warfarin with a goal INR of 2.0 to 3.0 for long-term anticoagulation [6]. Sufficient safety data for the use of DOACs is still lacking; therefore, they are not recommended for primary anticoagulation in patients with HVADs [3]. The presumed superiority of vitamin K antagonists may be explained by the underlying mechanism responsible for thrombus formation in this setting. In contrast to atrial fibrillation, where thrombi are formed mainly due to stasis and endothelial dysfunction in the left atrial appendage, the trigger for thrombosis in patients with ventricular assist devices is related to direct blood contact with the artificial surface of the device. This direct contact, in turn, leads to activation of the contact pathway (factors VII, IX, X, and II), all of which are inhibited by VKA [7,8]. To the best of our knowledge, this is the first reported case of HVAD pump thrombosis associated with apixaban after failing warfarin therapy.
As described by Loebstein et al., Warfarin resistance is defined as a dose requirement of >80 mg/week to maintain therapeutic INR [9]. A number of different gene mutations have been shown to influence the response to warfarin, specifically, mutations in VKORC1, which can be associated with up to 30% variance in warfarin dosing [9–11]. Our patient had the wild-type variant and this finding prompted a more in-depth exploration of external potentiating factors such as diet and over-the-counter medication use, which eventually led to the decision to re-challenge her with warfarin. The patient’s history of endometrial cancer was taken into account before restarting warfarin. VKAs are considered inferior to low molecular weight heparin and DOACs in the treatment of venous thromboembolic disease in patients with cancer [12]. Because our patient’s cancer was localized and completely resected, it was not thought to have played a role in this thrombotic event; therefore, warfarin remained our preferred agent.
When analyzing the unfavorable outcome our patient had while on apixaban, it is essential to consider patient-specific risk factors that predisposed to thrombosis; specifically, her weight of 144 kg (BMI of 44 kg/m2). In 2016, the International Society of Hemostasis and Thrombosis recommended against the use of direct oral anticoagulants in patients with BMI >40 or a weight >120 kg due to the lack of solid supportive clinical data [13]. Since then, a few studies have shown apixaban to be safe in patients with such extremes of weight without any dose adjustments [14,15], while others advocated for the use of drug-specific peak and trough levels [16]. However, there has not been any revision of the guidelines as of yet.
Conclusions
This case serves as a reminder that apixaban can be associated with an increased risk of thrombosis in patients with HVADs, despite the few case series supporting its use in patients with warfarin resistance. Until more convincing data is available, apixaban should be used with caution and selectively in patients with HVADs and preferably avoided in those at extremes of body weight (BMI >40), with poor renal function (eGFR <30), and who are taking drugs known to interact with DOACs [17]. | Recovered | ReactionOutcome | CC BY-NC-ND | 34880201 | 20,216,094 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic myeloid leukaemia'. | Chronic myelogenous leukemia in a child following treatment for bilateral retinoblastoma.
A 3-year-old child was incidentally found to have chronic myelogenous leukemia (CML) during an admission for a routine ophthalmic examination under anesthesia. The child had received systemic chemotherapy and focal treatment for Groups C and D retinoblastoma in the right and left eye, respectively, when she was 7 months old. CML was treated with dasatinib, and the child attained a major molecular response. The child is now 3 years after treatment of CML, and the retinoblastoma remains inactive. CML following treatment of retinoblastoma is a rare occurrence. Long term and close monitoring of retinoblastoma patients who received systemic chemotherapy using serial blood tests is essential.
pmcIntroduction
Retinoblastoma is the most common intraocular malignancy in children. It is estimated to affect one in 17,000 live births.[1]
Retinoblastoma is caused by mutations in the tumor suppressor gene, retinoblastoma gene 1 (RB1).[2] Germline mutations are heritable, give rise to bilateral multifocal disease, and an increased risk of second primary nonocular tumors. Bone, soft tissue, and skin cancers are the most common. Leukemias are rare, and when they occur, are usually acute (rather than chronic) leukemias related to prior radiation or chemotherapy.[3] It is thought that the RB1 gene does not contribute to leukemogenesis.[4]
We hereby present a rare case of chronic myelogenous leukemia (CML) diagnosed in a patient treated for bilateral retinoblastoma and the treatment outcome.
Case Report
A 3-year-old girl was diagnosed with Groups C and D retinoblastoma (International Classification of Retinoblastoma) in the right and left eye, respectively, in 2014, when she was 7 months old [Figures 1 and 2]. She was the first child born to consanguineous parents. There was no family history of retinoblastoma. Molecular genetic testing for the RB1 was positive for a heterozygous variant designated c19dupC and predicted to result in premature protein termination (p.Arg7Profs*24).[5] Chemoreduction protocol[6] using carboplatin, vincristine, and etoposide was initiated [Table 1 for cumulative dosage]. Chemotherapy resulted in full regression of the tumor in the right eye and partial regression in the left eye. Multiple sessions of focal therapy failed to result in complete regression of the tumor in the left eye. Intra-arterial chemotherapy was attempted but was abandoned due to failed cannulation of the ophthalmic artery. The left eye was eventually enucleated in 2015. Histopathological evaluation revealed choroidal invasion of <3 mm. There was no optic nerve invasion.
Figure 1 Fundus photograph of the right eye showing Group C retinoblastoma
Figure 2 Fundus photograph of the left eye showing Group D retinoblastoma
Table 1 Chemotherapy received by the child from November 2014 to April 2015
Drug Dosage (mg/kg) Cycles received Total cumulative dose (mg)
Vincristine 0.05 6 2.10
Carboplatin 28 6 936
Etoposide 12 6 504
In 2018, 3 years following the last cycle of chemotherapy, during a routine admission for ophthalmic examination under anesthesia (EUA), the peripheral blood showed a white blood cell count of 107 × 109/L. Subsequent bone marrow biopsy showed a hypercellular marrow with no blast cells. The genetic test was positive for the BCR/ABL p210 translocation. A diagnosis of CML was made. The EUA did not reveal any re-activation of the retinoblastoma tumors. Treatment was initiated with imatinib, but it was changed to dasatinib due to an inadequate response, resulting in a major molecular response. Three years after the diagnosis of CML, the patient remains in complete hematologic and cytogenetic remission, and the retinoblastoma continues to be inactive.
Discussion
This report presents a rare occurrence of CML in a 3-year-old child treated for bilateral retinoblastoma.
Patients with bilateral retinoblastoma have a germline mutation of the RB1 gene and so are at high lifetime risk of developing second primary nonocular tumors after the initial diagnosis of retinoblastoma. More than 50% of the second nonocular primary tumors are bone or soft tissue tumors.[3] Acute hematological malignancies occur rarely, and the risk is known to be magnified by exposure to radiation and chemotherapy.[37]
Leukemias in children are mostly acute and lymphoid in origin. CML accounts for only 1.5% of all leukemias.[8] Genetic susceptibility of the retinoblastoma patients to second primary nonocular tumors may play a major role in their occurrence, but the RB1 gene is thought to have no role in converting a hematopoietic cell into a malignant one. Marees et al.[9] reviewed the records of 668 retinoblastoma survivors diagnosed between 1945 and 2005 in the Dutch registry for second primary nonocular tumors with a median follow-up period of 21.9 years. The authors found only two cases of leukemia, and these two were in the nonhereditary retinoblastoma group. This supports the notion that leukemia might not be a second primary tumor related to genetic susceptibility alone but rather a condition occurring due to an interplay of various factors including the presence of the RB1 gene defect, chemoradiotherapy, and age at administration. Etoposide, in particular, is known to predispose to leukemia, usually of an acute type with short latency, and is dose dependent.[7] Most patients in the cohort reported by Gombos et al. were administered high-dose adjuvant chemotherapy.[7]
There is only one reported case in the literature of CML in a patient with bilateral retinoblastoma.[10] The patient developed CML over 20 years following treatment and responded well to dasatinib. The authors speculate that the CML was related to external beam radiotherapy. Our patient developed CML 2 years after the completion of chemotherapy and did not receive any radiotherapy. Treatment with dasatinib achieved a complete molecular therapeutic response. However, we cannot rule out the possibility that CML may well have resulted from a de novo mutation in the bone marrow.
Conclusion
We have reported CML in a child with bilateral retinoblastoma treated with chemoreduction. Further research is warranted to ascertain whether treated retinoblastoma patients are at increased risk for CML compared to the general population. Given the risk of leukemia related to chemotherapy, long term, and close monitoring of retinoblastoma patients who have received systemic chemotherapy with serial blood tests are mandatory.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
We would like to thank the staff at the Pediatric Ophthalmology Unit at Sultan Qaboos University Hospital. | CARBOPLATIN, ETOPOSIDE, VINCRISTINE | DrugsGivenReaction | CC BY-NC-SA | 34880582 | 20,479,530 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Chronic myelogenous leukemia in a child following treatment for bilateral retinoblastoma.
A 3-year-old child was incidentally found to have chronic myelogenous leukemia (CML) during an admission for a routine ophthalmic examination under anesthesia. The child had received systemic chemotherapy and focal treatment for Groups C and D retinoblastoma in the right and left eye, respectively, when she was 7 months old. CML was treated with dasatinib, and the child attained a major molecular response. The child is now 3 years after treatment of CML, and the retinoblastoma remains inactive. CML following treatment of retinoblastoma is a rare occurrence. Long term and close monitoring of retinoblastoma patients who received systemic chemotherapy using serial blood tests is essential.
pmcIntroduction
Retinoblastoma is the most common intraocular malignancy in children. It is estimated to affect one in 17,000 live births.[1]
Retinoblastoma is caused by mutations in the tumor suppressor gene, retinoblastoma gene 1 (RB1).[2] Germline mutations are heritable, give rise to bilateral multifocal disease, and an increased risk of second primary nonocular tumors. Bone, soft tissue, and skin cancers are the most common. Leukemias are rare, and when they occur, are usually acute (rather than chronic) leukemias related to prior radiation or chemotherapy.[3] It is thought that the RB1 gene does not contribute to leukemogenesis.[4]
We hereby present a rare case of chronic myelogenous leukemia (CML) diagnosed in a patient treated for bilateral retinoblastoma and the treatment outcome.
Case Report
A 3-year-old girl was diagnosed with Groups C and D retinoblastoma (International Classification of Retinoblastoma) in the right and left eye, respectively, in 2014, when she was 7 months old [Figures 1 and 2]. She was the first child born to consanguineous parents. There was no family history of retinoblastoma. Molecular genetic testing for the RB1 was positive for a heterozygous variant designated c19dupC and predicted to result in premature protein termination (p.Arg7Profs*24).[5] Chemoreduction protocol[6] using carboplatin, vincristine, and etoposide was initiated [Table 1 for cumulative dosage]. Chemotherapy resulted in full regression of the tumor in the right eye and partial regression in the left eye. Multiple sessions of focal therapy failed to result in complete regression of the tumor in the left eye. Intra-arterial chemotherapy was attempted but was abandoned due to failed cannulation of the ophthalmic artery. The left eye was eventually enucleated in 2015. Histopathological evaluation revealed choroidal invasion of <3 mm. There was no optic nerve invasion.
Figure 1 Fundus photograph of the right eye showing Group C retinoblastoma
Figure 2 Fundus photograph of the left eye showing Group D retinoblastoma
Table 1 Chemotherapy received by the child from November 2014 to April 2015
Drug Dosage (mg/kg) Cycles received Total cumulative dose (mg)
Vincristine 0.05 6 2.10
Carboplatin 28 6 936
Etoposide 12 6 504
In 2018, 3 years following the last cycle of chemotherapy, during a routine admission for ophthalmic examination under anesthesia (EUA), the peripheral blood showed a white blood cell count of 107 × 109/L. Subsequent bone marrow biopsy showed a hypercellular marrow with no blast cells. The genetic test was positive for the BCR/ABL p210 translocation. A diagnosis of CML was made. The EUA did not reveal any re-activation of the retinoblastoma tumors. Treatment was initiated with imatinib, but it was changed to dasatinib due to an inadequate response, resulting in a major molecular response. Three years after the diagnosis of CML, the patient remains in complete hematologic and cytogenetic remission, and the retinoblastoma continues to be inactive.
Discussion
This report presents a rare occurrence of CML in a 3-year-old child treated for bilateral retinoblastoma.
Patients with bilateral retinoblastoma have a germline mutation of the RB1 gene and so are at high lifetime risk of developing second primary nonocular tumors after the initial diagnosis of retinoblastoma. More than 50% of the second nonocular primary tumors are bone or soft tissue tumors.[3] Acute hematological malignancies occur rarely, and the risk is known to be magnified by exposure to radiation and chemotherapy.[37]
Leukemias in children are mostly acute and lymphoid in origin. CML accounts for only 1.5% of all leukemias.[8] Genetic susceptibility of the retinoblastoma patients to second primary nonocular tumors may play a major role in their occurrence, but the RB1 gene is thought to have no role in converting a hematopoietic cell into a malignant one. Marees et al.[9] reviewed the records of 668 retinoblastoma survivors diagnosed between 1945 and 2005 in the Dutch registry for second primary nonocular tumors with a median follow-up period of 21.9 years. The authors found only two cases of leukemia, and these two were in the nonhereditary retinoblastoma group. This supports the notion that leukemia might not be a second primary tumor related to genetic susceptibility alone but rather a condition occurring due to an interplay of various factors including the presence of the RB1 gene defect, chemoradiotherapy, and age at administration. Etoposide, in particular, is known to predispose to leukemia, usually of an acute type with short latency, and is dose dependent.[7] Most patients in the cohort reported by Gombos et al. were administered high-dose adjuvant chemotherapy.[7]
There is only one reported case in the literature of CML in a patient with bilateral retinoblastoma.[10] The patient developed CML over 20 years following treatment and responded well to dasatinib. The authors speculate that the CML was related to external beam radiotherapy. Our patient developed CML 2 years after the completion of chemotherapy and did not receive any radiotherapy. Treatment with dasatinib achieved a complete molecular therapeutic response. However, we cannot rule out the possibility that CML may well have resulted from a de novo mutation in the bone marrow.
Conclusion
We have reported CML in a child with bilateral retinoblastoma treated with chemoreduction. Further research is warranted to ascertain whether treated retinoblastoma patients are at increased risk for CML compared to the general population. Given the risk of leukemia related to chemotherapy, long term, and close monitoring of retinoblastoma patients who have received systemic chemotherapy with serial blood tests are mandatory.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
We would like to thank the staff at the Pediatric Ophthalmology Unit at Sultan Qaboos University Hospital. | CARBOPLATIN, ETOPOSIDE, VINCRISTINE | DrugsGivenReaction | CC BY-NC-SA | 34880582 | 20,479,530 | 2021 |
What was the outcome of reaction 'Chronic myeloid leukaemia'? | Chronic myelogenous leukemia in a child following treatment for bilateral retinoblastoma.
A 3-year-old child was incidentally found to have chronic myelogenous leukemia (CML) during an admission for a routine ophthalmic examination under anesthesia. The child had received systemic chemotherapy and focal treatment for Groups C and D retinoblastoma in the right and left eye, respectively, when she was 7 months old. CML was treated with dasatinib, and the child attained a major molecular response. The child is now 3 years after treatment of CML, and the retinoblastoma remains inactive. CML following treatment of retinoblastoma is a rare occurrence. Long term and close monitoring of retinoblastoma patients who received systemic chemotherapy using serial blood tests is essential.
pmcIntroduction
Retinoblastoma is the most common intraocular malignancy in children. It is estimated to affect one in 17,000 live births.[1]
Retinoblastoma is caused by mutations in the tumor suppressor gene, retinoblastoma gene 1 (RB1).[2] Germline mutations are heritable, give rise to bilateral multifocal disease, and an increased risk of second primary nonocular tumors. Bone, soft tissue, and skin cancers are the most common. Leukemias are rare, and when they occur, are usually acute (rather than chronic) leukemias related to prior radiation or chemotherapy.[3] It is thought that the RB1 gene does not contribute to leukemogenesis.[4]
We hereby present a rare case of chronic myelogenous leukemia (CML) diagnosed in a patient treated for bilateral retinoblastoma and the treatment outcome.
Case Report
A 3-year-old girl was diagnosed with Groups C and D retinoblastoma (International Classification of Retinoblastoma) in the right and left eye, respectively, in 2014, when she was 7 months old [Figures 1 and 2]. She was the first child born to consanguineous parents. There was no family history of retinoblastoma. Molecular genetic testing for the RB1 was positive for a heterozygous variant designated c19dupC and predicted to result in premature protein termination (p.Arg7Profs*24).[5] Chemoreduction protocol[6] using carboplatin, vincristine, and etoposide was initiated [Table 1 for cumulative dosage]. Chemotherapy resulted in full regression of the tumor in the right eye and partial regression in the left eye. Multiple sessions of focal therapy failed to result in complete regression of the tumor in the left eye. Intra-arterial chemotherapy was attempted but was abandoned due to failed cannulation of the ophthalmic artery. The left eye was eventually enucleated in 2015. Histopathological evaluation revealed choroidal invasion of <3 mm. There was no optic nerve invasion.
Figure 1 Fundus photograph of the right eye showing Group C retinoblastoma
Figure 2 Fundus photograph of the left eye showing Group D retinoblastoma
Table 1 Chemotherapy received by the child from November 2014 to April 2015
Drug Dosage (mg/kg) Cycles received Total cumulative dose (mg)
Vincristine 0.05 6 2.10
Carboplatin 28 6 936
Etoposide 12 6 504
In 2018, 3 years following the last cycle of chemotherapy, during a routine admission for ophthalmic examination under anesthesia (EUA), the peripheral blood showed a white blood cell count of 107 × 109/L. Subsequent bone marrow biopsy showed a hypercellular marrow with no blast cells. The genetic test was positive for the BCR/ABL p210 translocation. A diagnosis of CML was made. The EUA did not reveal any re-activation of the retinoblastoma tumors. Treatment was initiated with imatinib, but it was changed to dasatinib due to an inadequate response, resulting in a major molecular response. Three years after the diagnosis of CML, the patient remains in complete hematologic and cytogenetic remission, and the retinoblastoma continues to be inactive.
Discussion
This report presents a rare occurrence of CML in a 3-year-old child treated for bilateral retinoblastoma.
Patients with bilateral retinoblastoma have a germline mutation of the RB1 gene and so are at high lifetime risk of developing second primary nonocular tumors after the initial diagnosis of retinoblastoma. More than 50% of the second nonocular primary tumors are bone or soft tissue tumors.[3] Acute hematological malignancies occur rarely, and the risk is known to be magnified by exposure to radiation and chemotherapy.[37]
Leukemias in children are mostly acute and lymphoid in origin. CML accounts for only 1.5% of all leukemias.[8] Genetic susceptibility of the retinoblastoma patients to second primary nonocular tumors may play a major role in their occurrence, but the RB1 gene is thought to have no role in converting a hematopoietic cell into a malignant one. Marees et al.[9] reviewed the records of 668 retinoblastoma survivors diagnosed between 1945 and 2005 in the Dutch registry for second primary nonocular tumors with a median follow-up period of 21.9 years. The authors found only two cases of leukemia, and these two were in the nonhereditary retinoblastoma group. This supports the notion that leukemia might not be a second primary tumor related to genetic susceptibility alone but rather a condition occurring due to an interplay of various factors including the presence of the RB1 gene defect, chemoradiotherapy, and age at administration. Etoposide, in particular, is known to predispose to leukemia, usually of an acute type with short latency, and is dose dependent.[7] Most patients in the cohort reported by Gombos et al. were administered high-dose adjuvant chemotherapy.[7]
There is only one reported case in the literature of CML in a patient with bilateral retinoblastoma.[10] The patient developed CML over 20 years following treatment and responded well to dasatinib. The authors speculate that the CML was related to external beam radiotherapy. Our patient developed CML 2 years after the completion of chemotherapy and did not receive any radiotherapy. Treatment with dasatinib achieved a complete molecular therapeutic response. However, we cannot rule out the possibility that CML may well have resulted from a de novo mutation in the bone marrow.
Conclusion
We have reported CML in a child with bilateral retinoblastoma treated with chemoreduction. Further research is warranted to ascertain whether treated retinoblastoma patients are at increased risk for CML compared to the general population. Given the risk of leukemia related to chemotherapy, long term, and close monitoring of retinoblastoma patients who have received systemic chemotherapy with serial blood tests are mandatory.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
We would like to thank the staff at the Pediatric Ophthalmology Unit at Sultan Qaboos University Hospital. | Recovered | ReactionOutcome | CC BY-NC-SA | 34880582 | 20,479,530 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Extrapyramidal disorder'. | Case Report: Cariprazine Efficacy in Young Patients Diagnosed With Schizophrenia With Predominantly Negative Symptoms.
Negative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation. Although atypical antipsychotics have been associated with higher efficacy on negative symptoms than typical agents, not all of them are equally effective. Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several adverse events (e.g., extrapyramidal symptoms or hyperprolactinemia), and also for increasing this drug's efficacy over negative symptoms. This case series presents three young adults with predominantly negative symptoms during treatment with an atypical antipsychotic, administered in stable dose within the therapeutic range, and for at least 4 weeks prior to the cariprazine switch. These patients (two male and one female, mean age 35.7 years) were diagnosed with schizophrenia, according to the DSM-5 criteria. They were evaluated using Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and Global Assessment of Functioning (GAF). Their mean initial values were 80.3 on PANSS, 4.3 on CGI-S, and 48 on GAF. All these patients were already on a treatment with stable doses of atypical antipsychotics (olanzapine 10 mg/day, n = 1, risperidone 6 mg/day, n = 1, and quetiapine 600 mg/day, n = 1). Cross-titration to cariprazine was initiated, from 1.5 mg qd up to 6 mg qd, during a mean period of 2.7 weeks. After 12 weeks of cariprazine 6 mg/day, the positive scale of PANSS was relatively stable compared to baseline, while the negative mean score decreased by 22%. Also, the mean CGI-S improvement was 15.4% and the GAF mean score increased by 17%. The overall tolerability was good, without severe adverse events being reported. Conclusions: Cariprazine is well tolerated and efficient for patients diagnosed with schizophrenia who have significant negative symptoms that impair daily functioning. After 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression.
pmcIntroduction
Negative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation (1–3). Targeting negative symptoms (e.g., apathy, alogia, flat affect) can lead to significant improvements of daily functional and quality of life (4). Although atypical antipsychotics have been associated with higher efficacy over the negative symptoms than typical agents, not all the atypicals are equally effective. According to a meta-analysis of placebo-controlled and head-to-head randomized controlled trials (n = 402 studies, N = 53,463 participants) that compared 32 antipsychotics, only clozapine, amisulpride, olanzapine, and, to a lesser degree, zotepine and risperidone decreased negative symptoms severity more than other agents, while the differences between the remaining drugs were less supported by evidence (5). An important problem that may lead to uncertainty in the interpretation of negative symptoms improvement in clinical trials is represented by lack of discrimination using standard measurements between primary and secondary negative symptoms (6). Therefore, the clinician should address this problem during the psychiatric interview, and to take into account any other sources of information available (medical personnel, family members or other caregivers), in order to differentiate between primary and secondary negative symptoms. This is not of scholastic importance, but it has practical utility, due to the different treatment approaches for the two groups of symptoms.
Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several dopamine-related adverse events, and, in the same time, for increasing this drug's efficacy over negative symptoms (7). The efficacy and safety of cariprazine have been demonstrated in adults with schizophrenia during four short-term randomized, double-blind, placebo-controlled trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study vs. the active comparator risperidone (8). Post-hoc analyses supported efficacy of cariprazine across individual symptoms and domains of schizophrenia, and in areas like cognition, functioning, negative symptoms, hostility, and global well-being (8).
Cariprazine was generally well tolerated in clinical trials in patients with schizophrenia, and the most frequently reported adverse events were of mild to moderate severity (7). Cariprazine may reduce side effects when switching a patient from other antipsychotic because of its lower anticholinergic, anti-adrenergic, antihistaminergic, and metabolic effects, with a better cardiovascular safety profile (9, 10).
In a multicentric, randomized, double-blind, phase 3b trial (N = 533 patients with predominant negative symptoms), cariprazine (3–6 mg/day) was superior to risperidone (3–6 mg/day) in leading to significant greater least squares mean change in Positive and Negative Syndrome Scale- factor score for negative symptoms (PANSS-FSNS) after 26 weeks of treatment (11). This trial was well-controlled for secondary negative symptoms, but it was sponsored by the manufacturer of cariprazine (6, 11).
According to the recommendations from an International Panel for the management of schizophrenia, cariprazine is useful in patients with first episode of psychosis, predominant negative symptoms (maintenance/acute phase) and significant side effects (e.g., metabolic syndrome, sedation, hyperprolactinemia) with onset during the administration of other antipsychotics (9). If the weight is placed on the long-term efficacy and tolerability, cariprazine may become one of the first-line medications in schizophrenia, not only for prominent negative symptoms, but also for relatively severe positive symptoms (9). An overlap of at least 2–3 weeks is usually recommended in clinical practice when switching from other antipsychotics to cariprazine, in order to avoid a dopaminergic, antihistaminergic and/or muscarinic rebound (9).
This case series presents three young adults with persistent negative symptoms during treatment with an atypical antipsychotic, administered in stable doses within the therapeutic range and for at least 4 weeks, prior to the cariprazine switch.
Case Presentation
The first patient was a male, diagnosed with schizophrenia according to the DSM-5 criteria, age 37.5, who received treatment for the last 6 weeks prior to baseline with risperidone 6 mg daily. He was evaluated because of persistent negative symptoms, consisting mainly of anhedonia, alogia and avolition. This patient had a history of schizophrenia of more than 5 years, and received in the past olanzapine (10 mg qd, for almost 2 years) and amisulpride (800 mg daily, for 2 years), to which he responded partially, because several negative symptoms were still present. The patient accused tolerability issues, namely sedation to olanzapine, and extrapyramidal symptoms to amisulpride. The initial psychiatric examination detected residual positive symptoms- ideas of reference, mild suspiciousness and conceptual disorganization, as well as general symptoms- anxiety, insomnia, social withdrawal, poor attention and low memory performances. This patient had no family history of psychiatric disorder and no somatic comorbidity could be identified during the initial visit.
The first evaluation detected a total PANSS score of 80, with a negative scale score of 32, a CGI-S (Clinical Global Impression- Severity) value of 4 and a GAF (Global Assessment of Functioning) score of 52. Cariprazine was initiated based on this antipsychotic pharmacodynamics profile and its presumed efficacy over the negative symptoms. Risperidone was gradually tapered off, while cariprazine was initiated with 1.5 mg and titrated up to 6 mg qd, during a period of 15 days. No incident was reported during the cross-over period.
After 12 weeks of stable dose, the PANSS total score decreased to 66, with the negative scale showing a value of 26, the CGI-S score remained stable, and the GAF score increased to 60. The positive PANSS score decreased minimally, from 21 to 19. This patient reported no adverse events during the 12 weeks of the 6 mg qd cariprazine regimen.
The second patient was a male, age 33.5, diagnosed with schizophrenia for 11 years, who received treatment with olanzapine 10 mg qd for the last 8 weeks. He was previously on treatment with risperidone 8 mg/day for multiple periods of 6–12 months, interrupted by lack of adherence. Also, the patient received treatment with risperidone microspheres, up to 50 mg every 2 weeks, but after more than 1 year he declined the need for any injectable treatment and was switched back on oral medication. This patient had a family history of psychiatric disorder, as his father also had schizophrenia. No somatic comorbidity could be identified during the initial visit.
During the initial psychiatric evaluation this patient presented with fragmentary persecutory delusions without significant behavioral impact and prominent negative symptoms, especially flat affect, avolition, and anhedonia. His baseline PANSS total score was 78, with negative subscale score of 29, positive subscale score of 18, CGI-S score of 4, and GAF score=44. Olanzapine was gradually tapered off, while cariprazine was slowly titrated up to 6 mg qd, during 20 days. No clinical signs of positive or negative symptoms worsening was reported during the titration period.
After 12 weeks of cariprazine administered 6 mg qd, the PANSS total score decreased to 62, with the negative scale showing a value of 22, and the positive scale a value of 16. The CGI-S score decreased to three, while the GAF score improved by eight points, reaching a value of 52.
The third patient was a female, age 36, diagnosed with schizophrenia for 6 years, and she received treatment with quetiapine 600 mg qd for the last month. This patient had no family history of psychiatric disorder and no somatic disease could be identified during the initial visit. She had a personal history of multiple antipsychotics prior to the baseline treatment, including typical (haloperidol, zuclopentixol) and atypical (olanzapine, ziprasidone) agents. Her response to quetiapine was initially good, because it alleviated insomnia and anxiety, but the impact over the negative symptoms was less significant. Therefore, she was switched on cariprazine, starting from 1.5 mg, up to 6 mg qd, during a period of 22 days.
The initial psychiatric evaluation detected mainly negative symptoms, consisting of anhedonia, flat affect, avolition, low attention and memory performances. Her baseline PANSS total score was 83, with negative subscale score of 35 and positive subscale score of 23, CGI-S=5, and GAF=57. After 12 weeks of cariprazine stable dose treatment, PANSS total score decreased to 65, with negative score reaching a value of 27, while the positive score was relatively stable (22, final visit score). The CGI-S score at endpoint was 4, and the GAF improved to 60.
All these patients were screened for psychiatric comorbidities at baseline using Mini-International Neuropsychiatric Interview (MINI), but no specific diagnoses were detected except for schizophrenia. None of them required hospitalization during their switch and up to the final visit. Cross-titration to cariprazine was well tolerated in all cases, and all the other antipsychotics were tapered slowly in order to avoid antihistaminergic/antidopaminergic rebound. After 12 weeks of cariprazine 6 mg/day, the positive subscale of PANSS showed a relatively stable level, but the negative subscale mean score decreased with 22% (Figure 1). The overall PANSS mean score decreased by 19.5% (Figure 2), the CGI-S mean scores improved by 15.4% (Figure 3), while the mean GAF scores increased by 17%. The overall results are presented in Table 1. No severe adverse events was reported throughout the monitoring period.
Figure 1 Evolution of the PANSS negative subscale scores during cariprazine treatment.
Figure 2 Evolution of the PANSS total scores during cariprazine treatment.
Figure 3 Evolution of the CGI-S scores during cariprazine treatment.
Table 1 The results of the cariprazine switch during 12 weeks of monitoring.
Patient 1 Patient 2 Patient 3
Previous medication, dosage, and duration of its administration Risperidone, 6 mg/day, 6 weeks Olanzapine, 10 mg/day, 8 weeks Quetiapine 600 mg/day, 4 weeks
Switch to cariprazine duration 15 days 20 days 22 days
PANSS total score- initial visit 80 78 83
PANSS total score- final visit 66 62 65
PANSS Negative scale score- initial visit 32 29 35
PANSS Negative scale score- final visit 26 22 27
PANSS Positive scale score- initial visit 21 18 23
PANSS positive scale score- final visit 19 16 22
CGI-S initial score 4 4 5
CGI-S final score 4 3 4
GAF initial score 52 44 57
GAF final score 60 52 60
Self-reported/clinician-detected severe adverse events throughout the monitoring period None None None
Discussion
These patients presented a relatively long history of schizophrenia, between 2 and 11 years (mean value 6.3 years), although their mean age was 35.7 years. They all received multiple treatments before the initiation of cariprazine and presented negative symptoms under their current antipsychotic (olanzapine, quetiapine, or risperidone). Cariprazine is a distinctive antipsychotic agent due to its D3-preferential dopamine partial agonism, which make it preferable for patients with prominent negative symptoms. Patients tolerated well the antipsychotic switch from various antipsychotics to cariprazine. In this case series, after 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression. The positive symptoms were quite stable, but their low level of severity at baseline may have precluded the observation of a therapeutic effect.
Regarding the limitations of this case series, it must be taken into account the short period of monitoring, which may have prevented the observation of other, long-term, treament effects. Also, variables related to the antipsychotic's adverse events were not monitored in a structured manner, as we only collected patients' reports about tolerability and data from clinical exams during each visit. It is also important to mention that patients included in this case series were relatively stable, based on their initial PANSS, GAF, and CGI-S scores, without severe positive or behavioral symptoms and they did not require hospitalization.
Patient Perspective
“I was unable to take care of myself because I had no energy. No interest, either. And I was feeling scared or even frightened. I feel now I can go outside if I have to do something. I feel less blocked from within” (Patient number 1).
“I feel less tension inside me now than before. My thoughts are more synchronized with what I do… I can watch a TV movie, which I couldn't do before because I was sort of numb” (Patient number 2).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of Interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | AMISULPRIDE, OLANZAPINE, RISPERIDONE | DrugsGivenReaction | CC BY | 34880797 | 20,354,195 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sedation'. | Case Report: Cariprazine Efficacy in Young Patients Diagnosed With Schizophrenia With Predominantly Negative Symptoms.
Negative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation. Although atypical antipsychotics have been associated with higher efficacy on negative symptoms than typical agents, not all of them are equally effective. Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several adverse events (e.g., extrapyramidal symptoms or hyperprolactinemia), and also for increasing this drug's efficacy over negative symptoms. This case series presents three young adults with predominantly negative symptoms during treatment with an atypical antipsychotic, administered in stable dose within the therapeutic range, and for at least 4 weeks prior to the cariprazine switch. These patients (two male and one female, mean age 35.7 years) were diagnosed with schizophrenia, according to the DSM-5 criteria. They were evaluated using Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and Global Assessment of Functioning (GAF). Their mean initial values were 80.3 on PANSS, 4.3 on CGI-S, and 48 on GAF. All these patients were already on a treatment with stable doses of atypical antipsychotics (olanzapine 10 mg/day, n = 1, risperidone 6 mg/day, n = 1, and quetiapine 600 mg/day, n = 1). Cross-titration to cariprazine was initiated, from 1.5 mg qd up to 6 mg qd, during a mean period of 2.7 weeks. After 12 weeks of cariprazine 6 mg/day, the positive scale of PANSS was relatively stable compared to baseline, while the negative mean score decreased by 22%. Also, the mean CGI-S improvement was 15.4% and the GAF mean score increased by 17%. The overall tolerability was good, without severe adverse events being reported. Conclusions: Cariprazine is well tolerated and efficient for patients diagnosed with schizophrenia who have significant negative symptoms that impair daily functioning. After 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression.
pmcIntroduction
Negative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation (1–3). Targeting negative symptoms (e.g., apathy, alogia, flat affect) can lead to significant improvements of daily functional and quality of life (4). Although atypical antipsychotics have been associated with higher efficacy over the negative symptoms than typical agents, not all the atypicals are equally effective. According to a meta-analysis of placebo-controlled and head-to-head randomized controlled trials (n = 402 studies, N = 53,463 participants) that compared 32 antipsychotics, only clozapine, amisulpride, olanzapine, and, to a lesser degree, zotepine and risperidone decreased negative symptoms severity more than other agents, while the differences between the remaining drugs were less supported by evidence (5). An important problem that may lead to uncertainty in the interpretation of negative symptoms improvement in clinical trials is represented by lack of discrimination using standard measurements between primary and secondary negative symptoms (6). Therefore, the clinician should address this problem during the psychiatric interview, and to take into account any other sources of information available (medical personnel, family members or other caregivers), in order to differentiate between primary and secondary negative symptoms. This is not of scholastic importance, but it has practical utility, due to the different treatment approaches for the two groups of symptoms.
Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several dopamine-related adverse events, and, in the same time, for increasing this drug's efficacy over negative symptoms (7). The efficacy and safety of cariprazine have been demonstrated in adults with schizophrenia during four short-term randomized, double-blind, placebo-controlled trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study vs. the active comparator risperidone (8). Post-hoc analyses supported efficacy of cariprazine across individual symptoms and domains of schizophrenia, and in areas like cognition, functioning, negative symptoms, hostility, and global well-being (8).
Cariprazine was generally well tolerated in clinical trials in patients with schizophrenia, and the most frequently reported adverse events were of mild to moderate severity (7). Cariprazine may reduce side effects when switching a patient from other antipsychotic because of its lower anticholinergic, anti-adrenergic, antihistaminergic, and metabolic effects, with a better cardiovascular safety profile (9, 10).
In a multicentric, randomized, double-blind, phase 3b trial (N = 533 patients with predominant negative symptoms), cariprazine (3–6 mg/day) was superior to risperidone (3–6 mg/day) in leading to significant greater least squares mean change in Positive and Negative Syndrome Scale- factor score for negative symptoms (PANSS-FSNS) after 26 weeks of treatment (11). This trial was well-controlled for secondary negative symptoms, but it was sponsored by the manufacturer of cariprazine (6, 11).
According to the recommendations from an International Panel for the management of schizophrenia, cariprazine is useful in patients with first episode of psychosis, predominant negative symptoms (maintenance/acute phase) and significant side effects (e.g., metabolic syndrome, sedation, hyperprolactinemia) with onset during the administration of other antipsychotics (9). If the weight is placed on the long-term efficacy and tolerability, cariprazine may become one of the first-line medications in schizophrenia, not only for prominent negative symptoms, but also for relatively severe positive symptoms (9). An overlap of at least 2–3 weeks is usually recommended in clinical practice when switching from other antipsychotics to cariprazine, in order to avoid a dopaminergic, antihistaminergic and/or muscarinic rebound (9).
This case series presents three young adults with persistent negative symptoms during treatment with an atypical antipsychotic, administered in stable doses within the therapeutic range and for at least 4 weeks, prior to the cariprazine switch.
Case Presentation
The first patient was a male, diagnosed with schizophrenia according to the DSM-5 criteria, age 37.5, who received treatment for the last 6 weeks prior to baseline with risperidone 6 mg daily. He was evaluated because of persistent negative symptoms, consisting mainly of anhedonia, alogia and avolition. This patient had a history of schizophrenia of more than 5 years, and received in the past olanzapine (10 mg qd, for almost 2 years) and amisulpride (800 mg daily, for 2 years), to which he responded partially, because several negative symptoms were still present. The patient accused tolerability issues, namely sedation to olanzapine, and extrapyramidal symptoms to amisulpride. The initial psychiatric examination detected residual positive symptoms- ideas of reference, mild suspiciousness and conceptual disorganization, as well as general symptoms- anxiety, insomnia, social withdrawal, poor attention and low memory performances. This patient had no family history of psychiatric disorder and no somatic comorbidity could be identified during the initial visit.
The first evaluation detected a total PANSS score of 80, with a negative scale score of 32, a CGI-S (Clinical Global Impression- Severity) value of 4 and a GAF (Global Assessment of Functioning) score of 52. Cariprazine was initiated based on this antipsychotic pharmacodynamics profile and its presumed efficacy over the negative symptoms. Risperidone was gradually tapered off, while cariprazine was initiated with 1.5 mg and titrated up to 6 mg qd, during a period of 15 days. No incident was reported during the cross-over period.
After 12 weeks of stable dose, the PANSS total score decreased to 66, with the negative scale showing a value of 26, the CGI-S score remained stable, and the GAF score increased to 60. The positive PANSS score decreased minimally, from 21 to 19. This patient reported no adverse events during the 12 weeks of the 6 mg qd cariprazine regimen.
The second patient was a male, age 33.5, diagnosed with schizophrenia for 11 years, who received treatment with olanzapine 10 mg qd for the last 8 weeks. He was previously on treatment with risperidone 8 mg/day for multiple periods of 6–12 months, interrupted by lack of adherence. Also, the patient received treatment with risperidone microspheres, up to 50 mg every 2 weeks, but after more than 1 year he declined the need for any injectable treatment and was switched back on oral medication. This patient had a family history of psychiatric disorder, as his father also had schizophrenia. No somatic comorbidity could be identified during the initial visit.
During the initial psychiatric evaluation this patient presented with fragmentary persecutory delusions without significant behavioral impact and prominent negative symptoms, especially flat affect, avolition, and anhedonia. His baseline PANSS total score was 78, with negative subscale score of 29, positive subscale score of 18, CGI-S score of 4, and GAF score=44. Olanzapine was gradually tapered off, while cariprazine was slowly titrated up to 6 mg qd, during 20 days. No clinical signs of positive or negative symptoms worsening was reported during the titration period.
After 12 weeks of cariprazine administered 6 mg qd, the PANSS total score decreased to 62, with the negative scale showing a value of 22, and the positive scale a value of 16. The CGI-S score decreased to three, while the GAF score improved by eight points, reaching a value of 52.
The third patient was a female, age 36, diagnosed with schizophrenia for 6 years, and she received treatment with quetiapine 600 mg qd for the last month. This patient had no family history of psychiatric disorder and no somatic disease could be identified during the initial visit. She had a personal history of multiple antipsychotics prior to the baseline treatment, including typical (haloperidol, zuclopentixol) and atypical (olanzapine, ziprasidone) agents. Her response to quetiapine was initially good, because it alleviated insomnia and anxiety, but the impact over the negative symptoms was less significant. Therefore, she was switched on cariprazine, starting from 1.5 mg, up to 6 mg qd, during a period of 22 days.
The initial psychiatric evaluation detected mainly negative symptoms, consisting of anhedonia, flat affect, avolition, low attention and memory performances. Her baseline PANSS total score was 83, with negative subscale score of 35 and positive subscale score of 23, CGI-S=5, and GAF=57. After 12 weeks of cariprazine stable dose treatment, PANSS total score decreased to 65, with negative score reaching a value of 27, while the positive score was relatively stable (22, final visit score). The CGI-S score at endpoint was 4, and the GAF improved to 60.
All these patients were screened for psychiatric comorbidities at baseline using Mini-International Neuropsychiatric Interview (MINI), but no specific diagnoses were detected except for schizophrenia. None of them required hospitalization during their switch and up to the final visit. Cross-titration to cariprazine was well tolerated in all cases, and all the other antipsychotics were tapered slowly in order to avoid antihistaminergic/antidopaminergic rebound. After 12 weeks of cariprazine 6 mg/day, the positive subscale of PANSS showed a relatively stable level, but the negative subscale mean score decreased with 22% (Figure 1). The overall PANSS mean score decreased by 19.5% (Figure 2), the CGI-S mean scores improved by 15.4% (Figure 3), while the mean GAF scores increased by 17%. The overall results are presented in Table 1. No severe adverse events was reported throughout the monitoring period.
Figure 1 Evolution of the PANSS negative subscale scores during cariprazine treatment.
Figure 2 Evolution of the PANSS total scores during cariprazine treatment.
Figure 3 Evolution of the CGI-S scores during cariprazine treatment.
Table 1 The results of the cariprazine switch during 12 weeks of monitoring.
Patient 1 Patient 2 Patient 3
Previous medication, dosage, and duration of its administration Risperidone, 6 mg/day, 6 weeks Olanzapine, 10 mg/day, 8 weeks Quetiapine 600 mg/day, 4 weeks
Switch to cariprazine duration 15 days 20 days 22 days
PANSS total score- initial visit 80 78 83
PANSS total score- final visit 66 62 65
PANSS Negative scale score- initial visit 32 29 35
PANSS Negative scale score- final visit 26 22 27
PANSS Positive scale score- initial visit 21 18 23
PANSS positive scale score- final visit 19 16 22
CGI-S initial score 4 4 5
CGI-S final score 4 3 4
GAF initial score 52 44 57
GAF final score 60 52 60
Self-reported/clinician-detected severe adverse events throughout the monitoring period None None None
Discussion
These patients presented a relatively long history of schizophrenia, between 2 and 11 years (mean value 6.3 years), although their mean age was 35.7 years. They all received multiple treatments before the initiation of cariprazine and presented negative symptoms under their current antipsychotic (olanzapine, quetiapine, or risperidone). Cariprazine is a distinctive antipsychotic agent due to its D3-preferential dopamine partial agonism, which make it preferable for patients with prominent negative symptoms. Patients tolerated well the antipsychotic switch from various antipsychotics to cariprazine. In this case series, after 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression. The positive symptoms were quite stable, but their low level of severity at baseline may have precluded the observation of a therapeutic effect.
Regarding the limitations of this case series, it must be taken into account the short period of monitoring, which may have prevented the observation of other, long-term, treament effects. Also, variables related to the antipsychotic's adverse events were not monitored in a structured manner, as we only collected patients' reports about tolerability and data from clinical exams during each visit. It is also important to mention that patients included in this case series were relatively stable, based on their initial PANSS, GAF, and CGI-S scores, without severe positive or behavioral symptoms and they did not require hospitalization.
Patient Perspective
“I was unable to take care of myself because I had no energy. No interest, either. And I was feeling scared or even frightened. I feel now I can go outside if I have to do something. I feel less blocked from within” (Patient number 1).
“I feel less tension inside me now than before. My thoughts are more synchronized with what I do… I can watch a TV movie, which I couldn't do before because I was sort of numb” (Patient number 2).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of Interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | AMISULPRIDE, OLANZAPINE, RISPERIDONE | DrugsGivenReaction | CC BY | 34880797 | 20,354,195 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Case Report: Cariprazine Efficacy in Young Patients Diagnosed With Schizophrenia With Predominantly Negative Symptoms.
Negative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation. Although atypical antipsychotics have been associated with higher efficacy on negative symptoms than typical agents, not all of them are equally effective. Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several adverse events (e.g., extrapyramidal symptoms or hyperprolactinemia), and also for increasing this drug's efficacy over negative symptoms. This case series presents three young adults with predominantly negative symptoms during treatment with an atypical antipsychotic, administered in stable dose within the therapeutic range, and for at least 4 weeks prior to the cariprazine switch. These patients (two male and one female, mean age 35.7 years) were diagnosed with schizophrenia, according to the DSM-5 criteria. They were evaluated using Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and Global Assessment of Functioning (GAF). Their mean initial values were 80.3 on PANSS, 4.3 on CGI-S, and 48 on GAF. All these patients were already on a treatment with stable doses of atypical antipsychotics (olanzapine 10 mg/day, n = 1, risperidone 6 mg/day, n = 1, and quetiapine 600 mg/day, n = 1). Cross-titration to cariprazine was initiated, from 1.5 mg qd up to 6 mg qd, during a mean period of 2.7 weeks. After 12 weeks of cariprazine 6 mg/day, the positive scale of PANSS was relatively stable compared to baseline, while the negative mean score decreased by 22%. Also, the mean CGI-S improvement was 15.4% and the GAF mean score increased by 17%. The overall tolerability was good, without severe adverse events being reported. Conclusions: Cariprazine is well tolerated and efficient for patients diagnosed with schizophrenia who have significant negative symptoms that impair daily functioning. After 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression.
pmcIntroduction
Negative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation (1–3). Targeting negative symptoms (e.g., apathy, alogia, flat affect) can lead to significant improvements of daily functional and quality of life (4). Although atypical antipsychotics have been associated with higher efficacy over the negative symptoms than typical agents, not all the atypicals are equally effective. According to a meta-analysis of placebo-controlled and head-to-head randomized controlled trials (n = 402 studies, N = 53,463 participants) that compared 32 antipsychotics, only clozapine, amisulpride, olanzapine, and, to a lesser degree, zotepine and risperidone decreased negative symptoms severity more than other agents, while the differences between the remaining drugs were less supported by evidence (5). An important problem that may lead to uncertainty in the interpretation of negative symptoms improvement in clinical trials is represented by lack of discrimination using standard measurements between primary and secondary negative symptoms (6). Therefore, the clinician should address this problem during the psychiatric interview, and to take into account any other sources of information available (medical personnel, family members or other caregivers), in order to differentiate between primary and secondary negative symptoms. This is not of scholastic importance, but it has practical utility, due to the different treatment approaches for the two groups of symptoms.
Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several dopamine-related adverse events, and, in the same time, for increasing this drug's efficacy over negative symptoms (7). The efficacy and safety of cariprazine have been demonstrated in adults with schizophrenia during four short-term randomized, double-blind, placebo-controlled trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study vs. the active comparator risperidone (8). Post-hoc analyses supported efficacy of cariprazine across individual symptoms and domains of schizophrenia, and in areas like cognition, functioning, negative symptoms, hostility, and global well-being (8).
Cariprazine was generally well tolerated in clinical trials in patients with schizophrenia, and the most frequently reported adverse events were of mild to moderate severity (7). Cariprazine may reduce side effects when switching a patient from other antipsychotic because of its lower anticholinergic, anti-adrenergic, antihistaminergic, and metabolic effects, with a better cardiovascular safety profile (9, 10).
In a multicentric, randomized, double-blind, phase 3b trial (N = 533 patients with predominant negative symptoms), cariprazine (3–6 mg/day) was superior to risperidone (3–6 mg/day) in leading to significant greater least squares mean change in Positive and Negative Syndrome Scale- factor score for negative symptoms (PANSS-FSNS) after 26 weeks of treatment (11). This trial was well-controlled for secondary negative symptoms, but it was sponsored by the manufacturer of cariprazine (6, 11).
According to the recommendations from an International Panel for the management of schizophrenia, cariprazine is useful in patients with first episode of psychosis, predominant negative symptoms (maintenance/acute phase) and significant side effects (e.g., metabolic syndrome, sedation, hyperprolactinemia) with onset during the administration of other antipsychotics (9). If the weight is placed on the long-term efficacy and tolerability, cariprazine may become one of the first-line medications in schizophrenia, not only for prominent negative symptoms, but also for relatively severe positive symptoms (9). An overlap of at least 2–3 weeks is usually recommended in clinical practice when switching from other antipsychotics to cariprazine, in order to avoid a dopaminergic, antihistaminergic and/or muscarinic rebound (9).
This case series presents three young adults with persistent negative symptoms during treatment with an atypical antipsychotic, administered in stable doses within the therapeutic range and for at least 4 weeks, prior to the cariprazine switch.
Case Presentation
The first patient was a male, diagnosed with schizophrenia according to the DSM-5 criteria, age 37.5, who received treatment for the last 6 weeks prior to baseline with risperidone 6 mg daily. He was evaluated because of persistent negative symptoms, consisting mainly of anhedonia, alogia and avolition. This patient had a history of schizophrenia of more than 5 years, and received in the past olanzapine (10 mg qd, for almost 2 years) and amisulpride (800 mg daily, for 2 years), to which he responded partially, because several negative symptoms were still present. The patient accused tolerability issues, namely sedation to olanzapine, and extrapyramidal symptoms to amisulpride. The initial psychiatric examination detected residual positive symptoms- ideas of reference, mild suspiciousness and conceptual disorganization, as well as general symptoms- anxiety, insomnia, social withdrawal, poor attention and low memory performances. This patient had no family history of psychiatric disorder and no somatic comorbidity could be identified during the initial visit.
The first evaluation detected a total PANSS score of 80, with a negative scale score of 32, a CGI-S (Clinical Global Impression- Severity) value of 4 and a GAF (Global Assessment of Functioning) score of 52. Cariprazine was initiated based on this antipsychotic pharmacodynamics profile and its presumed efficacy over the negative symptoms. Risperidone was gradually tapered off, while cariprazine was initiated with 1.5 mg and titrated up to 6 mg qd, during a period of 15 days. No incident was reported during the cross-over period.
After 12 weeks of stable dose, the PANSS total score decreased to 66, with the negative scale showing a value of 26, the CGI-S score remained stable, and the GAF score increased to 60. The positive PANSS score decreased minimally, from 21 to 19. This patient reported no adverse events during the 12 weeks of the 6 mg qd cariprazine regimen.
The second patient was a male, age 33.5, diagnosed with schizophrenia for 11 years, who received treatment with olanzapine 10 mg qd for the last 8 weeks. He was previously on treatment with risperidone 8 mg/day for multiple periods of 6–12 months, interrupted by lack of adherence. Also, the patient received treatment with risperidone microspheres, up to 50 mg every 2 weeks, but after more than 1 year he declined the need for any injectable treatment and was switched back on oral medication. This patient had a family history of psychiatric disorder, as his father also had schizophrenia. No somatic comorbidity could be identified during the initial visit.
During the initial psychiatric evaluation this patient presented with fragmentary persecutory delusions without significant behavioral impact and prominent negative symptoms, especially flat affect, avolition, and anhedonia. His baseline PANSS total score was 78, with negative subscale score of 29, positive subscale score of 18, CGI-S score of 4, and GAF score=44. Olanzapine was gradually tapered off, while cariprazine was slowly titrated up to 6 mg qd, during 20 days. No clinical signs of positive or negative symptoms worsening was reported during the titration period.
After 12 weeks of cariprazine administered 6 mg qd, the PANSS total score decreased to 62, with the negative scale showing a value of 22, and the positive scale a value of 16. The CGI-S score decreased to three, while the GAF score improved by eight points, reaching a value of 52.
The third patient was a female, age 36, diagnosed with schizophrenia for 6 years, and she received treatment with quetiapine 600 mg qd for the last month. This patient had no family history of psychiatric disorder and no somatic disease could be identified during the initial visit. She had a personal history of multiple antipsychotics prior to the baseline treatment, including typical (haloperidol, zuclopentixol) and atypical (olanzapine, ziprasidone) agents. Her response to quetiapine was initially good, because it alleviated insomnia and anxiety, but the impact over the negative symptoms was less significant. Therefore, she was switched on cariprazine, starting from 1.5 mg, up to 6 mg qd, during a period of 22 days.
The initial psychiatric evaluation detected mainly negative symptoms, consisting of anhedonia, flat affect, avolition, low attention and memory performances. Her baseline PANSS total score was 83, with negative subscale score of 35 and positive subscale score of 23, CGI-S=5, and GAF=57. After 12 weeks of cariprazine stable dose treatment, PANSS total score decreased to 65, with negative score reaching a value of 27, while the positive score was relatively stable (22, final visit score). The CGI-S score at endpoint was 4, and the GAF improved to 60.
All these patients were screened for psychiatric comorbidities at baseline using Mini-International Neuropsychiatric Interview (MINI), but no specific diagnoses were detected except for schizophrenia. None of them required hospitalization during their switch and up to the final visit. Cross-titration to cariprazine was well tolerated in all cases, and all the other antipsychotics were tapered slowly in order to avoid antihistaminergic/antidopaminergic rebound. After 12 weeks of cariprazine 6 mg/day, the positive subscale of PANSS showed a relatively stable level, but the negative subscale mean score decreased with 22% (Figure 1). The overall PANSS mean score decreased by 19.5% (Figure 2), the CGI-S mean scores improved by 15.4% (Figure 3), while the mean GAF scores increased by 17%. The overall results are presented in Table 1. No severe adverse events was reported throughout the monitoring period.
Figure 1 Evolution of the PANSS negative subscale scores during cariprazine treatment.
Figure 2 Evolution of the PANSS total scores during cariprazine treatment.
Figure 3 Evolution of the CGI-S scores during cariprazine treatment.
Table 1 The results of the cariprazine switch during 12 weeks of monitoring.
Patient 1 Patient 2 Patient 3
Previous medication, dosage, and duration of its administration Risperidone, 6 mg/day, 6 weeks Olanzapine, 10 mg/day, 8 weeks Quetiapine 600 mg/day, 4 weeks
Switch to cariprazine duration 15 days 20 days 22 days
PANSS total score- initial visit 80 78 83
PANSS total score- final visit 66 62 65
PANSS Negative scale score- initial visit 32 29 35
PANSS Negative scale score- final visit 26 22 27
PANSS Positive scale score- initial visit 21 18 23
PANSS positive scale score- final visit 19 16 22
CGI-S initial score 4 4 5
CGI-S final score 4 3 4
GAF initial score 52 44 57
GAF final score 60 52 60
Self-reported/clinician-detected severe adverse events throughout the monitoring period None None None
Discussion
These patients presented a relatively long history of schizophrenia, between 2 and 11 years (mean value 6.3 years), although their mean age was 35.7 years. They all received multiple treatments before the initiation of cariprazine and presented negative symptoms under their current antipsychotic (olanzapine, quetiapine, or risperidone). Cariprazine is a distinctive antipsychotic agent due to its D3-preferential dopamine partial agonism, which make it preferable for patients with prominent negative symptoms. Patients tolerated well the antipsychotic switch from various antipsychotics to cariprazine. In this case series, after 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression. The positive symptoms were quite stable, but their low level of severity at baseline may have precluded the observation of a therapeutic effect.
Regarding the limitations of this case series, it must be taken into account the short period of monitoring, which may have prevented the observation of other, long-term, treament effects. Also, variables related to the antipsychotic's adverse events were not monitored in a structured manner, as we only collected patients' reports about tolerability and data from clinical exams during each visit. It is also important to mention that patients included in this case series were relatively stable, based on their initial PANSS, GAF, and CGI-S scores, without severe positive or behavioral symptoms and they did not require hospitalization.
Patient Perspective
“I was unable to take care of myself because I had no energy. No interest, either. And I was feeling scared or even frightened. I feel now I can go outside if I have to do something. I feel less blocked from within” (Patient number 1).
“I feel less tension inside me now than before. My thoughts are more synchronized with what I do… I can watch a TV movie, which I couldn't do before because I was sort of numb” (Patient number 2).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of Interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | AMISULPRIDE, OLANZAPINE, RISPERIDONE | DrugsGivenReaction | CC BY | 34880797 | 20,354,195 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment noncompliance'. | Case Report: Cariprazine Efficacy in Young Patients Diagnosed With Schizophrenia With Predominantly Negative Symptoms.
Negative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation. Although atypical antipsychotics have been associated with higher efficacy on negative symptoms than typical agents, not all of them are equally effective. Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several adverse events (e.g., extrapyramidal symptoms or hyperprolactinemia), and also for increasing this drug's efficacy over negative symptoms. This case series presents three young adults with predominantly negative symptoms during treatment with an atypical antipsychotic, administered in stable dose within the therapeutic range, and for at least 4 weeks prior to the cariprazine switch. These patients (two male and one female, mean age 35.7 years) were diagnosed with schizophrenia, according to the DSM-5 criteria. They were evaluated using Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and Global Assessment of Functioning (GAF). Their mean initial values were 80.3 on PANSS, 4.3 on CGI-S, and 48 on GAF. All these patients were already on a treatment with stable doses of atypical antipsychotics (olanzapine 10 mg/day, n = 1, risperidone 6 mg/day, n = 1, and quetiapine 600 mg/day, n = 1). Cross-titration to cariprazine was initiated, from 1.5 mg qd up to 6 mg qd, during a mean period of 2.7 weeks. After 12 weeks of cariprazine 6 mg/day, the positive scale of PANSS was relatively stable compared to baseline, while the negative mean score decreased by 22%. Also, the mean CGI-S improvement was 15.4% and the GAF mean score increased by 17%. The overall tolerability was good, without severe adverse events being reported. Conclusions: Cariprazine is well tolerated and efficient for patients diagnosed with schizophrenia who have significant negative symptoms that impair daily functioning. After 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression.
pmcIntroduction
Negative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation (1–3). Targeting negative symptoms (e.g., apathy, alogia, flat affect) can lead to significant improvements of daily functional and quality of life (4). Although atypical antipsychotics have been associated with higher efficacy over the negative symptoms than typical agents, not all the atypicals are equally effective. According to a meta-analysis of placebo-controlled and head-to-head randomized controlled trials (n = 402 studies, N = 53,463 participants) that compared 32 antipsychotics, only clozapine, amisulpride, olanzapine, and, to a lesser degree, zotepine and risperidone decreased negative symptoms severity more than other agents, while the differences between the remaining drugs were less supported by evidence (5). An important problem that may lead to uncertainty in the interpretation of negative symptoms improvement in clinical trials is represented by lack of discrimination using standard measurements between primary and secondary negative symptoms (6). Therefore, the clinician should address this problem during the psychiatric interview, and to take into account any other sources of information available (medical personnel, family members or other caregivers), in order to differentiate between primary and secondary negative symptoms. This is not of scholastic importance, but it has practical utility, due to the different treatment approaches for the two groups of symptoms.
Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several dopamine-related adverse events, and, in the same time, for increasing this drug's efficacy over negative symptoms (7). The efficacy and safety of cariprazine have been demonstrated in adults with schizophrenia during four short-term randomized, double-blind, placebo-controlled trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study vs. the active comparator risperidone (8). Post-hoc analyses supported efficacy of cariprazine across individual symptoms and domains of schizophrenia, and in areas like cognition, functioning, negative symptoms, hostility, and global well-being (8).
Cariprazine was generally well tolerated in clinical trials in patients with schizophrenia, and the most frequently reported adverse events were of mild to moderate severity (7). Cariprazine may reduce side effects when switching a patient from other antipsychotic because of its lower anticholinergic, anti-adrenergic, antihistaminergic, and metabolic effects, with a better cardiovascular safety profile (9, 10).
In a multicentric, randomized, double-blind, phase 3b trial (N = 533 patients with predominant negative symptoms), cariprazine (3–6 mg/day) was superior to risperidone (3–6 mg/day) in leading to significant greater least squares mean change in Positive and Negative Syndrome Scale- factor score for negative symptoms (PANSS-FSNS) after 26 weeks of treatment (11). This trial was well-controlled for secondary negative symptoms, but it was sponsored by the manufacturer of cariprazine (6, 11).
According to the recommendations from an International Panel for the management of schizophrenia, cariprazine is useful in patients with first episode of psychosis, predominant negative symptoms (maintenance/acute phase) and significant side effects (e.g., metabolic syndrome, sedation, hyperprolactinemia) with onset during the administration of other antipsychotics (9). If the weight is placed on the long-term efficacy and tolerability, cariprazine may become one of the first-line medications in schizophrenia, not only for prominent negative symptoms, but also for relatively severe positive symptoms (9). An overlap of at least 2–3 weeks is usually recommended in clinical practice when switching from other antipsychotics to cariprazine, in order to avoid a dopaminergic, antihistaminergic and/or muscarinic rebound (9).
This case series presents three young adults with persistent negative symptoms during treatment with an atypical antipsychotic, administered in stable doses within the therapeutic range and for at least 4 weeks, prior to the cariprazine switch.
Case Presentation
The first patient was a male, diagnosed with schizophrenia according to the DSM-5 criteria, age 37.5, who received treatment for the last 6 weeks prior to baseline with risperidone 6 mg daily. He was evaluated because of persistent negative symptoms, consisting mainly of anhedonia, alogia and avolition. This patient had a history of schizophrenia of more than 5 years, and received in the past olanzapine (10 mg qd, for almost 2 years) and amisulpride (800 mg daily, for 2 years), to which he responded partially, because several negative symptoms were still present. The patient accused tolerability issues, namely sedation to olanzapine, and extrapyramidal symptoms to amisulpride. The initial psychiatric examination detected residual positive symptoms- ideas of reference, mild suspiciousness and conceptual disorganization, as well as general symptoms- anxiety, insomnia, social withdrawal, poor attention and low memory performances. This patient had no family history of psychiatric disorder and no somatic comorbidity could be identified during the initial visit.
The first evaluation detected a total PANSS score of 80, with a negative scale score of 32, a CGI-S (Clinical Global Impression- Severity) value of 4 and a GAF (Global Assessment of Functioning) score of 52. Cariprazine was initiated based on this antipsychotic pharmacodynamics profile and its presumed efficacy over the negative symptoms. Risperidone was gradually tapered off, while cariprazine was initiated with 1.5 mg and titrated up to 6 mg qd, during a period of 15 days. No incident was reported during the cross-over period.
After 12 weeks of stable dose, the PANSS total score decreased to 66, with the negative scale showing a value of 26, the CGI-S score remained stable, and the GAF score increased to 60. The positive PANSS score decreased minimally, from 21 to 19. This patient reported no adverse events during the 12 weeks of the 6 mg qd cariprazine regimen.
The second patient was a male, age 33.5, diagnosed with schizophrenia for 11 years, who received treatment with olanzapine 10 mg qd for the last 8 weeks. He was previously on treatment with risperidone 8 mg/day for multiple periods of 6–12 months, interrupted by lack of adherence. Also, the patient received treatment with risperidone microspheres, up to 50 mg every 2 weeks, but after more than 1 year he declined the need for any injectable treatment and was switched back on oral medication. This patient had a family history of psychiatric disorder, as his father also had schizophrenia. No somatic comorbidity could be identified during the initial visit.
During the initial psychiatric evaluation this patient presented with fragmentary persecutory delusions without significant behavioral impact and prominent negative symptoms, especially flat affect, avolition, and anhedonia. His baseline PANSS total score was 78, with negative subscale score of 29, positive subscale score of 18, CGI-S score of 4, and GAF score=44. Olanzapine was gradually tapered off, while cariprazine was slowly titrated up to 6 mg qd, during 20 days. No clinical signs of positive or negative symptoms worsening was reported during the titration period.
After 12 weeks of cariprazine administered 6 mg qd, the PANSS total score decreased to 62, with the negative scale showing a value of 22, and the positive scale a value of 16. The CGI-S score decreased to three, while the GAF score improved by eight points, reaching a value of 52.
The third patient was a female, age 36, diagnosed with schizophrenia for 6 years, and she received treatment with quetiapine 600 mg qd for the last month. This patient had no family history of psychiatric disorder and no somatic disease could be identified during the initial visit. She had a personal history of multiple antipsychotics prior to the baseline treatment, including typical (haloperidol, zuclopentixol) and atypical (olanzapine, ziprasidone) agents. Her response to quetiapine was initially good, because it alleviated insomnia and anxiety, but the impact over the negative symptoms was less significant. Therefore, she was switched on cariprazine, starting from 1.5 mg, up to 6 mg qd, during a period of 22 days.
The initial psychiatric evaluation detected mainly negative symptoms, consisting of anhedonia, flat affect, avolition, low attention and memory performances. Her baseline PANSS total score was 83, with negative subscale score of 35 and positive subscale score of 23, CGI-S=5, and GAF=57. After 12 weeks of cariprazine stable dose treatment, PANSS total score decreased to 65, with negative score reaching a value of 27, while the positive score was relatively stable (22, final visit score). The CGI-S score at endpoint was 4, and the GAF improved to 60.
All these patients were screened for psychiatric comorbidities at baseline using Mini-International Neuropsychiatric Interview (MINI), but no specific diagnoses were detected except for schizophrenia. None of them required hospitalization during their switch and up to the final visit. Cross-titration to cariprazine was well tolerated in all cases, and all the other antipsychotics were tapered slowly in order to avoid antihistaminergic/antidopaminergic rebound. After 12 weeks of cariprazine 6 mg/day, the positive subscale of PANSS showed a relatively stable level, but the negative subscale mean score decreased with 22% (Figure 1). The overall PANSS mean score decreased by 19.5% (Figure 2), the CGI-S mean scores improved by 15.4% (Figure 3), while the mean GAF scores increased by 17%. The overall results are presented in Table 1. No severe adverse events was reported throughout the monitoring period.
Figure 1 Evolution of the PANSS negative subscale scores during cariprazine treatment.
Figure 2 Evolution of the PANSS total scores during cariprazine treatment.
Figure 3 Evolution of the CGI-S scores during cariprazine treatment.
Table 1 The results of the cariprazine switch during 12 weeks of monitoring.
Patient 1 Patient 2 Patient 3
Previous medication, dosage, and duration of its administration Risperidone, 6 mg/day, 6 weeks Olanzapine, 10 mg/day, 8 weeks Quetiapine 600 mg/day, 4 weeks
Switch to cariprazine duration 15 days 20 days 22 days
PANSS total score- initial visit 80 78 83
PANSS total score- final visit 66 62 65
PANSS Negative scale score- initial visit 32 29 35
PANSS Negative scale score- final visit 26 22 27
PANSS Positive scale score- initial visit 21 18 23
PANSS positive scale score- final visit 19 16 22
CGI-S initial score 4 4 5
CGI-S final score 4 3 4
GAF initial score 52 44 57
GAF final score 60 52 60
Self-reported/clinician-detected severe adverse events throughout the monitoring period None None None
Discussion
These patients presented a relatively long history of schizophrenia, between 2 and 11 years (mean value 6.3 years), although their mean age was 35.7 years. They all received multiple treatments before the initiation of cariprazine and presented negative symptoms under their current antipsychotic (olanzapine, quetiapine, or risperidone). Cariprazine is a distinctive antipsychotic agent due to its D3-preferential dopamine partial agonism, which make it preferable for patients with prominent negative symptoms. Patients tolerated well the antipsychotic switch from various antipsychotics to cariprazine. In this case series, after 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression. The positive symptoms were quite stable, but their low level of severity at baseline may have precluded the observation of a therapeutic effect.
Regarding the limitations of this case series, it must be taken into account the short period of monitoring, which may have prevented the observation of other, long-term, treament effects. Also, variables related to the antipsychotic's adverse events were not monitored in a structured manner, as we only collected patients' reports about tolerability and data from clinical exams during each visit. It is also important to mention that patients included in this case series were relatively stable, based on their initial PANSS, GAF, and CGI-S scores, without severe positive or behavioral symptoms and they did not require hospitalization.
Patient Perspective
“I was unable to take care of myself because I had no energy. No interest, either. And I was feeling scared or even frightened. I feel now I can go outside if I have to do something. I feel less blocked from within” (Patient number 1).
“I feel less tension inside me now than before. My thoughts are more synchronized with what I do… I can watch a TV movie, which I couldn't do before because I was sort of numb” (Patient number 2).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of Interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | CARIPRAZINE, OLANZAPINE, RISPERIDONE | DrugsGivenReaction | CC BY | 34880797 | 20,354,162 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Case Report: Take a Second Look: Covid-19 Vaccination-Related Cerebral Venous Thrombosis and Thrombotic Thrombocytopenia Syndrome.
We present two cases of ChAdOx1 nCov-19 (AstraZeneca)-associated thrombotic thrombocytopenia syndrome (TTS) and cerebral venous sinus thrombosis (CVST). At the time of emergency room presentation due to persistent headache, blood serum levels revealed reduced platelet counts. Yet, 1 or 4 days after the onset of the symptom, the first MR-angiography provided no evidence of CVST. Follow-up imaging, performed upon headache refractory to nonsteroidal pain medication verified CVST 2-10 days after initial negative MRI. Both the patients received combined treatment with intravenous immunoglobulins and parenteral anticoagulation leading to an increase of platelet concentration in both the individuals and resolution of the occluded cerebral sinus in one patient.
pmcIntroduction
In the current SARS-Cov2-pandemic, cerebral venous sinus thrombosis (CVST) associated with thrombotic thrombocytopenia syndrome (TTS) following vaccination with vector vaccines (by AstraZeneca- and Johnson & Johnson) is an intensely studied and hotly debated topic.
Here, we report two cases of TTS-associated CVST. Both the patients had verified TTS (according to the American Society of Hematology 2021 guideline), presented with refractory headache, and were investigated for CVST using CT and MR angiography. The initial scans of both patients were normal without evidence of CVST. Strikingly, follow-up imaging performed because of persistent headache, a few days after initial imaging, revealed significant CVST.
The report of this phenomenon is harboring significant implications for clinical routine. We believe this finding is unlikely to be unique and may potentially be overseen in current out-patients and in-hospital management of patients with TTS presenting with postvector-vaccination headache.
Case Descriptions
We present a 21-year-old male who had no relevant prior medical history or medication. A few hours after the first vaccination with ChAdOx1 nCov-19-vaccine, he developed flu-like symptoms with fever (38.0°C) and headache that lasted for 2 days. As the symptoms reappeared 8 days after vaccination, he was presented the following day to our hospital, with a complaint of malaise and fever. On physical examination, he showed no signs or symptoms. Laboratory testing revealed thrombocytopenia (135 G/l), elevated C-reactive protein (CRP) value (103 mg/l), and increased D-dimers (5.83 μg/ml) (Figure 1A depicts the time course of symptoms and relevant laboratory results). Covid-PCR testing was negative. Chest X-ray, urine status, and blood cultures showed no evidence of a specific infection, and the patient was started on empiric therapy with ampicillin/sulbactame. Because of elevated D-dimers and thrombocytopenia, he received weight-adjusted anticoagulation with enoxaparin. Diagnostic workup revealed no evidence of pulmonary artery embolism or thrombosis of peripheral veins. Cranial MRI with venous angiography was performed because of headache on day 12 following vaccination, providing insignificant findings (Figure 1B).
Figure 1 (A) Time course of symptom onset, laboratory findings of platelet count (solid line)/D-Dimer (dashed line), and imaging studies. The x-axis represents the number of days after vaccination. (B–D) show sagittal contrast-enhanced T1-weighted MRI-sequences; (B) no evidence of thrombosis in the sagittal superior sinus at day 12 following vaccination; (C) thrombosis of the sagittal superior sinus (circle) at day 14 following vaccination; (D) regression of thrombosis at day 20 following vaccination.
With steady decreasing platelet concentration, enoxaparin was stopped after 4 days of therapy. The patient was discharged without medication on day 13 following vaccination with the diagnosis of infection of unclear etiology and differential diagnosis of a protracted vaccination reaction. One day later, the attending physicians were notified of a positive anti-platelet factor-4-(PF4)-ELISA. The HIPA-test, on the other hand, was negative with heparin but positive with AZD1222. Therefore, heparin-induced thrombocytopenia (HIT) type 2 was excluded by laboratory testing. The patient was immediately readmitted. The diagnosis of vaccination-related TTS was confirmed by flow cytometry. The patient complained of no new symptoms apart from the persisting headache. Because of the non-resolving headache, cerebral MRI was repeated (Figure 1C). There was thrombosis of the superior sagittal sinus, starting above the confluence and extending over approximately 29 mm to the inside of the right transverse sinus. Ischemia or intracerebral hemorrhage were not present. Meanwhile, the platelet count had reached its lowest value (57 G/l). D-dimers had increased to a maximum value of 6.63 μg/ml.
Anticoagulation with fondaparinux of 7.5 mg/d was started immediately and weight-adjusted intravenous immunoglobulins were applied for 2 days. Further course was without complications with an adequate increase in the platelet count. A follow-up of native cerebral CT examination, 16 days after vaccination, provided normal findings consistent with age. Twenty days after vaccination, cranial MRI with venous angiography showed partial recanalization of thrombosis (Figure 1D). A residual thrombus was found in the sagittal sinus beginning above the confluence measuring approximately 18 mm. From day 20 after vaccination, the headache was resolved. Anticoagulation was switched to dabigatran of 150 mg, two times, and the patient was discharged.
The second patient was a 63-year-old male who was presented under the suspicion of meningitis to a tertiary hospital. There was no relevant medical history or medication. He had experienced flu-like symptoms following the first ChAdOx1 nCov-19-vaccination 8 days ago. The day before, he experienced fever (39 °C), blurred vision, and headache. His general practitioner (GP) had diagnosed meningism and therefore started treatment with cefuroxime. Neurological examination was unremarkable. However, on the day of presentation, elevated D-dimer levels (25.9 μg/ml), thrombocytopenia (69 G/l), and CRP elevation (52.4 mg/l) were apparent (Figure 2A depicts the time course of symptoms and relevant laboratory results). Cranial MRI with venous angiography was performed and yielded insignificant findings (Figure 2B). A lumbar puncture could not be performed because of thrombocytopenia. Laboratory changes were attributed to the vaccination, and the patient was discharged.
Figure 2 (A) Time course of symptom onset, laboratory findings of platelet count (solid line)/D-Dimer (dashed line), and imaging studies. The x-axis represents the number of days after vaccination. (B,C) show axial contrast-enhanced T1-weighted MRI-sequences: (B) no evidence of thrombosis in the left-sided lateral transverse sinus at day 8 following vaccination; (C) thrombosis in the left-sided lateral transverse (circle) sinus at day 18 following vaccination; (D) axial cranial CT showing a left-sided, space-occupying atypical intracranial hemorrhage (ICH) with subarachnoidal hemorrhage at day 21 following vaccination.
The following day, he was presented to a primary hospital with mild retroauricular pain on coughing, blurred vision, and a persisting headache. Clinical examination revealed no findings. Because of thrombocytopenia (31 G/l) and D-dimer elevation (104.8 μg/ml), the patient was admitted. The following day, a cranial CT with venous angiography was performed, which yielded normal findings. Because of the pathologic coagulation, parameters with simultaneous lack of evidence of manifest thrombosis (inconspicuous findings in venous CT-angiography, duplex sonography of peripheral veins, and abdominal sonography), anticoagulation with 7.5 mg of fondaparinux was initiated, which was discontinued 2 days later in favor of 2.5 mg of apixaban two times. A contrast-enhanced CT of the chest was performed on day 13 after vaccination when the patient complained of dyspnea, which showed bipulmonary peripheral pulmonary artery emboli. Full anticoagulation with apixaban (2 times, 10 mg) and 2 days of intravenous administration of weight-adjusted immunoglobulins were started.
On day 14 after vaccination, an immunologic examination confirmed TTS (positive antiplatelet factor-4-(PF4)-ELISA; HIPA-test and flow cytometry were positive with AZD1222 but was negative for HIPA-test with heparin). A new cranial CT was performed on the 17th day after vaccination because of headache and vertigo and showed no relevant changes. One day later, cranial MRI with venous angiography showed left-sided thrombosis in the internal jugular vein, sigmoid sinus, and lateral portion of the transverse sinus (Figure 2C). In addition, ischemia could be detected in the left cerebellar and the right high parietal and parietooccipital cortex. The patient was transferred to our hospital. On admission, neurological examination was insignificant. Anticoagulation with apixaban was switched to partial thromboplastin time (PTT)-controlled argatroban.
After 3 days, the patient vomited and presented anisocoria, right-sided hemiplegia, and aphasia. Cranial CT revealed a left-sided, space-occupying atypical intracranial hemorrhage (ICH) suitable for stasis bleeding in sinus thrombosis with concomitant subarachnoid hemorrhage (SAH) and marked midline shift (Figure 2D). On the same day, left-sided hemicraniectomy was performed. Postoperative cranial CT showed a regredient space-occupying effect of ICH with unchanged sinus thrombosis. To treat TTS, we administered 40 mg of dexamethasone and weight-adjusted immunoglobulins for 2 days. On the following day, the clinical condition of the patient declined. Despite the resumption of argatroban, mild hypothermia (36°C), administration of hypertonic saline, and deep analgesia, subsequent CT follow-up showed an increase in hemorrhage and perifocal edema with an increase in midline shift. On day 24 after vaccination, the patient had wide pupils and subfalcial and uncal entrapment and extracranial herniation throughout the craniectomy defects were visible on CCT. The patient died the next day.
Discussion
Cerebral venous sinus thrombosis is an uncommon disease and occurs in younger patients. Risk factors are female gender, intake of oral contraceptives or hormone replacement therapy, pregnancy and puerperium, obesity, smoking, and thrombophilia. Symptoms usually develop gradually and consist of headache, focal symptoms, encephalopathy, and epileptic seizures. When CVST is suspected, thrombosis of cerebral sinus or veins can be identified by venous angiography with contrast-enhanced CT or MRI. Intracerebral hemorrhages, as a result of venous infarction, can be detected as well. In patients with confirmed CVST, anticoagulation with unfractionated or low molecular weight heparin is started, even in the presence of intracerebral hemorrhage. After initial parenteral anticoagulation, oral anticoagulation (usually vitamin k antagonists) is initiated for 3 to 12 months (1). Recently, dabigatran was identified as a safe alternative (2). Venous recanalization is achieved in 85% of patients, but there is only limited data on the temporal profile (3).
Cerebral venous sinus thrombosis following SARS-Cov2-vaccination has been reported following SARS-Cov2-vaccines in case reports and registers. It has also been reported in conjunction with messenger RNA (mRNA) vaccination against SARS-Cov2, but only in patients with vector vaccines, TTS was detected. CVST following mRNA-vaccination has been discussed as a background coincidence (4). In a German register, the incidence of CVST was significantly higher following AstraZeneca-vaccination as compared to the pre-SARS-Cov2-vaccination period, especially in women (5). A systematic review identified headache as the most common presenting symptom. Symptoms occurred within 1 week after the first dose of vaccination. Intracerebral hemorrhage or subarachnoid hemorrhage (SAH) was reported in 49% of the patients (6).
The phenomenon of thrombocytopenia and or HIT was retrospectively assessed in a database of 865 patients with CSVT from 1987 to 2018. Thrombocytopenia was reported in 8.4% and HIT in 0.1% of the patients. No patient had anti-PF4-antibodies (7). The rarity of these findings underlines the distinct type of vaccine-associated CVST. High mortality was described when this phenomenon occurred for the first time in literature (8). The presence of intracranial bleeding and a baseline platelet count below 30.000 were identified as independent predictors for mortality (9). Currently, mortality is thought to be declining, which could be explained by the rising knowledge of TTS-associated CVST (8).
Patients vaccinated with ChAdOx1 nCov-19 (10) (AstraZeneca) and the Ad26.COV2.S vaccine (Johnson & Johnson/Janssen) (11) can develop TTS that is thought to cause CVST. TTS has not been described in mRNA vaccines. The criteria for TTS were lately defined as follows: (a) COVID vaccine (Johnson & Johnson/Astra Zeneca) 4 to 30 days previously, (b) venous or arterial thrombosis (often cerebral or abdominal), (c) thrombocytopenia, and (d) positive PF4 “HIT” ELISA (12). The antibodies against PF4-polyanion complexes are thought to cause massive platelet activation and thrombocytopenia. In this prothrombotic state, patients might develop CSVT. The mechanisms seem to be similar to HIT (10, 13, 14). In HIT, it is recommended to start the patients on intravenous immunoglobulins (1 g/kg body weight daily for 2 days) and anticoagulation with argatroban, bivalirudin, danaparoid, fondaparinux, or a direct oral anticoagulant at a therapeutic dose. Heparin should be avoided (14). There are currently no guidelines for the duration of anticoagulation. As to the diagnosis, in TTS-associated CVST, the necessary imaging is of course the same as in non-TTS-associated CVST.
Headaches are common after COVID-19-vaccination and are usually resolved the next day. The recurrence of unprecedented headaches raises the suspicion of CVST. However, even though both the patients complained of persisting headaches, CSVT was not detected by initial imaging performed on day 8 and day 12 after vaccination, respectively. At the time of marked thrombocytopenia, a follow-up MRI finally revealed thromboses. Therefore, performing a single investigation is not sufficient in patients with persistent headaches following ChAdOx1 nCov-19-vaccination. We hypothesize that the persisting headache following vaccination might represent a state of ongoing thrombosis and auto-thrombolysis in the cerebral sinus veins. In comparison, patients with “common” CVST complain of headaches when thrombosis is present (1).
In our surviving patient, partial recanalization occurred earlier as would be expected in non-TTS-associated CVST and was associated with normalization of the platelet count. The mechanism in TTS-associated CVST represents an immunological phenomenon opposed to non-TTS-associated CVST that is usually caused by a congenital or acquired coagulopathy. This might explain why treatment with immunoglobulins, which interrupts the immunological reaction, leads to a prompt onset of recanalization. This is also different from “common” CVST, in which patients usually have to be treated with anticoagulants for many months (1).
A similar case has been described by Ikenberg et al. (15) who reported a young woman complaining of headache 7 days after ChAdOx1 nCov-19-vaccination. The initial MRI did not show any changes. A second MRI, 3 days later, showed extensive CVST. TTS was confirmed and the patient recovered after treatment with intravenous immunoglobulins and argatroban (15).
The clinical course and treatment of the patients were similar to the already reported cases, apart from the inconclusive first imaging. Physicians must be aware of this phenomenon when treating patients with headaches following vaccination and should repeat imaging in patients with thrombocytopenia and elevated D-Dimer. People undergoing vector vaccination for SARS-Cov2 should be educated by the physician administering the vector vaccine to seek help in case of non-remitting headache.
The risk for “occult” vaccine-associated CSVT seems to be low and when detected, the current treatment regime is thought to be effective. Given the mortality of SARS-Cov2-infection with possible long-term effects, vaccination should continue unchanged (16).
Conclusion
In patients with TTS complaining of persisting headache, a normal venous angiography might suggest a false sense of security for patients and treating physicians. Follow-up imaging several days later is necessary for patients with non-remitting headaches, to identify patients with CSVT and initiate the proper therapy to avoid a potentially fatal cause.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.
Author Contributions
TB, MJ, FR, HH, and MV treated the patients. TS performed and analyzed the CT and MRI results. FS performed the craniectomy. TB and FR wrote the manuscript. Each author approved the manuscript and contributed important intellectual content. All authors were involved in the analysis and interpretation of the findings, contributed to the writing, approved the final manuscript, read the ICMJE criteria for authorship, read, and agreed with the results of the study and conclusion.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
CRP C-reactive protein
CT computed tomography
CVST cerebral venous sinus thrombosis
GP general practitioner
ICH intracranial hemorrhage
HIT heparin-induced thrombocytopenia
MRI magnetic resonance imaging
PTT partial thromboplastin time
SAH subarachnoid hemorrhage
TTS thrombotic thrombocytopenic syndrome. | ARGATROBAN, DEXAMETHASONE, HUMAN IMMUNOGLOBULIN G, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 34880826 | 20,386,048 | 2021 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Case Report: Take a Second Look: Covid-19 Vaccination-Related Cerebral Venous Thrombosis and Thrombotic Thrombocytopenia Syndrome.
We present two cases of ChAdOx1 nCov-19 (AstraZeneca)-associated thrombotic thrombocytopenia syndrome (TTS) and cerebral venous sinus thrombosis (CVST). At the time of emergency room presentation due to persistent headache, blood serum levels revealed reduced platelet counts. Yet, 1 or 4 days after the onset of the symptom, the first MR-angiography provided no evidence of CVST. Follow-up imaging, performed upon headache refractory to nonsteroidal pain medication verified CVST 2-10 days after initial negative MRI. Both the patients received combined treatment with intravenous immunoglobulins and parenteral anticoagulation leading to an increase of platelet concentration in both the individuals and resolution of the occluded cerebral sinus in one patient.
pmcIntroduction
In the current SARS-Cov2-pandemic, cerebral venous sinus thrombosis (CVST) associated with thrombotic thrombocytopenia syndrome (TTS) following vaccination with vector vaccines (by AstraZeneca- and Johnson & Johnson) is an intensely studied and hotly debated topic.
Here, we report two cases of TTS-associated CVST. Both the patients had verified TTS (according to the American Society of Hematology 2021 guideline), presented with refractory headache, and were investigated for CVST using CT and MR angiography. The initial scans of both patients were normal without evidence of CVST. Strikingly, follow-up imaging performed because of persistent headache, a few days after initial imaging, revealed significant CVST.
The report of this phenomenon is harboring significant implications for clinical routine. We believe this finding is unlikely to be unique and may potentially be overseen in current out-patients and in-hospital management of patients with TTS presenting with postvector-vaccination headache.
Case Descriptions
We present a 21-year-old male who had no relevant prior medical history or medication. A few hours after the first vaccination with ChAdOx1 nCov-19-vaccine, he developed flu-like symptoms with fever (38.0°C) and headache that lasted for 2 days. As the symptoms reappeared 8 days after vaccination, he was presented the following day to our hospital, with a complaint of malaise and fever. On physical examination, he showed no signs or symptoms. Laboratory testing revealed thrombocytopenia (135 G/l), elevated C-reactive protein (CRP) value (103 mg/l), and increased D-dimers (5.83 μg/ml) (Figure 1A depicts the time course of symptoms and relevant laboratory results). Covid-PCR testing was negative. Chest X-ray, urine status, and blood cultures showed no evidence of a specific infection, and the patient was started on empiric therapy with ampicillin/sulbactame. Because of elevated D-dimers and thrombocytopenia, he received weight-adjusted anticoagulation with enoxaparin. Diagnostic workup revealed no evidence of pulmonary artery embolism or thrombosis of peripheral veins. Cranial MRI with venous angiography was performed because of headache on day 12 following vaccination, providing insignificant findings (Figure 1B).
Figure 1 (A) Time course of symptom onset, laboratory findings of platelet count (solid line)/D-Dimer (dashed line), and imaging studies. The x-axis represents the number of days after vaccination. (B–D) show sagittal contrast-enhanced T1-weighted MRI-sequences; (B) no evidence of thrombosis in the sagittal superior sinus at day 12 following vaccination; (C) thrombosis of the sagittal superior sinus (circle) at day 14 following vaccination; (D) regression of thrombosis at day 20 following vaccination.
With steady decreasing platelet concentration, enoxaparin was stopped after 4 days of therapy. The patient was discharged without medication on day 13 following vaccination with the diagnosis of infection of unclear etiology and differential diagnosis of a protracted vaccination reaction. One day later, the attending physicians were notified of a positive anti-platelet factor-4-(PF4)-ELISA. The HIPA-test, on the other hand, was negative with heparin but positive with AZD1222. Therefore, heparin-induced thrombocytopenia (HIT) type 2 was excluded by laboratory testing. The patient was immediately readmitted. The diagnosis of vaccination-related TTS was confirmed by flow cytometry. The patient complained of no new symptoms apart from the persisting headache. Because of the non-resolving headache, cerebral MRI was repeated (Figure 1C). There was thrombosis of the superior sagittal sinus, starting above the confluence and extending over approximately 29 mm to the inside of the right transverse sinus. Ischemia or intracerebral hemorrhage were not present. Meanwhile, the platelet count had reached its lowest value (57 G/l). D-dimers had increased to a maximum value of 6.63 μg/ml.
Anticoagulation with fondaparinux of 7.5 mg/d was started immediately and weight-adjusted intravenous immunoglobulins were applied for 2 days. Further course was without complications with an adequate increase in the platelet count. A follow-up of native cerebral CT examination, 16 days after vaccination, provided normal findings consistent with age. Twenty days after vaccination, cranial MRI with venous angiography showed partial recanalization of thrombosis (Figure 1D). A residual thrombus was found in the sagittal sinus beginning above the confluence measuring approximately 18 mm. From day 20 after vaccination, the headache was resolved. Anticoagulation was switched to dabigatran of 150 mg, two times, and the patient was discharged.
The second patient was a 63-year-old male who was presented under the suspicion of meningitis to a tertiary hospital. There was no relevant medical history or medication. He had experienced flu-like symptoms following the first ChAdOx1 nCov-19-vaccination 8 days ago. The day before, he experienced fever (39 °C), blurred vision, and headache. His general practitioner (GP) had diagnosed meningism and therefore started treatment with cefuroxime. Neurological examination was unremarkable. However, on the day of presentation, elevated D-dimer levels (25.9 μg/ml), thrombocytopenia (69 G/l), and CRP elevation (52.4 mg/l) were apparent (Figure 2A depicts the time course of symptoms and relevant laboratory results). Cranial MRI with venous angiography was performed and yielded insignificant findings (Figure 2B). A lumbar puncture could not be performed because of thrombocytopenia. Laboratory changes were attributed to the vaccination, and the patient was discharged.
Figure 2 (A) Time course of symptom onset, laboratory findings of platelet count (solid line)/D-Dimer (dashed line), and imaging studies. The x-axis represents the number of days after vaccination. (B,C) show axial contrast-enhanced T1-weighted MRI-sequences: (B) no evidence of thrombosis in the left-sided lateral transverse sinus at day 8 following vaccination; (C) thrombosis in the left-sided lateral transverse (circle) sinus at day 18 following vaccination; (D) axial cranial CT showing a left-sided, space-occupying atypical intracranial hemorrhage (ICH) with subarachnoidal hemorrhage at day 21 following vaccination.
The following day, he was presented to a primary hospital with mild retroauricular pain on coughing, blurred vision, and a persisting headache. Clinical examination revealed no findings. Because of thrombocytopenia (31 G/l) and D-dimer elevation (104.8 μg/ml), the patient was admitted. The following day, a cranial CT with venous angiography was performed, which yielded normal findings. Because of the pathologic coagulation, parameters with simultaneous lack of evidence of manifest thrombosis (inconspicuous findings in venous CT-angiography, duplex sonography of peripheral veins, and abdominal sonography), anticoagulation with 7.5 mg of fondaparinux was initiated, which was discontinued 2 days later in favor of 2.5 mg of apixaban two times. A contrast-enhanced CT of the chest was performed on day 13 after vaccination when the patient complained of dyspnea, which showed bipulmonary peripheral pulmonary artery emboli. Full anticoagulation with apixaban (2 times, 10 mg) and 2 days of intravenous administration of weight-adjusted immunoglobulins were started.
On day 14 after vaccination, an immunologic examination confirmed TTS (positive antiplatelet factor-4-(PF4)-ELISA; HIPA-test and flow cytometry were positive with AZD1222 but was negative for HIPA-test with heparin). A new cranial CT was performed on the 17th day after vaccination because of headache and vertigo and showed no relevant changes. One day later, cranial MRI with venous angiography showed left-sided thrombosis in the internal jugular vein, sigmoid sinus, and lateral portion of the transverse sinus (Figure 2C). In addition, ischemia could be detected in the left cerebellar and the right high parietal and parietooccipital cortex. The patient was transferred to our hospital. On admission, neurological examination was insignificant. Anticoagulation with apixaban was switched to partial thromboplastin time (PTT)-controlled argatroban.
After 3 days, the patient vomited and presented anisocoria, right-sided hemiplegia, and aphasia. Cranial CT revealed a left-sided, space-occupying atypical intracranial hemorrhage (ICH) suitable for stasis bleeding in sinus thrombosis with concomitant subarachnoid hemorrhage (SAH) and marked midline shift (Figure 2D). On the same day, left-sided hemicraniectomy was performed. Postoperative cranial CT showed a regredient space-occupying effect of ICH with unchanged sinus thrombosis. To treat TTS, we administered 40 mg of dexamethasone and weight-adjusted immunoglobulins for 2 days. On the following day, the clinical condition of the patient declined. Despite the resumption of argatroban, mild hypothermia (36°C), administration of hypertonic saline, and deep analgesia, subsequent CT follow-up showed an increase in hemorrhage and perifocal edema with an increase in midline shift. On day 24 after vaccination, the patient had wide pupils and subfalcial and uncal entrapment and extracranial herniation throughout the craniectomy defects were visible on CCT. The patient died the next day.
Discussion
Cerebral venous sinus thrombosis is an uncommon disease and occurs in younger patients. Risk factors are female gender, intake of oral contraceptives or hormone replacement therapy, pregnancy and puerperium, obesity, smoking, and thrombophilia. Symptoms usually develop gradually and consist of headache, focal symptoms, encephalopathy, and epileptic seizures. When CVST is suspected, thrombosis of cerebral sinus or veins can be identified by venous angiography with contrast-enhanced CT or MRI. Intracerebral hemorrhages, as a result of venous infarction, can be detected as well. In patients with confirmed CVST, anticoagulation with unfractionated or low molecular weight heparin is started, even in the presence of intracerebral hemorrhage. After initial parenteral anticoagulation, oral anticoagulation (usually vitamin k antagonists) is initiated for 3 to 12 months (1). Recently, dabigatran was identified as a safe alternative (2). Venous recanalization is achieved in 85% of patients, but there is only limited data on the temporal profile (3).
Cerebral venous sinus thrombosis following SARS-Cov2-vaccination has been reported following SARS-Cov2-vaccines in case reports and registers. It has also been reported in conjunction with messenger RNA (mRNA) vaccination against SARS-Cov2, but only in patients with vector vaccines, TTS was detected. CVST following mRNA-vaccination has been discussed as a background coincidence (4). In a German register, the incidence of CVST was significantly higher following AstraZeneca-vaccination as compared to the pre-SARS-Cov2-vaccination period, especially in women (5). A systematic review identified headache as the most common presenting symptom. Symptoms occurred within 1 week after the first dose of vaccination. Intracerebral hemorrhage or subarachnoid hemorrhage (SAH) was reported in 49% of the patients (6).
The phenomenon of thrombocytopenia and or HIT was retrospectively assessed in a database of 865 patients with CSVT from 1987 to 2018. Thrombocytopenia was reported in 8.4% and HIT in 0.1% of the patients. No patient had anti-PF4-antibodies (7). The rarity of these findings underlines the distinct type of vaccine-associated CVST. High mortality was described when this phenomenon occurred for the first time in literature (8). The presence of intracranial bleeding and a baseline platelet count below 30.000 were identified as independent predictors for mortality (9). Currently, mortality is thought to be declining, which could be explained by the rising knowledge of TTS-associated CVST (8).
Patients vaccinated with ChAdOx1 nCov-19 (10) (AstraZeneca) and the Ad26.COV2.S vaccine (Johnson & Johnson/Janssen) (11) can develop TTS that is thought to cause CVST. TTS has not been described in mRNA vaccines. The criteria for TTS were lately defined as follows: (a) COVID vaccine (Johnson & Johnson/Astra Zeneca) 4 to 30 days previously, (b) venous or arterial thrombosis (often cerebral or abdominal), (c) thrombocytopenia, and (d) positive PF4 “HIT” ELISA (12). The antibodies against PF4-polyanion complexes are thought to cause massive platelet activation and thrombocytopenia. In this prothrombotic state, patients might develop CSVT. The mechanisms seem to be similar to HIT (10, 13, 14). In HIT, it is recommended to start the patients on intravenous immunoglobulins (1 g/kg body weight daily for 2 days) and anticoagulation with argatroban, bivalirudin, danaparoid, fondaparinux, or a direct oral anticoagulant at a therapeutic dose. Heparin should be avoided (14). There are currently no guidelines for the duration of anticoagulation. As to the diagnosis, in TTS-associated CVST, the necessary imaging is of course the same as in non-TTS-associated CVST.
Headaches are common after COVID-19-vaccination and are usually resolved the next day. The recurrence of unprecedented headaches raises the suspicion of CVST. However, even though both the patients complained of persisting headaches, CSVT was not detected by initial imaging performed on day 8 and day 12 after vaccination, respectively. At the time of marked thrombocytopenia, a follow-up MRI finally revealed thromboses. Therefore, performing a single investigation is not sufficient in patients with persistent headaches following ChAdOx1 nCov-19-vaccination. We hypothesize that the persisting headache following vaccination might represent a state of ongoing thrombosis and auto-thrombolysis in the cerebral sinus veins. In comparison, patients with “common” CVST complain of headaches when thrombosis is present (1).
In our surviving patient, partial recanalization occurred earlier as would be expected in non-TTS-associated CVST and was associated with normalization of the platelet count. The mechanism in TTS-associated CVST represents an immunological phenomenon opposed to non-TTS-associated CVST that is usually caused by a congenital or acquired coagulopathy. This might explain why treatment with immunoglobulins, which interrupts the immunological reaction, leads to a prompt onset of recanalization. This is also different from “common” CVST, in which patients usually have to be treated with anticoagulants for many months (1).
A similar case has been described by Ikenberg et al. (15) who reported a young woman complaining of headache 7 days after ChAdOx1 nCov-19-vaccination. The initial MRI did not show any changes. A second MRI, 3 days later, showed extensive CVST. TTS was confirmed and the patient recovered after treatment with intravenous immunoglobulins and argatroban (15).
The clinical course and treatment of the patients were similar to the already reported cases, apart from the inconclusive first imaging. Physicians must be aware of this phenomenon when treating patients with headaches following vaccination and should repeat imaging in patients with thrombocytopenia and elevated D-Dimer. People undergoing vector vaccination for SARS-Cov2 should be educated by the physician administering the vector vaccine to seek help in case of non-remitting headache.
The risk for “occult” vaccine-associated CSVT seems to be low and when detected, the current treatment regime is thought to be effective. Given the mortality of SARS-Cov2-infection with possible long-term effects, vaccination should continue unchanged (16).
Conclusion
In patients with TTS complaining of persisting headache, a normal venous angiography might suggest a false sense of security for patients and treating physicians. Follow-up imaging several days later is necessary for patients with non-remitting headaches, to identify patients with CSVT and initiate the proper therapy to avoid a potentially fatal cause.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.
Author Contributions
TB, MJ, FR, HH, and MV treated the patients. TS performed and analyzed the CT and MRI results. FS performed the craniectomy. TB and FR wrote the manuscript. Each author approved the manuscript and contributed important intellectual content. All authors were involved in the analysis and interpretation of the findings, contributed to the writing, approved the final manuscript, read the ICMJE criteria for authorship, read, and agreed with the results of the study and conclusion.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
CRP C-reactive protein
CT computed tomography
CVST cerebral venous sinus thrombosis
GP general practitioner
ICH intracranial hemorrhage
HIT heparin-induced thrombocytopenia
MRI magnetic resonance imaging
PTT partial thromboplastin time
SAH subarachnoid hemorrhage
TTS thrombotic thrombocytopenic syndrome. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 34880826 | 20,386,048 | 2021 |
What was the dosage of drug 'DEXAMETHASONE'? | Case Report: Take a Second Look: Covid-19 Vaccination-Related Cerebral Venous Thrombosis and Thrombotic Thrombocytopenia Syndrome.
We present two cases of ChAdOx1 nCov-19 (AstraZeneca)-associated thrombotic thrombocytopenia syndrome (TTS) and cerebral venous sinus thrombosis (CVST). At the time of emergency room presentation due to persistent headache, blood serum levels revealed reduced platelet counts. Yet, 1 or 4 days after the onset of the symptom, the first MR-angiography provided no evidence of CVST. Follow-up imaging, performed upon headache refractory to nonsteroidal pain medication verified CVST 2-10 days after initial negative MRI. Both the patients received combined treatment with intravenous immunoglobulins and parenteral anticoagulation leading to an increase of platelet concentration in both the individuals and resolution of the occluded cerebral sinus in one patient.
pmcIntroduction
In the current SARS-Cov2-pandemic, cerebral venous sinus thrombosis (CVST) associated with thrombotic thrombocytopenia syndrome (TTS) following vaccination with vector vaccines (by AstraZeneca- and Johnson & Johnson) is an intensely studied and hotly debated topic.
Here, we report two cases of TTS-associated CVST. Both the patients had verified TTS (according to the American Society of Hematology 2021 guideline), presented with refractory headache, and were investigated for CVST using CT and MR angiography. The initial scans of both patients were normal without evidence of CVST. Strikingly, follow-up imaging performed because of persistent headache, a few days after initial imaging, revealed significant CVST.
The report of this phenomenon is harboring significant implications for clinical routine. We believe this finding is unlikely to be unique and may potentially be overseen in current out-patients and in-hospital management of patients with TTS presenting with postvector-vaccination headache.
Case Descriptions
We present a 21-year-old male who had no relevant prior medical history or medication. A few hours after the first vaccination with ChAdOx1 nCov-19-vaccine, he developed flu-like symptoms with fever (38.0°C) and headache that lasted for 2 days. As the symptoms reappeared 8 days after vaccination, he was presented the following day to our hospital, with a complaint of malaise and fever. On physical examination, he showed no signs or symptoms. Laboratory testing revealed thrombocytopenia (135 G/l), elevated C-reactive protein (CRP) value (103 mg/l), and increased D-dimers (5.83 μg/ml) (Figure 1A depicts the time course of symptoms and relevant laboratory results). Covid-PCR testing was negative. Chest X-ray, urine status, and blood cultures showed no evidence of a specific infection, and the patient was started on empiric therapy with ampicillin/sulbactame. Because of elevated D-dimers and thrombocytopenia, he received weight-adjusted anticoagulation with enoxaparin. Diagnostic workup revealed no evidence of pulmonary artery embolism or thrombosis of peripheral veins. Cranial MRI with venous angiography was performed because of headache on day 12 following vaccination, providing insignificant findings (Figure 1B).
Figure 1 (A) Time course of symptom onset, laboratory findings of platelet count (solid line)/D-Dimer (dashed line), and imaging studies. The x-axis represents the number of days after vaccination. (B–D) show sagittal contrast-enhanced T1-weighted MRI-sequences; (B) no evidence of thrombosis in the sagittal superior sinus at day 12 following vaccination; (C) thrombosis of the sagittal superior sinus (circle) at day 14 following vaccination; (D) regression of thrombosis at day 20 following vaccination.
With steady decreasing platelet concentration, enoxaparin was stopped after 4 days of therapy. The patient was discharged without medication on day 13 following vaccination with the diagnosis of infection of unclear etiology and differential diagnosis of a protracted vaccination reaction. One day later, the attending physicians were notified of a positive anti-platelet factor-4-(PF4)-ELISA. The HIPA-test, on the other hand, was negative with heparin but positive with AZD1222. Therefore, heparin-induced thrombocytopenia (HIT) type 2 was excluded by laboratory testing. The patient was immediately readmitted. The diagnosis of vaccination-related TTS was confirmed by flow cytometry. The patient complained of no new symptoms apart from the persisting headache. Because of the non-resolving headache, cerebral MRI was repeated (Figure 1C). There was thrombosis of the superior sagittal sinus, starting above the confluence and extending over approximately 29 mm to the inside of the right transverse sinus. Ischemia or intracerebral hemorrhage were not present. Meanwhile, the platelet count had reached its lowest value (57 G/l). D-dimers had increased to a maximum value of 6.63 μg/ml.
Anticoagulation with fondaparinux of 7.5 mg/d was started immediately and weight-adjusted intravenous immunoglobulins were applied for 2 days. Further course was without complications with an adequate increase in the platelet count. A follow-up of native cerebral CT examination, 16 days after vaccination, provided normal findings consistent with age. Twenty days after vaccination, cranial MRI with venous angiography showed partial recanalization of thrombosis (Figure 1D). A residual thrombus was found in the sagittal sinus beginning above the confluence measuring approximately 18 mm. From day 20 after vaccination, the headache was resolved. Anticoagulation was switched to dabigatran of 150 mg, two times, and the patient was discharged.
The second patient was a 63-year-old male who was presented under the suspicion of meningitis to a tertiary hospital. There was no relevant medical history or medication. He had experienced flu-like symptoms following the first ChAdOx1 nCov-19-vaccination 8 days ago. The day before, he experienced fever (39 °C), blurred vision, and headache. His general practitioner (GP) had diagnosed meningism and therefore started treatment with cefuroxime. Neurological examination was unremarkable. However, on the day of presentation, elevated D-dimer levels (25.9 μg/ml), thrombocytopenia (69 G/l), and CRP elevation (52.4 mg/l) were apparent (Figure 2A depicts the time course of symptoms and relevant laboratory results). Cranial MRI with venous angiography was performed and yielded insignificant findings (Figure 2B). A lumbar puncture could not be performed because of thrombocytopenia. Laboratory changes were attributed to the vaccination, and the patient was discharged.
Figure 2 (A) Time course of symptom onset, laboratory findings of platelet count (solid line)/D-Dimer (dashed line), and imaging studies. The x-axis represents the number of days after vaccination. (B,C) show axial contrast-enhanced T1-weighted MRI-sequences: (B) no evidence of thrombosis in the left-sided lateral transverse sinus at day 8 following vaccination; (C) thrombosis in the left-sided lateral transverse (circle) sinus at day 18 following vaccination; (D) axial cranial CT showing a left-sided, space-occupying atypical intracranial hemorrhage (ICH) with subarachnoidal hemorrhage at day 21 following vaccination.
The following day, he was presented to a primary hospital with mild retroauricular pain on coughing, blurred vision, and a persisting headache. Clinical examination revealed no findings. Because of thrombocytopenia (31 G/l) and D-dimer elevation (104.8 μg/ml), the patient was admitted. The following day, a cranial CT with venous angiography was performed, which yielded normal findings. Because of the pathologic coagulation, parameters with simultaneous lack of evidence of manifest thrombosis (inconspicuous findings in venous CT-angiography, duplex sonography of peripheral veins, and abdominal sonography), anticoagulation with 7.5 mg of fondaparinux was initiated, which was discontinued 2 days later in favor of 2.5 mg of apixaban two times. A contrast-enhanced CT of the chest was performed on day 13 after vaccination when the patient complained of dyspnea, which showed bipulmonary peripheral pulmonary artery emboli. Full anticoagulation with apixaban (2 times, 10 mg) and 2 days of intravenous administration of weight-adjusted immunoglobulins were started.
On day 14 after vaccination, an immunologic examination confirmed TTS (positive antiplatelet factor-4-(PF4)-ELISA; HIPA-test and flow cytometry were positive with AZD1222 but was negative for HIPA-test with heparin). A new cranial CT was performed on the 17th day after vaccination because of headache and vertigo and showed no relevant changes. One day later, cranial MRI with venous angiography showed left-sided thrombosis in the internal jugular vein, sigmoid sinus, and lateral portion of the transverse sinus (Figure 2C). In addition, ischemia could be detected in the left cerebellar and the right high parietal and parietooccipital cortex. The patient was transferred to our hospital. On admission, neurological examination was insignificant. Anticoagulation with apixaban was switched to partial thromboplastin time (PTT)-controlled argatroban.
After 3 days, the patient vomited and presented anisocoria, right-sided hemiplegia, and aphasia. Cranial CT revealed a left-sided, space-occupying atypical intracranial hemorrhage (ICH) suitable for stasis bleeding in sinus thrombosis with concomitant subarachnoid hemorrhage (SAH) and marked midline shift (Figure 2D). On the same day, left-sided hemicraniectomy was performed. Postoperative cranial CT showed a regredient space-occupying effect of ICH with unchanged sinus thrombosis. To treat TTS, we administered 40 mg of dexamethasone and weight-adjusted immunoglobulins for 2 days. On the following day, the clinical condition of the patient declined. Despite the resumption of argatroban, mild hypothermia (36°C), administration of hypertonic saline, and deep analgesia, subsequent CT follow-up showed an increase in hemorrhage and perifocal edema with an increase in midline shift. On day 24 after vaccination, the patient had wide pupils and subfalcial and uncal entrapment and extracranial herniation throughout the craniectomy defects were visible on CCT. The patient died the next day.
Discussion
Cerebral venous sinus thrombosis is an uncommon disease and occurs in younger patients. Risk factors are female gender, intake of oral contraceptives or hormone replacement therapy, pregnancy and puerperium, obesity, smoking, and thrombophilia. Symptoms usually develop gradually and consist of headache, focal symptoms, encephalopathy, and epileptic seizures. When CVST is suspected, thrombosis of cerebral sinus or veins can be identified by venous angiography with contrast-enhanced CT or MRI. Intracerebral hemorrhages, as a result of venous infarction, can be detected as well. In patients with confirmed CVST, anticoagulation with unfractionated or low molecular weight heparin is started, even in the presence of intracerebral hemorrhage. After initial parenteral anticoagulation, oral anticoagulation (usually vitamin k antagonists) is initiated for 3 to 12 months (1). Recently, dabigatran was identified as a safe alternative (2). Venous recanalization is achieved in 85% of patients, but there is only limited data on the temporal profile (3).
Cerebral venous sinus thrombosis following SARS-Cov2-vaccination has been reported following SARS-Cov2-vaccines in case reports and registers. It has also been reported in conjunction with messenger RNA (mRNA) vaccination against SARS-Cov2, but only in patients with vector vaccines, TTS was detected. CVST following mRNA-vaccination has been discussed as a background coincidence (4). In a German register, the incidence of CVST was significantly higher following AstraZeneca-vaccination as compared to the pre-SARS-Cov2-vaccination period, especially in women (5). A systematic review identified headache as the most common presenting symptom. Symptoms occurred within 1 week after the first dose of vaccination. Intracerebral hemorrhage or subarachnoid hemorrhage (SAH) was reported in 49% of the patients (6).
The phenomenon of thrombocytopenia and or HIT was retrospectively assessed in a database of 865 patients with CSVT from 1987 to 2018. Thrombocytopenia was reported in 8.4% and HIT in 0.1% of the patients. No patient had anti-PF4-antibodies (7). The rarity of these findings underlines the distinct type of vaccine-associated CVST. High mortality was described when this phenomenon occurred for the first time in literature (8). The presence of intracranial bleeding and a baseline platelet count below 30.000 were identified as independent predictors for mortality (9). Currently, mortality is thought to be declining, which could be explained by the rising knowledge of TTS-associated CVST (8).
Patients vaccinated with ChAdOx1 nCov-19 (10) (AstraZeneca) and the Ad26.COV2.S vaccine (Johnson & Johnson/Janssen) (11) can develop TTS that is thought to cause CVST. TTS has not been described in mRNA vaccines. The criteria for TTS were lately defined as follows: (a) COVID vaccine (Johnson & Johnson/Astra Zeneca) 4 to 30 days previously, (b) venous or arterial thrombosis (often cerebral or abdominal), (c) thrombocytopenia, and (d) positive PF4 “HIT” ELISA (12). The antibodies against PF4-polyanion complexes are thought to cause massive platelet activation and thrombocytopenia. In this prothrombotic state, patients might develop CSVT. The mechanisms seem to be similar to HIT (10, 13, 14). In HIT, it is recommended to start the patients on intravenous immunoglobulins (1 g/kg body weight daily for 2 days) and anticoagulation with argatroban, bivalirudin, danaparoid, fondaparinux, or a direct oral anticoagulant at a therapeutic dose. Heparin should be avoided (14). There are currently no guidelines for the duration of anticoagulation. As to the diagnosis, in TTS-associated CVST, the necessary imaging is of course the same as in non-TTS-associated CVST.
Headaches are common after COVID-19-vaccination and are usually resolved the next day. The recurrence of unprecedented headaches raises the suspicion of CVST. However, even though both the patients complained of persisting headaches, CSVT was not detected by initial imaging performed on day 8 and day 12 after vaccination, respectively. At the time of marked thrombocytopenia, a follow-up MRI finally revealed thromboses. Therefore, performing a single investigation is not sufficient in patients with persistent headaches following ChAdOx1 nCov-19-vaccination. We hypothesize that the persisting headache following vaccination might represent a state of ongoing thrombosis and auto-thrombolysis in the cerebral sinus veins. In comparison, patients with “common” CVST complain of headaches when thrombosis is present (1).
In our surviving patient, partial recanalization occurred earlier as would be expected in non-TTS-associated CVST and was associated with normalization of the platelet count. The mechanism in TTS-associated CVST represents an immunological phenomenon opposed to non-TTS-associated CVST that is usually caused by a congenital or acquired coagulopathy. This might explain why treatment with immunoglobulins, which interrupts the immunological reaction, leads to a prompt onset of recanalization. This is also different from “common” CVST, in which patients usually have to be treated with anticoagulants for many months (1).
A similar case has been described by Ikenberg et al. (15) who reported a young woman complaining of headache 7 days after ChAdOx1 nCov-19-vaccination. The initial MRI did not show any changes. A second MRI, 3 days later, showed extensive CVST. TTS was confirmed and the patient recovered after treatment with intravenous immunoglobulins and argatroban (15).
The clinical course and treatment of the patients were similar to the already reported cases, apart from the inconclusive first imaging. Physicians must be aware of this phenomenon when treating patients with headaches following vaccination and should repeat imaging in patients with thrombocytopenia and elevated D-Dimer. People undergoing vector vaccination for SARS-Cov2 should be educated by the physician administering the vector vaccine to seek help in case of non-remitting headache.
The risk for “occult” vaccine-associated CSVT seems to be low and when detected, the current treatment regime is thought to be effective. Given the mortality of SARS-Cov2-infection with possible long-term effects, vaccination should continue unchanged (16).
Conclusion
In patients with TTS complaining of persisting headache, a normal venous angiography might suggest a false sense of security for patients and treating physicians. Follow-up imaging several days later is necessary for patients with non-remitting headaches, to identify patients with CSVT and initiate the proper therapy to avoid a potentially fatal cause.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.
Author Contributions
TB, MJ, FR, HH, and MV treated the patients. TS performed and analyzed the CT and MRI results. FS performed the craniectomy. TB and FR wrote the manuscript. Each author approved the manuscript and contributed important intellectual content. All authors were involved in the analysis and interpretation of the findings, contributed to the writing, approved the final manuscript, read the ICMJE criteria for authorship, read, and agreed with the results of the study and conclusion.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
CRP C-reactive protein
CT computed tomography
CVST cerebral venous sinus thrombosis
GP general practitioner
ICH intracranial hemorrhage
HIT heparin-induced thrombocytopenia
MRI magnetic resonance imaging
PTT partial thromboplastin time
SAH subarachnoid hemorrhage
TTS thrombotic thrombocytopenic syndrome. | 40 mg (milligrams). | DrugDosage | CC BY | 34880826 | 20,386,048 | 2021 |
What was the outcome of reaction 'Drug ineffective'? | Case Report: Take a Second Look: Covid-19 Vaccination-Related Cerebral Venous Thrombosis and Thrombotic Thrombocytopenia Syndrome.
We present two cases of ChAdOx1 nCov-19 (AstraZeneca)-associated thrombotic thrombocytopenia syndrome (TTS) and cerebral venous sinus thrombosis (CVST). At the time of emergency room presentation due to persistent headache, blood serum levels revealed reduced platelet counts. Yet, 1 or 4 days after the onset of the symptom, the first MR-angiography provided no evidence of CVST. Follow-up imaging, performed upon headache refractory to nonsteroidal pain medication verified CVST 2-10 days after initial negative MRI. Both the patients received combined treatment with intravenous immunoglobulins and parenteral anticoagulation leading to an increase of platelet concentration in both the individuals and resolution of the occluded cerebral sinus in one patient.
pmcIntroduction
In the current SARS-Cov2-pandemic, cerebral venous sinus thrombosis (CVST) associated with thrombotic thrombocytopenia syndrome (TTS) following vaccination with vector vaccines (by AstraZeneca- and Johnson & Johnson) is an intensely studied and hotly debated topic.
Here, we report two cases of TTS-associated CVST. Both the patients had verified TTS (according to the American Society of Hematology 2021 guideline), presented with refractory headache, and were investigated for CVST using CT and MR angiography. The initial scans of both patients were normal without evidence of CVST. Strikingly, follow-up imaging performed because of persistent headache, a few days after initial imaging, revealed significant CVST.
The report of this phenomenon is harboring significant implications for clinical routine. We believe this finding is unlikely to be unique and may potentially be overseen in current out-patients and in-hospital management of patients with TTS presenting with postvector-vaccination headache.
Case Descriptions
We present a 21-year-old male who had no relevant prior medical history or medication. A few hours after the first vaccination with ChAdOx1 nCov-19-vaccine, he developed flu-like symptoms with fever (38.0°C) and headache that lasted for 2 days. As the symptoms reappeared 8 days after vaccination, he was presented the following day to our hospital, with a complaint of malaise and fever. On physical examination, he showed no signs or symptoms. Laboratory testing revealed thrombocytopenia (135 G/l), elevated C-reactive protein (CRP) value (103 mg/l), and increased D-dimers (5.83 μg/ml) (Figure 1A depicts the time course of symptoms and relevant laboratory results). Covid-PCR testing was negative. Chest X-ray, urine status, and blood cultures showed no evidence of a specific infection, and the patient was started on empiric therapy with ampicillin/sulbactame. Because of elevated D-dimers and thrombocytopenia, he received weight-adjusted anticoagulation with enoxaparin. Diagnostic workup revealed no evidence of pulmonary artery embolism or thrombosis of peripheral veins. Cranial MRI with venous angiography was performed because of headache on day 12 following vaccination, providing insignificant findings (Figure 1B).
Figure 1 (A) Time course of symptom onset, laboratory findings of platelet count (solid line)/D-Dimer (dashed line), and imaging studies. The x-axis represents the number of days after vaccination. (B–D) show sagittal contrast-enhanced T1-weighted MRI-sequences; (B) no evidence of thrombosis in the sagittal superior sinus at day 12 following vaccination; (C) thrombosis of the sagittal superior sinus (circle) at day 14 following vaccination; (D) regression of thrombosis at day 20 following vaccination.
With steady decreasing platelet concentration, enoxaparin was stopped after 4 days of therapy. The patient was discharged without medication on day 13 following vaccination with the diagnosis of infection of unclear etiology and differential diagnosis of a protracted vaccination reaction. One day later, the attending physicians were notified of a positive anti-platelet factor-4-(PF4)-ELISA. The HIPA-test, on the other hand, was negative with heparin but positive with AZD1222. Therefore, heparin-induced thrombocytopenia (HIT) type 2 was excluded by laboratory testing. The patient was immediately readmitted. The diagnosis of vaccination-related TTS was confirmed by flow cytometry. The patient complained of no new symptoms apart from the persisting headache. Because of the non-resolving headache, cerebral MRI was repeated (Figure 1C). There was thrombosis of the superior sagittal sinus, starting above the confluence and extending over approximately 29 mm to the inside of the right transverse sinus. Ischemia or intracerebral hemorrhage were not present. Meanwhile, the platelet count had reached its lowest value (57 G/l). D-dimers had increased to a maximum value of 6.63 μg/ml.
Anticoagulation with fondaparinux of 7.5 mg/d was started immediately and weight-adjusted intravenous immunoglobulins were applied for 2 days. Further course was without complications with an adequate increase in the platelet count. A follow-up of native cerebral CT examination, 16 days after vaccination, provided normal findings consistent with age. Twenty days after vaccination, cranial MRI with venous angiography showed partial recanalization of thrombosis (Figure 1D). A residual thrombus was found in the sagittal sinus beginning above the confluence measuring approximately 18 mm. From day 20 after vaccination, the headache was resolved. Anticoagulation was switched to dabigatran of 150 mg, two times, and the patient was discharged.
The second patient was a 63-year-old male who was presented under the suspicion of meningitis to a tertiary hospital. There was no relevant medical history or medication. He had experienced flu-like symptoms following the first ChAdOx1 nCov-19-vaccination 8 days ago. The day before, he experienced fever (39 °C), blurred vision, and headache. His general practitioner (GP) had diagnosed meningism and therefore started treatment with cefuroxime. Neurological examination was unremarkable. However, on the day of presentation, elevated D-dimer levels (25.9 μg/ml), thrombocytopenia (69 G/l), and CRP elevation (52.4 mg/l) were apparent (Figure 2A depicts the time course of symptoms and relevant laboratory results). Cranial MRI with venous angiography was performed and yielded insignificant findings (Figure 2B). A lumbar puncture could not be performed because of thrombocytopenia. Laboratory changes were attributed to the vaccination, and the patient was discharged.
Figure 2 (A) Time course of symptom onset, laboratory findings of platelet count (solid line)/D-Dimer (dashed line), and imaging studies. The x-axis represents the number of days after vaccination. (B,C) show axial contrast-enhanced T1-weighted MRI-sequences: (B) no evidence of thrombosis in the left-sided lateral transverse sinus at day 8 following vaccination; (C) thrombosis in the left-sided lateral transverse (circle) sinus at day 18 following vaccination; (D) axial cranial CT showing a left-sided, space-occupying atypical intracranial hemorrhage (ICH) with subarachnoidal hemorrhage at day 21 following vaccination.
The following day, he was presented to a primary hospital with mild retroauricular pain on coughing, blurred vision, and a persisting headache. Clinical examination revealed no findings. Because of thrombocytopenia (31 G/l) and D-dimer elevation (104.8 μg/ml), the patient was admitted. The following day, a cranial CT with venous angiography was performed, which yielded normal findings. Because of the pathologic coagulation, parameters with simultaneous lack of evidence of manifest thrombosis (inconspicuous findings in venous CT-angiography, duplex sonography of peripheral veins, and abdominal sonography), anticoagulation with 7.5 mg of fondaparinux was initiated, which was discontinued 2 days later in favor of 2.5 mg of apixaban two times. A contrast-enhanced CT of the chest was performed on day 13 after vaccination when the patient complained of dyspnea, which showed bipulmonary peripheral pulmonary artery emboli. Full anticoagulation with apixaban (2 times, 10 mg) and 2 days of intravenous administration of weight-adjusted immunoglobulins were started.
On day 14 after vaccination, an immunologic examination confirmed TTS (positive antiplatelet factor-4-(PF4)-ELISA; HIPA-test and flow cytometry were positive with AZD1222 but was negative for HIPA-test with heparin). A new cranial CT was performed on the 17th day after vaccination because of headache and vertigo and showed no relevant changes. One day later, cranial MRI with venous angiography showed left-sided thrombosis in the internal jugular vein, sigmoid sinus, and lateral portion of the transverse sinus (Figure 2C). In addition, ischemia could be detected in the left cerebellar and the right high parietal and parietooccipital cortex. The patient was transferred to our hospital. On admission, neurological examination was insignificant. Anticoagulation with apixaban was switched to partial thromboplastin time (PTT)-controlled argatroban.
After 3 days, the patient vomited and presented anisocoria, right-sided hemiplegia, and aphasia. Cranial CT revealed a left-sided, space-occupying atypical intracranial hemorrhage (ICH) suitable for stasis bleeding in sinus thrombosis with concomitant subarachnoid hemorrhage (SAH) and marked midline shift (Figure 2D). On the same day, left-sided hemicraniectomy was performed. Postoperative cranial CT showed a regredient space-occupying effect of ICH with unchanged sinus thrombosis. To treat TTS, we administered 40 mg of dexamethasone and weight-adjusted immunoglobulins for 2 days. On the following day, the clinical condition of the patient declined. Despite the resumption of argatroban, mild hypothermia (36°C), administration of hypertonic saline, and deep analgesia, subsequent CT follow-up showed an increase in hemorrhage and perifocal edema with an increase in midline shift. On day 24 after vaccination, the patient had wide pupils and subfalcial and uncal entrapment and extracranial herniation throughout the craniectomy defects were visible on CCT. The patient died the next day.
Discussion
Cerebral venous sinus thrombosis is an uncommon disease and occurs in younger patients. Risk factors are female gender, intake of oral contraceptives or hormone replacement therapy, pregnancy and puerperium, obesity, smoking, and thrombophilia. Symptoms usually develop gradually and consist of headache, focal symptoms, encephalopathy, and epileptic seizures. When CVST is suspected, thrombosis of cerebral sinus or veins can be identified by venous angiography with contrast-enhanced CT or MRI. Intracerebral hemorrhages, as a result of venous infarction, can be detected as well. In patients with confirmed CVST, anticoagulation with unfractionated or low molecular weight heparin is started, even in the presence of intracerebral hemorrhage. After initial parenteral anticoagulation, oral anticoagulation (usually vitamin k antagonists) is initiated for 3 to 12 months (1). Recently, dabigatran was identified as a safe alternative (2). Venous recanalization is achieved in 85% of patients, but there is only limited data on the temporal profile (3).
Cerebral venous sinus thrombosis following SARS-Cov2-vaccination has been reported following SARS-Cov2-vaccines in case reports and registers. It has also been reported in conjunction with messenger RNA (mRNA) vaccination against SARS-Cov2, but only in patients with vector vaccines, TTS was detected. CVST following mRNA-vaccination has been discussed as a background coincidence (4). In a German register, the incidence of CVST was significantly higher following AstraZeneca-vaccination as compared to the pre-SARS-Cov2-vaccination period, especially in women (5). A systematic review identified headache as the most common presenting symptom. Symptoms occurred within 1 week after the first dose of vaccination. Intracerebral hemorrhage or subarachnoid hemorrhage (SAH) was reported in 49% of the patients (6).
The phenomenon of thrombocytopenia and or HIT was retrospectively assessed in a database of 865 patients with CSVT from 1987 to 2018. Thrombocytopenia was reported in 8.4% and HIT in 0.1% of the patients. No patient had anti-PF4-antibodies (7). The rarity of these findings underlines the distinct type of vaccine-associated CVST. High mortality was described when this phenomenon occurred for the first time in literature (8). The presence of intracranial bleeding and a baseline platelet count below 30.000 were identified as independent predictors for mortality (9). Currently, mortality is thought to be declining, which could be explained by the rising knowledge of TTS-associated CVST (8).
Patients vaccinated with ChAdOx1 nCov-19 (10) (AstraZeneca) and the Ad26.COV2.S vaccine (Johnson & Johnson/Janssen) (11) can develop TTS that is thought to cause CVST. TTS has not been described in mRNA vaccines. The criteria for TTS were lately defined as follows: (a) COVID vaccine (Johnson & Johnson/Astra Zeneca) 4 to 30 days previously, (b) venous or arterial thrombosis (often cerebral or abdominal), (c) thrombocytopenia, and (d) positive PF4 “HIT” ELISA (12). The antibodies against PF4-polyanion complexes are thought to cause massive platelet activation and thrombocytopenia. In this prothrombotic state, patients might develop CSVT. The mechanisms seem to be similar to HIT (10, 13, 14). In HIT, it is recommended to start the patients on intravenous immunoglobulins (1 g/kg body weight daily for 2 days) and anticoagulation with argatroban, bivalirudin, danaparoid, fondaparinux, or a direct oral anticoagulant at a therapeutic dose. Heparin should be avoided (14). There are currently no guidelines for the duration of anticoagulation. As to the diagnosis, in TTS-associated CVST, the necessary imaging is of course the same as in non-TTS-associated CVST.
Headaches are common after COVID-19-vaccination and are usually resolved the next day. The recurrence of unprecedented headaches raises the suspicion of CVST. However, even though both the patients complained of persisting headaches, CSVT was not detected by initial imaging performed on day 8 and day 12 after vaccination, respectively. At the time of marked thrombocytopenia, a follow-up MRI finally revealed thromboses. Therefore, performing a single investigation is not sufficient in patients with persistent headaches following ChAdOx1 nCov-19-vaccination. We hypothesize that the persisting headache following vaccination might represent a state of ongoing thrombosis and auto-thrombolysis in the cerebral sinus veins. In comparison, patients with “common” CVST complain of headaches when thrombosis is present (1).
In our surviving patient, partial recanalization occurred earlier as would be expected in non-TTS-associated CVST and was associated with normalization of the platelet count. The mechanism in TTS-associated CVST represents an immunological phenomenon opposed to non-TTS-associated CVST that is usually caused by a congenital or acquired coagulopathy. This might explain why treatment with immunoglobulins, which interrupts the immunological reaction, leads to a prompt onset of recanalization. This is also different from “common” CVST, in which patients usually have to be treated with anticoagulants for many months (1).
A similar case has been described by Ikenberg et al. (15) who reported a young woman complaining of headache 7 days after ChAdOx1 nCov-19-vaccination. The initial MRI did not show any changes. A second MRI, 3 days later, showed extensive CVST. TTS was confirmed and the patient recovered after treatment with intravenous immunoglobulins and argatroban (15).
The clinical course and treatment of the patients were similar to the already reported cases, apart from the inconclusive first imaging. Physicians must be aware of this phenomenon when treating patients with headaches following vaccination and should repeat imaging in patients with thrombocytopenia and elevated D-Dimer. People undergoing vector vaccination for SARS-Cov2 should be educated by the physician administering the vector vaccine to seek help in case of non-remitting headache.
The risk for “occult” vaccine-associated CSVT seems to be low and when detected, the current treatment regime is thought to be effective. Given the mortality of SARS-Cov2-infection with possible long-term effects, vaccination should continue unchanged (16).
Conclusion
In patients with TTS complaining of persisting headache, a normal venous angiography might suggest a false sense of security for patients and treating physicians. Follow-up imaging several days later is necessary for patients with non-remitting headaches, to identify patients with CSVT and initiate the proper therapy to avoid a potentially fatal cause.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.
Author Contributions
TB, MJ, FR, HH, and MV treated the patients. TS performed and analyzed the CT and MRI results. FS performed the craniectomy. TB and FR wrote the manuscript. Each author approved the manuscript and contributed important intellectual content. All authors were involved in the analysis and interpretation of the findings, contributed to the writing, approved the final manuscript, read the ICMJE criteria for authorship, read, and agreed with the results of the study and conclusion.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
CRP C-reactive protein
CT computed tomography
CVST cerebral venous sinus thrombosis
GP general practitioner
ICH intracranial hemorrhage
HIT heparin-induced thrombocytopenia
MRI magnetic resonance imaging
PTT partial thromboplastin time
SAH subarachnoid hemorrhage
TTS thrombotic thrombocytopenic syndrome. | Fatal | ReactionOutcome | CC BY | 34880826 | 20,386,048 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Successful Immunotherapy for Pancreatic Cancer in a Patient With TSC2 and SMAD4 Mutations: A Case Report.
Pancreatic cancer has a poor prognosis, and it is traditionally treated with chemotherapy. Fortunately, immunotherapy has rapidly changed the landscape of solid tumor treatment, and improving the survival of cancer patients. However, pancreatic cancer is non-immunogenic, and single agent immunotherapies are unfavorable to its prognosis.
Here, we report a case of stage IV pancreatic cancer in a patient with TSC2 and SMAD4 mutations treated with immunotherapy when the disease progressed after multi-line chemotherapy. Next generation sequencing (NGS) confirmed the presence of TSC2 and SMAD4 mutations and microsatellite stability (MSS). When the disease progressed after chemotherapy, a combination strategy was devised consisting of chemotherapy (S-1) and sintilimab. The patient had a partial response to therapy with this regimen, the lesions were significantly reduced and nearly disappeared. In metastatic pancreatic cancer, responses of this magnitude are rarely seen.
This outcome reveals that this combination can be effective in treating metastatic pancreatic cancer, especially in pancreatic cancer patients with SMAD4 and TSC2 mutations. This may help increase the use of this therapy in large-scale clinical research.
pmcIntroduction
Pancreatic cancer has a high incidence and mortality, and its special structure can protect pancreatic cancer cells from chemotherapeutic agents (1, 2). However, pancreatic cancer is non-immunogenic and single agent immunotherapies are unfavorable to the prognosis of patients. Several clinical trials showed that single agent immunotherapies are ineffective for the treatment of advanced pancreatic cancer (3–5). Moreover, there was a clinical trial confirmed that objective response rate (ORR) was 0 for patients receiving single agent immunotherapies (5).
However, the effect of combination therapy is also not optimistic. As for chemotherapy plus immunotherapy, some clinical trials confirmed that the safety profile of combination therapy at standard doses in advanced pancreatic cancer was manageable (6, 7), but there was no significant improvement in progression-free survival (PFS) and overall survival (OS) (6, 8).
Though, the pancreatic cancer has little response rate to immunotherapy, it may be effective for specific patient. For example, several gene mutations can improve the effective of immunotherapy (9), including high levels of microsatellite instability (MSI-H), POLE, POLD1, et al.
Case Presentation
We present the case of a 56-year-old Chinese man who had been smoking and drinking for decades. He was hospitalized for six months with abdominal pain. In September 2019, magnetic resonance imaging (MRI) of the upper abdomen identified a pancreatic head mass, multiple retroperitoneal enlarged lymph nodes, and abnormal enhancement near the inferior vena cava in right lobe of the liver. Ultrasound guided biopsy of the pancreas was performed. Pathology diagnosis was pancreatic ductal adenocarcinoma (stage IV) ( Figures 1A, B ). Next generation sequencing (NGS) confirmed the tumor was microsatellite stability (MSS), and a total of 6 gene mutations, TSC2, CREBBP, HIST1H3I, MAP2K4, SMAD4, and STK11 were detected. Additionally, frame shift mutation occurred in exon 17 of TSC2 gene (32.13%); missense mutation occurred in exon 9 (7.47%) and nonsense mutation occurred in exon 5 (9.49%) of SMAD4 gene. The NGS confirmed that there were no targeted drug-related gene mutations and the tumor mutational burden (TMB) was 7.1 mut/Mb.
Figure 1 (A, B) pancreatic ductal adenocarcinoma. (A) 200X, (B) 400X. The pancreatic head puncture smear showed significant atypical epithelial mass, irregular nuclei, which was consistent with the changes of adenocarcinoma. (C–F) PET/CT images in April 2020. (C) showed a 6.0cm *6.0 cm mass in pancreatic head (arrow); (D) confirmed enlarged lymph nodes in pancreatic head (arrow), and low-density shadows in liver (within cycle); panels (E, F) revealed enlarged multiple lymph nodes in different sizes in retroperitoneum (arrow).
In October 2019, the patient’s primary oncologist started him on AG (gemcitabine and nab-paclitaxel). The gemcitabine (1000mg/m² over 30 minutes, weekly for 2 weeks, every 21 days) and nab-paclitaxel (125mg/m², weekly for 2 weeks, every 21 days) were administered intravenously. However, in the first three cycles and the fifth cycle of chemotherapy, for several reasons (such as COVID-19), he only received chemotherapeutic agents (AG) on the first day. In March 2020, the repeated MRI showed progressive disease. In late March 2020, the patient developed back pain and underwent endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic metal biliary endoprosthesis (EMBE) due to obstructive jaundice. In April 2020, positron emission tomography/computed tomography (PET/CT) revealed a 6.0 cm × 6.0 cm mass in pancreatic head, multiple enlarged lymph nodes in different sizes were found in pancreatic head and retroperitoneum, and multiple low-density shadows in the liver ( Figures 1C–F ).
Based on these findings, the patient was treated with FOLFIRINOX (oxaliplatin, Irinotecan, calcium folinate and 5-Fluorouracil). However, considering that the patient had just undergone surgery, the patient was asked by his doctor to eat S-1 for 14 days (from April 2, 2020 to April 16, 2020) before he received FOLFIRINOX treatment on April 25, 2020. In June 2020, after 4 cycles of chemotherapy, upper-abdomen enhanced CT revealed that the size of pancreatic head lesion was significantly decreased to 2.3 cm × 2.5 cm ( Figure 2A ), more that 50% decrease, and multiple low-density shadows in the liver. The patient was repeated CT about every two months ( Figures 2B, C ). Until October 2020, the CT only revealed a mass in the pancreatic head, and the lesion was slightly low density with peripheral lymph node metastasis.
Figure 2 Enhanced CT images. The pancreatic mass indicated by the arrow on upper-abdomen enhanced CT took in June 2020 (A), in August 2020 (B), in October 2020 (C) and in November 2020 (D). The pancreatic cancer was responded to chemotherapy initially, but the disease was still progressed at later time. After sintilimab combined with S-1 treatment, the pancreatic lesion was significantly reduced in, and nearly disappeared in June 2021 (E). The hepatic metastases indicated by the arrows on upper-abdomen enhanced CT took in October 2020 (F), and in June 2021 (G). The hepatic metastasis was significantly reduced (G).
In October 2020, the patient underwent one cycle of Olaparib by himself, although he did not have the targeted drug-related gene mutation. On October 16, his abdomen enhanced CT scan revealed multiple liver metastases ( Figure 2F ), and the largest measured 2.3 cm. We changed the chemotherapy regimen to AG again (gemcitabine and nab-paclitaxel). In November 2020, the abdomen enhanced CT scan revealed progressive disease ( Figure 2D ), and the size of the pancreatic head lesion was 6.4 cm.
The patient has undergone multi-line chemotherapy, chemotherapy alone could not inhibit the progression of the disease, and there was no standard treatment after two or more lines of systemic chemotherapy. In addition, his Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was 2, he suffered from severe cancer pain all over the body (OxyContin 30mg, every 12 hours) and weight loss, the aspartate transaminase and alanine transaminase were at normal level, and alkaline phosphatase increased slightly (not higher than 2 times the normal value). Thus, we decided to use chemotherapy (S-1) combined with immunotherapy (sintilimab). Considering the economic status of patient, we decided to choose sintilimab (more economical). The sintilimab is a fully human IgG4 monoclonal antibody; it can bind to PD-1, block the interaction of PD-1 with its ligands, and help recover the anti-tumor response of T-cells, and it has been approved to treat relapsed or refractory classical Hodgkin lymphoma, advanced non-small cell lung cancer and metastatic hepatocellular carcinoma. The anti-tumor effect of sintilimab is similar to that of other anti-PD-1/PD-L1 antibodies (10). Sintilimab was administered intravenously (200mg, every 3 weeks); and S-1was orally (40mg, twice a day orally for 2 weeks, every 21 days). The patient started to receive S-1 on November 24, 2020, and sintilimab on November 27, 2020.
The patient did not come to our hospital again until June 2021 ( Figure 3 ). He said he was treated at a local hospital during these seven months, and received a total of 10 cycles of sintilimab combined with S-1. The performance status was better than before (his PS improved to ECOG-PS 1); his severe cancer pain was well controlled (OxyContin 10mg, every 12 hours). The abdomen enhanced CT scan showed that the intrahepatic metastases ( Figure 2G ) and pancreatic head lesion ( Figure 2E ) were significantly reduced (the size of the pancreatic head lesion was 1 cm). By standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1, the patient had a partial response (more than 80% decrease) to therapy with this regimen. Moreover, throughout his treatment, the CA 19-9 level was always normal.
Figure 3 Timeline of the treament. The patient was diagnosed with pancreatic cancer in September 2019, and received chemotherapy (AG) in October 2019. Before receiving immunotherapy in November 2020, the patient had undergone multi-line chemotherapy (including AG, FOLFIRINOX, AG). And until August 2021 (the latest follow-up), the patient was still receiving immunotherapy combined with chemotherapy.
At the latest follow-up (August 2021), the patient still had a partial response to this regimen (S-1 combined with sintilimab), and the duration of partial response was 8 months.
Discussion
Chemotherapy has been the mainstay of treatment for many malignant tumors, including pancreatic cancer. Due to the lack of effective screening tools, most patients lose the opportunity to undergo surgery, which makes chemotherapy the standard treatment. However, chemotherapy has a poor therapeutic effect on pancreatic cancer due to its aggressive nature. Pancreatic cancer is composed of malignant cells and desmoplastic stroma (1). Desmoplastic stoma serves as a physical barrier that protects pancreatic cancer cells and prevent the effective delivery of chemotherapeutic agents (2).
In this case, the chemotherapy was effective for this patient at first. Additionally, after the disease progressed, the immunotherapy combined with chemotherapy had a significant effect. In the past 5 years, immunotherapy has rapidly changed the landscape of solid tumor treatment. What is more, tumor testing can help patients to get a better treatment. The results of a tumor testing making a patient eligible for treatment with immunotherapy, whose disease (advanced pancreatic cancer) progressed after neoadjuvant chemotherapy and adjuvant chemotherapy (11). Recent studies have identified several positive predictive markers for immune checkpoint inhibitors (ICIs), such as high levels of MSI-H, PD-L1 overexpression, high TMB, and gene mutations (9).
TSC2 is a tumor suppressor gene; it negatively regulates the cellular signaling networks that control cellular growth and proliferation (12). The TSC2 protein forms a complex and functions as a tumor suppressor by inhibiting mTORC1 kinase (13). It has been shown that, in TSC2-deficient tumors, the single-agent PD-1 or CTLA-4 blockade, or a combination of them, can inhibit the growth of tumors (14). Additionally, the combination of PD-1 and CTLA-4 antibody treatment or single-agent treatment can increase CD8+ T-cell infiltration in TSC2-deficient human tumors (14), and the level of infiltration is correlated with the degree of response to therapy.
Transforming growth factor beta (TGF-β) is an immune regulator; it can suppress the immune response via many different mechanisms (15). Moreover, it can inhibit tumor growth at the early stages of disease and promote tumor development at the later stages (16). However, the tumor-suppressive role of TGF-β is only effective when the TGF-β signaling pathway is not defective (17). SMAD4 serves as the central mediator of the TGF-β signaling pathway (18), and it is the only common mediator. The TGF-β/SMAD4 signaling pathway plays a tumor suppressive role in early stages of disease, mainly by inducing cell cycle arrest and apoptosis. TGF-β can stimulate regulatory T-cells, which inhibit the function of other lymphocytes (19). PD-1 is highly expressed on tumor infiltrating lymphocytes; it has been shown that human PD-1 expression may under direct transcriptional control by TGF-β, and TGF-β can enhance the expression of PD-1, suppressing anti-tumor immunity (20). TGF-β inhibits CD8+ T-cell effector function through TGF-β signaling pathway (21). Pancreatic cancer cells have lost their tumor-suppressive roles, but they possess tumor-promoting effects induced by increased TGF-β (22). In a tumor microenvironment, TGF-β expression is very high.
In pancreatic cancer, alterations of TGF-β signaling occur through the mutation of the genes involved in the pathway (including SMAD4); this activity is present in 47% of pancreatic cancer patients (23). The loss of SMAD4 will abrogate the canonical TGF-β/SMAD4 signaling pathway (24), and it may make pancreatic cancer more aggressive (25). It has been shown that SMAD4-deleted pancreatic ductal adenocarcinoma cells are sensitive to agents modulating the cell cycle (26). The loss of SMAD4 counteracted TGF-β-induced cell cycle arrest and apoptosis (27). Furthermore, it has been reported that the loss of SMAD4 expression is significantly associated with better survival after resection (28). The inhibition of TGF-β has been reported to have a variety of antitumor effects (29). A TGF-β blockade can reverse the suppressive effects of apoptotic cells on inflammation and adaptive immunity (30). In T-cell excluded mouse models, immune checkpoint-resistant MSS colorectal cancers and liver tumors were rendered susceptible to anti-PD-1/PD-L1 therapy with a TGF-β blockade (31).
Blockade of immune checkpoints by anti-CTLA-4 or anti-PD-1/anti-PD-L1 agents leads to T-cell activation, and it provides an effective approach for tumor immunotherapy (32). And the high PD-L1 expression may have a better clinical benefit. There was a case report showed that blocking the PD-L1 pathway combined with chemotherapy was effective for pancreatic squamous cell carcinoma patients with high PD-L1 expression (33).
Pancreatic cancer is intrinsically non-immunogenic (34). Single agent immunotherapies are unlikely to be successful in treating this type of cancer (35), but immunotherapy combined with chemotherapy has a synergistic effect (36). Chemotherapeutic agents could promote the release of tumor antigens from the cancer cells and reactivate an anti-cancer immune response to suppress tumor growth (37). Besides, according to several ongoing clinical trials, there are other regimens of combination therapy for the treatment of pancreatic cancer, such as BL-8040 (chemokine receptor type 4 inhibitors) and pembrolizumab combined with chemotherapy (NCT02826486), olaparib plus pembrolizumab (NCT04666740 and NCT04548752), olaparib or selumetinib plus durvalumab (NCT04348045). Additionally, the COMBAT/KEYNOTE-202 Trial (NCT02826486) revealed that the ORR was 21.1%, and the triple combination of BL-8040, pembrolizumab, and chemotherapy was safe and well tolerated, but no significant improvement in PFS and OS (38).
Other ICIs can also improve the effect of therapy. TMB is the total number of mutations per coding area of a tumor gene, which can increase the sensitivity to immunotherapy (39). Generally, we defined TMB ≥ 20 mutations/Mb as high TMB, TMB ≤ 10 mutations/Mb as low TMB. Patients with a high TMB also have a better prognosis with immunotherapy. For example, a higher TMB was associated with better response in non-small cell lung cancer patients receiving pembrolizumab (40). A higher TMB had a clinical benefit in malignant melanoma patients receiving either ipilimumab or tremelimumab (41). Additionally, a case report revealed that combined antiangiogenic therapy and immunotherapy is effective for pancreatic cancer with high TMB (42). However, patients with pancreatic cancer generally have a low TMB in comparison to patients with other malignancies (43). Moreover, pancreatic cancer is a tumor with low immunogenicity, which is attributed to low TMB (36).
Conclusion
In this case, the effect of immunotherapy combined with chemotherapy seems to be very effective. We also established a hypothesis that the SMAD4 and TSC2 mutations improved the efficacy of immunotherapy, prolonging the survival of patients. However, very few studies have investigated the relationship between SMAD4 mutation and immunotherapy in pancreatic cancer. Thus, more studies and clinical trials are needed.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
SZ is the guarantor. YY wrote the manuscript. All authors read, provided feedback, and approved the final version.
Funding
The National Natural Science Foundation of China (81372660), Zhejiang Province Public Welfare Technology Application Research Project (2017C33200), and Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
MRI, magnetic resonance imaging; PET, positron emission tomography; CT, computed tomography; NGS, next generation sequencing; TGF-β, transforming growth factor beta; TMB, tumor mutational burden; MSS, microsatellite stable; MSI, microsatellite instability; MSI-H, high levels of microsatellite instability; ICI, immune checkpoint inhibitor; ORR, objective response rate; PFS, progression-free survival; OS, overall survival. | GEMCITABINE, PACLITAXEL | DrugsGivenReaction | CC BY | 34880877 | 20,296,465 | 2021 |
What was the administration route of drug 'PACLITAXEL'? | Successful Immunotherapy for Pancreatic Cancer in a Patient With TSC2 and SMAD4 Mutations: A Case Report.
Pancreatic cancer has a poor prognosis, and it is traditionally treated with chemotherapy. Fortunately, immunotherapy has rapidly changed the landscape of solid tumor treatment, and improving the survival of cancer patients. However, pancreatic cancer is non-immunogenic, and single agent immunotherapies are unfavorable to its prognosis.
Here, we report a case of stage IV pancreatic cancer in a patient with TSC2 and SMAD4 mutations treated with immunotherapy when the disease progressed after multi-line chemotherapy. Next generation sequencing (NGS) confirmed the presence of TSC2 and SMAD4 mutations and microsatellite stability (MSS). When the disease progressed after chemotherapy, a combination strategy was devised consisting of chemotherapy (S-1) and sintilimab. The patient had a partial response to therapy with this regimen, the lesions were significantly reduced and nearly disappeared. In metastatic pancreatic cancer, responses of this magnitude are rarely seen.
This outcome reveals that this combination can be effective in treating metastatic pancreatic cancer, especially in pancreatic cancer patients with SMAD4 and TSC2 mutations. This may help increase the use of this therapy in large-scale clinical research.
pmcIntroduction
Pancreatic cancer has a high incidence and mortality, and its special structure can protect pancreatic cancer cells from chemotherapeutic agents (1, 2). However, pancreatic cancer is non-immunogenic and single agent immunotherapies are unfavorable to the prognosis of patients. Several clinical trials showed that single agent immunotherapies are ineffective for the treatment of advanced pancreatic cancer (3–5). Moreover, there was a clinical trial confirmed that objective response rate (ORR) was 0 for patients receiving single agent immunotherapies (5).
However, the effect of combination therapy is also not optimistic. As for chemotherapy plus immunotherapy, some clinical trials confirmed that the safety profile of combination therapy at standard doses in advanced pancreatic cancer was manageable (6, 7), but there was no significant improvement in progression-free survival (PFS) and overall survival (OS) (6, 8).
Though, the pancreatic cancer has little response rate to immunotherapy, it may be effective for specific patient. For example, several gene mutations can improve the effective of immunotherapy (9), including high levels of microsatellite instability (MSI-H), POLE, POLD1, et al.
Case Presentation
We present the case of a 56-year-old Chinese man who had been smoking and drinking for decades. He was hospitalized for six months with abdominal pain. In September 2019, magnetic resonance imaging (MRI) of the upper abdomen identified a pancreatic head mass, multiple retroperitoneal enlarged lymph nodes, and abnormal enhancement near the inferior vena cava in right lobe of the liver. Ultrasound guided biopsy of the pancreas was performed. Pathology diagnosis was pancreatic ductal adenocarcinoma (stage IV) ( Figures 1A, B ). Next generation sequencing (NGS) confirmed the tumor was microsatellite stability (MSS), and a total of 6 gene mutations, TSC2, CREBBP, HIST1H3I, MAP2K4, SMAD4, and STK11 were detected. Additionally, frame shift mutation occurred in exon 17 of TSC2 gene (32.13%); missense mutation occurred in exon 9 (7.47%) and nonsense mutation occurred in exon 5 (9.49%) of SMAD4 gene. The NGS confirmed that there were no targeted drug-related gene mutations and the tumor mutational burden (TMB) was 7.1 mut/Mb.
Figure 1 (A, B) pancreatic ductal adenocarcinoma. (A) 200X, (B) 400X. The pancreatic head puncture smear showed significant atypical epithelial mass, irregular nuclei, which was consistent with the changes of adenocarcinoma. (C–F) PET/CT images in April 2020. (C) showed a 6.0cm *6.0 cm mass in pancreatic head (arrow); (D) confirmed enlarged lymph nodes in pancreatic head (arrow), and low-density shadows in liver (within cycle); panels (E, F) revealed enlarged multiple lymph nodes in different sizes in retroperitoneum (arrow).
In October 2019, the patient’s primary oncologist started him on AG (gemcitabine and nab-paclitaxel). The gemcitabine (1000mg/m² over 30 minutes, weekly for 2 weeks, every 21 days) and nab-paclitaxel (125mg/m², weekly for 2 weeks, every 21 days) were administered intravenously. However, in the first three cycles and the fifth cycle of chemotherapy, for several reasons (such as COVID-19), he only received chemotherapeutic agents (AG) on the first day. In March 2020, the repeated MRI showed progressive disease. In late March 2020, the patient developed back pain and underwent endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic metal biliary endoprosthesis (EMBE) due to obstructive jaundice. In April 2020, positron emission tomography/computed tomography (PET/CT) revealed a 6.0 cm × 6.0 cm mass in pancreatic head, multiple enlarged lymph nodes in different sizes were found in pancreatic head and retroperitoneum, and multiple low-density shadows in the liver ( Figures 1C–F ).
Based on these findings, the patient was treated with FOLFIRINOX (oxaliplatin, Irinotecan, calcium folinate and 5-Fluorouracil). However, considering that the patient had just undergone surgery, the patient was asked by his doctor to eat S-1 for 14 days (from April 2, 2020 to April 16, 2020) before he received FOLFIRINOX treatment on April 25, 2020. In June 2020, after 4 cycles of chemotherapy, upper-abdomen enhanced CT revealed that the size of pancreatic head lesion was significantly decreased to 2.3 cm × 2.5 cm ( Figure 2A ), more that 50% decrease, and multiple low-density shadows in the liver. The patient was repeated CT about every two months ( Figures 2B, C ). Until October 2020, the CT only revealed a mass in the pancreatic head, and the lesion was slightly low density with peripheral lymph node metastasis.
Figure 2 Enhanced CT images. The pancreatic mass indicated by the arrow on upper-abdomen enhanced CT took in June 2020 (A), in August 2020 (B), in October 2020 (C) and in November 2020 (D). The pancreatic cancer was responded to chemotherapy initially, but the disease was still progressed at later time. After sintilimab combined with S-1 treatment, the pancreatic lesion was significantly reduced in, and nearly disappeared in June 2021 (E). The hepatic metastases indicated by the arrows on upper-abdomen enhanced CT took in October 2020 (F), and in June 2021 (G). The hepatic metastasis was significantly reduced (G).
In October 2020, the patient underwent one cycle of Olaparib by himself, although he did not have the targeted drug-related gene mutation. On October 16, his abdomen enhanced CT scan revealed multiple liver metastases ( Figure 2F ), and the largest measured 2.3 cm. We changed the chemotherapy regimen to AG again (gemcitabine and nab-paclitaxel). In November 2020, the abdomen enhanced CT scan revealed progressive disease ( Figure 2D ), and the size of the pancreatic head lesion was 6.4 cm.
The patient has undergone multi-line chemotherapy, chemotherapy alone could not inhibit the progression of the disease, and there was no standard treatment after two or more lines of systemic chemotherapy. In addition, his Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was 2, he suffered from severe cancer pain all over the body (OxyContin 30mg, every 12 hours) and weight loss, the aspartate transaminase and alanine transaminase were at normal level, and alkaline phosphatase increased slightly (not higher than 2 times the normal value). Thus, we decided to use chemotherapy (S-1) combined with immunotherapy (sintilimab). Considering the economic status of patient, we decided to choose sintilimab (more economical). The sintilimab is a fully human IgG4 monoclonal antibody; it can bind to PD-1, block the interaction of PD-1 with its ligands, and help recover the anti-tumor response of T-cells, and it has been approved to treat relapsed or refractory classical Hodgkin lymphoma, advanced non-small cell lung cancer and metastatic hepatocellular carcinoma. The anti-tumor effect of sintilimab is similar to that of other anti-PD-1/PD-L1 antibodies (10). Sintilimab was administered intravenously (200mg, every 3 weeks); and S-1was orally (40mg, twice a day orally for 2 weeks, every 21 days). The patient started to receive S-1 on November 24, 2020, and sintilimab on November 27, 2020.
The patient did not come to our hospital again until June 2021 ( Figure 3 ). He said he was treated at a local hospital during these seven months, and received a total of 10 cycles of sintilimab combined with S-1. The performance status was better than before (his PS improved to ECOG-PS 1); his severe cancer pain was well controlled (OxyContin 10mg, every 12 hours). The abdomen enhanced CT scan showed that the intrahepatic metastases ( Figure 2G ) and pancreatic head lesion ( Figure 2E ) were significantly reduced (the size of the pancreatic head lesion was 1 cm). By standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1, the patient had a partial response (more than 80% decrease) to therapy with this regimen. Moreover, throughout his treatment, the CA 19-9 level was always normal.
Figure 3 Timeline of the treament. The patient was diagnosed with pancreatic cancer in September 2019, and received chemotherapy (AG) in October 2019. Before receiving immunotherapy in November 2020, the patient had undergone multi-line chemotherapy (including AG, FOLFIRINOX, AG). And until August 2021 (the latest follow-up), the patient was still receiving immunotherapy combined with chemotherapy.
At the latest follow-up (August 2021), the patient still had a partial response to this regimen (S-1 combined with sintilimab), and the duration of partial response was 8 months.
Discussion
Chemotherapy has been the mainstay of treatment for many malignant tumors, including pancreatic cancer. Due to the lack of effective screening tools, most patients lose the opportunity to undergo surgery, which makes chemotherapy the standard treatment. However, chemotherapy has a poor therapeutic effect on pancreatic cancer due to its aggressive nature. Pancreatic cancer is composed of malignant cells and desmoplastic stroma (1). Desmoplastic stoma serves as a physical barrier that protects pancreatic cancer cells and prevent the effective delivery of chemotherapeutic agents (2).
In this case, the chemotherapy was effective for this patient at first. Additionally, after the disease progressed, the immunotherapy combined with chemotherapy had a significant effect. In the past 5 years, immunotherapy has rapidly changed the landscape of solid tumor treatment. What is more, tumor testing can help patients to get a better treatment. The results of a tumor testing making a patient eligible for treatment with immunotherapy, whose disease (advanced pancreatic cancer) progressed after neoadjuvant chemotherapy and adjuvant chemotherapy (11). Recent studies have identified several positive predictive markers for immune checkpoint inhibitors (ICIs), such as high levels of MSI-H, PD-L1 overexpression, high TMB, and gene mutations (9).
TSC2 is a tumor suppressor gene; it negatively regulates the cellular signaling networks that control cellular growth and proliferation (12). The TSC2 protein forms a complex and functions as a tumor suppressor by inhibiting mTORC1 kinase (13). It has been shown that, in TSC2-deficient tumors, the single-agent PD-1 or CTLA-4 blockade, or a combination of them, can inhibit the growth of tumors (14). Additionally, the combination of PD-1 and CTLA-4 antibody treatment or single-agent treatment can increase CD8+ T-cell infiltration in TSC2-deficient human tumors (14), and the level of infiltration is correlated with the degree of response to therapy.
Transforming growth factor beta (TGF-β) is an immune regulator; it can suppress the immune response via many different mechanisms (15). Moreover, it can inhibit tumor growth at the early stages of disease and promote tumor development at the later stages (16). However, the tumor-suppressive role of TGF-β is only effective when the TGF-β signaling pathway is not defective (17). SMAD4 serves as the central mediator of the TGF-β signaling pathway (18), and it is the only common mediator. The TGF-β/SMAD4 signaling pathway plays a tumor suppressive role in early stages of disease, mainly by inducing cell cycle arrest and apoptosis. TGF-β can stimulate regulatory T-cells, which inhibit the function of other lymphocytes (19). PD-1 is highly expressed on tumor infiltrating lymphocytes; it has been shown that human PD-1 expression may under direct transcriptional control by TGF-β, and TGF-β can enhance the expression of PD-1, suppressing anti-tumor immunity (20). TGF-β inhibits CD8+ T-cell effector function through TGF-β signaling pathway (21). Pancreatic cancer cells have lost their tumor-suppressive roles, but they possess tumor-promoting effects induced by increased TGF-β (22). In a tumor microenvironment, TGF-β expression is very high.
In pancreatic cancer, alterations of TGF-β signaling occur through the mutation of the genes involved in the pathway (including SMAD4); this activity is present in 47% of pancreatic cancer patients (23). The loss of SMAD4 will abrogate the canonical TGF-β/SMAD4 signaling pathway (24), and it may make pancreatic cancer more aggressive (25). It has been shown that SMAD4-deleted pancreatic ductal adenocarcinoma cells are sensitive to agents modulating the cell cycle (26). The loss of SMAD4 counteracted TGF-β-induced cell cycle arrest and apoptosis (27). Furthermore, it has been reported that the loss of SMAD4 expression is significantly associated with better survival after resection (28). The inhibition of TGF-β has been reported to have a variety of antitumor effects (29). A TGF-β blockade can reverse the suppressive effects of apoptotic cells on inflammation and adaptive immunity (30). In T-cell excluded mouse models, immune checkpoint-resistant MSS colorectal cancers and liver tumors were rendered susceptible to anti-PD-1/PD-L1 therapy with a TGF-β blockade (31).
Blockade of immune checkpoints by anti-CTLA-4 or anti-PD-1/anti-PD-L1 agents leads to T-cell activation, and it provides an effective approach for tumor immunotherapy (32). And the high PD-L1 expression may have a better clinical benefit. There was a case report showed that blocking the PD-L1 pathway combined with chemotherapy was effective for pancreatic squamous cell carcinoma patients with high PD-L1 expression (33).
Pancreatic cancer is intrinsically non-immunogenic (34). Single agent immunotherapies are unlikely to be successful in treating this type of cancer (35), but immunotherapy combined with chemotherapy has a synergistic effect (36). Chemotherapeutic agents could promote the release of tumor antigens from the cancer cells and reactivate an anti-cancer immune response to suppress tumor growth (37). Besides, according to several ongoing clinical trials, there are other regimens of combination therapy for the treatment of pancreatic cancer, such as BL-8040 (chemokine receptor type 4 inhibitors) and pembrolizumab combined with chemotherapy (NCT02826486), olaparib plus pembrolizumab (NCT04666740 and NCT04548752), olaparib or selumetinib plus durvalumab (NCT04348045). Additionally, the COMBAT/KEYNOTE-202 Trial (NCT02826486) revealed that the ORR was 21.1%, and the triple combination of BL-8040, pembrolizumab, and chemotherapy was safe and well tolerated, but no significant improvement in PFS and OS (38).
Other ICIs can also improve the effect of therapy. TMB is the total number of mutations per coding area of a tumor gene, which can increase the sensitivity to immunotherapy (39). Generally, we defined TMB ≥ 20 mutations/Mb as high TMB, TMB ≤ 10 mutations/Mb as low TMB. Patients with a high TMB also have a better prognosis with immunotherapy. For example, a higher TMB was associated with better response in non-small cell lung cancer patients receiving pembrolizumab (40). A higher TMB had a clinical benefit in malignant melanoma patients receiving either ipilimumab or tremelimumab (41). Additionally, a case report revealed that combined antiangiogenic therapy and immunotherapy is effective for pancreatic cancer with high TMB (42). However, patients with pancreatic cancer generally have a low TMB in comparison to patients with other malignancies (43). Moreover, pancreatic cancer is a tumor with low immunogenicity, which is attributed to low TMB (36).
Conclusion
In this case, the effect of immunotherapy combined with chemotherapy seems to be very effective. We also established a hypothesis that the SMAD4 and TSC2 mutations improved the efficacy of immunotherapy, prolonging the survival of patients. However, very few studies have investigated the relationship between SMAD4 mutation and immunotherapy in pancreatic cancer. Thus, more studies and clinical trials are needed.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
SZ is the guarantor. YY wrote the manuscript. All authors read, provided feedback, and approved the final version.
Funding
The National Natural Science Foundation of China (81372660), Zhejiang Province Public Welfare Technology Application Research Project (2017C33200), and Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
MRI, magnetic resonance imaging; PET, positron emission tomography; CT, computed tomography; NGS, next generation sequencing; TGF-β, transforming growth factor beta; TMB, tumor mutational burden; MSS, microsatellite stable; MSI, microsatellite instability; MSI-H, high levels of microsatellite instability; ICI, immune checkpoint inhibitor; ORR, objective response rate; PFS, progression-free survival; OS, overall survival. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 34880877 | 20,296,465 | 2021 |
What was the dosage of drug 'GEMCITABINE'? | Successful Immunotherapy for Pancreatic Cancer in a Patient With TSC2 and SMAD4 Mutations: A Case Report.
Pancreatic cancer has a poor prognosis, and it is traditionally treated with chemotherapy. Fortunately, immunotherapy has rapidly changed the landscape of solid tumor treatment, and improving the survival of cancer patients. However, pancreatic cancer is non-immunogenic, and single agent immunotherapies are unfavorable to its prognosis.
Here, we report a case of stage IV pancreatic cancer in a patient with TSC2 and SMAD4 mutations treated with immunotherapy when the disease progressed after multi-line chemotherapy. Next generation sequencing (NGS) confirmed the presence of TSC2 and SMAD4 mutations and microsatellite stability (MSS). When the disease progressed after chemotherapy, a combination strategy was devised consisting of chemotherapy (S-1) and sintilimab. The patient had a partial response to therapy with this regimen, the lesions were significantly reduced and nearly disappeared. In metastatic pancreatic cancer, responses of this magnitude are rarely seen.
This outcome reveals that this combination can be effective in treating metastatic pancreatic cancer, especially in pancreatic cancer patients with SMAD4 and TSC2 mutations. This may help increase the use of this therapy in large-scale clinical research.
pmcIntroduction
Pancreatic cancer has a high incidence and mortality, and its special structure can protect pancreatic cancer cells from chemotherapeutic agents (1, 2). However, pancreatic cancer is non-immunogenic and single agent immunotherapies are unfavorable to the prognosis of patients. Several clinical trials showed that single agent immunotherapies are ineffective for the treatment of advanced pancreatic cancer (3–5). Moreover, there was a clinical trial confirmed that objective response rate (ORR) was 0 for patients receiving single agent immunotherapies (5).
However, the effect of combination therapy is also not optimistic. As for chemotherapy plus immunotherapy, some clinical trials confirmed that the safety profile of combination therapy at standard doses in advanced pancreatic cancer was manageable (6, 7), but there was no significant improvement in progression-free survival (PFS) and overall survival (OS) (6, 8).
Though, the pancreatic cancer has little response rate to immunotherapy, it may be effective for specific patient. For example, several gene mutations can improve the effective of immunotherapy (9), including high levels of microsatellite instability (MSI-H), POLE, POLD1, et al.
Case Presentation
We present the case of a 56-year-old Chinese man who had been smoking and drinking for decades. He was hospitalized for six months with abdominal pain. In September 2019, magnetic resonance imaging (MRI) of the upper abdomen identified a pancreatic head mass, multiple retroperitoneal enlarged lymph nodes, and abnormal enhancement near the inferior vena cava in right lobe of the liver. Ultrasound guided biopsy of the pancreas was performed. Pathology diagnosis was pancreatic ductal adenocarcinoma (stage IV) ( Figures 1A, B ). Next generation sequencing (NGS) confirmed the tumor was microsatellite stability (MSS), and a total of 6 gene mutations, TSC2, CREBBP, HIST1H3I, MAP2K4, SMAD4, and STK11 were detected. Additionally, frame shift mutation occurred in exon 17 of TSC2 gene (32.13%); missense mutation occurred in exon 9 (7.47%) and nonsense mutation occurred in exon 5 (9.49%) of SMAD4 gene. The NGS confirmed that there were no targeted drug-related gene mutations and the tumor mutational burden (TMB) was 7.1 mut/Mb.
Figure 1 (A, B) pancreatic ductal adenocarcinoma. (A) 200X, (B) 400X. The pancreatic head puncture smear showed significant atypical epithelial mass, irregular nuclei, which was consistent with the changes of adenocarcinoma. (C–F) PET/CT images in April 2020. (C) showed a 6.0cm *6.0 cm mass in pancreatic head (arrow); (D) confirmed enlarged lymph nodes in pancreatic head (arrow), and low-density shadows in liver (within cycle); panels (E, F) revealed enlarged multiple lymph nodes in different sizes in retroperitoneum (arrow).
In October 2019, the patient’s primary oncologist started him on AG (gemcitabine and nab-paclitaxel). The gemcitabine (1000mg/m² over 30 minutes, weekly for 2 weeks, every 21 days) and nab-paclitaxel (125mg/m², weekly for 2 weeks, every 21 days) were administered intravenously. However, in the first three cycles and the fifth cycle of chemotherapy, for several reasons (such as COVID-19), he only received chemotherapeutic agents (AG) on the first day. In March 2020, the repeated MRI showed progressive disease. In late March 2020, the patient developed back pain and underwent endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic metal biliary endoprosthesis (EMBE) due to obstructive jaundice. In April 2020, positron emission tomography/computed tomography (PET/CT) revealed a 6.0 cm × 6.0 cm mass in pancreatic head, multiple enlarged lymph nodes in different sizes were found in pancreatic head and retroperitoneum, and multiple low-density shadows in the liver ( Figures 1C–F ).
Based on these findings, the patient was treated with FOLFIRINOX (oxaliplatin, Irinotecan, calcium folinate and 5-Fluorouracil). However, considering that the patient had just undergone surgery, the patient was asked by his doctor to eat S-1 for 14 days (from April 2, 2020 to April 16, 2020) before he received FOLFIRINOX treatment on April 25, 2020. In June 2020, after 4 cycles of chemotherapy, upper-abdomen enhanced CT revealed that the size of pancreatic head lesion was significantly decreased to 2.3 cm × 2.5 cm ( Figure 2A ), more that 50% decrease, and multiple low-density shadows in the liver. The patient was repeated CT about every two months ( Figures 2B, C ). Until October 2020, the CT only revealed a mass in the pancreatic head, and the lesion was slightly low density with peripheral lymph node metastasis.
Figure 2 Enhanced CT images. The pancreatic mass indicated by the arrow on upper-abdomen enhanced CT took in June 2020 (A), in August 2020 (B), in October 2020 (C) and in November 2020 (D). The pancreatic cancer was responded to chemotherapy initially, but the disease was still progressed at later time. After sintilimab combined with S-1 treatment, the pancreatic lesion was significantly reduced in, and nearly disappeared in June 2021 (E). The hepatic metastases indicated by the arrows on upper-abdomen enhanced CT took in October 2020 (F), and in June 2021 (G). The hepatic metastasis was significantly reduced (G).
In October 2020, the patient underwent one cycle of Olaparib by himself, although he did not have the targeted drug-related gene mutation. On October 16, his abdomen enhanced CT scan revealed multiple liver metastases ( Figure 2F ), and the largest measured 2.3 cm. We changed the chemotherapy regimen to AG again (gemcitabine and nab-paclitaxel). In November 2020, the abdomen enhanced CT scan revealed progressive disease ( Figure 2D ), and the size of the pancreatic head lesion was 6.4 cm.
The patient has undergone multi-line chemotherapy, chemotherapy alone could not inhibit the progression of the disease, and there was no standard treatment after two or more lines of systemic chemotherapy. In addition, his Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was 2, he suffered from severe cancer pain all over the body (OxyContin 30mg, every 12 hours) and weight loss, the aspartate transaminase and alanine transaminase were at normal level, and alkaline phosphatase increased slightly (not higher than 2 times the normal value). Thus, we decided to use chemotherapy (S-1) combined with immunotherapy (sintilimab). Considering the economic status of patient, we decided to choose sintilimab (more economical). The sintilimab is a fully human IgG4 monoclonal antibody; it can bind to PD-1, block the interaction of PD-1 with its ligands, and help recover the anti-tumor response of T-cells, and it has been approved to treat relapsed or refractory classical Hodgkin lymphoma, advanced non-small cell lung cancer and metastatic hepatocellular carcinoma. The anti-tumor effect of sintilimab is similar to that of other anti-PD-1/PD-L1 antibodies (10). Sintilimab was administered intravenously (200mg, every 3 weeks); and S-1was orally (40mg, twice a day orally for 2 weeks, every 21 days). The patient started to receive S-1 on November 24, 2020, and sintilimab on November 27, 2020.
The patient did not come to our hospital again until June 2021 ( Figure 3 ). He said he was treated at a local hospital during these seven months, and received a total of 10 cycles of sintilimab combined with S-1. The performance status was better than before (his PS improved to ECOG-PS 1); his severe cancer pain was well controlled (OxyContin 10mg, every 12 hours). The abdomen enhanced CT scan showed that the intrahepatic metastases ( Figure 2G ) and pancreatic head lesion ( Figure 2E ) were significantly reduced (the size of the pancreatic head lesion was 1 cm). By standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1, the patient had a partial response (more than 80% decrease) to therapy with this regimen. Moreover, throughout his treatment, the CA 19-9 level was always normal.
Figure 3 Timeline of the treament. The patient was diagnosed with pancreatic cancer in September 2019, and received chemotherapy (AG) in October 2019. Before receiving immunotherapy in November 2020, the patient had undergone multi-line chemotherapy (including AG, FOLFIRINOX, AG). And until August 2021 (the latest follow-up), the patient was still receiving immunotherapy combined with chemotherapy.
At the latest follow-up (August 2021), the patient still had a partial response to this regimen (S-1 combined with sintilimab), and the duration of partial response was 8 months.
Discussion
Chemotherapy has been the mainstay of treatment for many malignant tumors, including pancreatic cancer. Due to the lack of effective screening tools, most patients lose the opportunity to undergo surgery, which makes chemotherapy the standard treatment. However, chemotherapy has a poor therapeutic effect on pancreatic cancer due to its aggressive nature. Pancreatic cancer is composed of malignant cells and desmoplastic stroma (1). Desmoplastic stoma serves as a physical barrier that protects pancreatic cancer cells and prevent the effective delivery of chemotherapeutic agents (2).
In this case, the chemotherapy was effective for this patient at first. Additionally, after the disease progressed, the immunotherapy combined with chemotherapy had a significant effect. In the past 5 years, immunotherapy has rapidly changed the landscape of solid tumor treatment. What is more, tumor testing can help patients to get a better treatment. The results of a tumor testing making a patient eligible for treatment with immunotherapy, whose disease (advanced pancreatic cancer) progressed after neoadjuvant chemotherapy and adjuvant chemotherapy (11). Recent studies have identified several positive predictive markers for immune checkpoint inhibitors (ICIs), such as high levels of MSI-H, PD-L1 overexpression, high TMB, and gene mutations (9).
TSC2 is a tumor suppressor gene; it negatively regulates the cellular signaling networks that control cellular growth and proliferation (12). The TSC2 protein forms a complex and functions as a tumor suppressor by inhibiting mTORC1 kinase (13). It has been shown that, in TSC2-deficient tumors, the single-agent PD-1 or CTLA-4 blockade, or a combination of them, can inhibit the growth of tumors (14). Additionally, the combination of PD-1 and CTLA-4 antibody treatment or single-agent treatment can increase CD8+ T-cell infiltration in TSC2-deficient human tumors (14), and the level of infiltration is correlated with the degree of response to therapy.
Transforming growth factor beta (TGF-β) is an immune regulator; it can suppress the immune response via many different mechanisms (15). Moreover, it can inhibit tumor growth at the early stages of disease and promote tumor development at the later stages (16). However, the tumor-suppressive role of TGF-β is only effective when the TGF-β signaling pathway is not defective (17). SMAD4 serves as the central mediator of the TGF-β signaling pathway (18), and it is the only common mediator. The TGF-β/SMAD4 signaling pathway plays a tumor suppressive role in early stages of disease, mainly by inducing cell cycle arrest and apoptosis. TGF-β can stimulate regulatory T-cells, which inhibit the function of other lymphocytes (19). PD-1 is highly expressed on tumor infiltrating lymphocytes; it has been shown that human PD-1 expression may under direct transcriptional control by TGF-β, and TGF-β can enhance the expression of PD-1, suppressing anti-tumor immunity (20). TGF-β inhibits CD8+ T-cell effector function through TGF-β signaling pathway (21). Pancreatic cancer cells have lost their tumor-suppressive roles, but they possess tumor-promoting effects induced by increased TGF-β (22). In a tumor microenvironment, TGF-β expression is very high.
In pancreatic cancer, alterations of TGF-β signaling occur through the mutation of the genes involved in the pathway (including SMAD4); this activity is present in 47% of pancreatic cancer patients (23). The loss of SMAD4 will abrogate the canonical TGF-β/SMAD4 signaling pathway (24), and it may make pancreatic cancer more aggressive (25). It has been shown that SMAD4-deleted pancreatic ductal adenocarcinoma cells are sensitive to agents modulating the cell cycle (26). The loss of SMAD4 counteracted TGF-β-induced cell cycle arrest and apoptosis (27). Furthermore, it has been reported that the loss of SMAD4 expression is significantly associated with better survival after resection (28). The inhibition of TGF-β has been reported to have a variety of antitumor effects (29). A TGF-β blockade can reverse the suppressive effects of apoptotic cells on inflammation and adaptive immunity (30). In T-cell excluded mouse models, immune checkpoint-resistant MSS colorectal cancers and liver tumors were rendered susceptible to anti-PD-1/PD-L1 therapy with a TGF-β blockade (31).
Blockade of immune checkpoints by anti-CTLA-4 or anti-PD-1/anti-PD-L1 agents leads to T-cell activation, and it provides an effective approach for tumor immunotherapy (32). And the high PD-L1 expression may have a better clinical benefit. There was a case report showed that blocking the PD-L1 pathway combined with chemotherapy was effective for pancreatic squamous cell carcinoma patients with high PD-L1 expression (33).
Pancreatic cancer is intrinsically non-immunogenic (34). Single agent immunotherapies are unlikely to be successful in treating this type of cancer (35), but immunotherapy combined with chemotherapy has a synergistic effect (36). Chemotherapeutic agents could promote the release of tumor antigens from the cancer cells and reactivate an anti-cancer immune response to suppress tumor growth (37). Besides, according to several ongoing clinical trials, there are other regimens of combination therapy for the treatment of pancreatic cancer, such as BL-8040 (chemokine receptor type 4 inhibitors) and pembrolizumab combined with chemotherapy (NCT02826486), olaparib plus pembrolizumab (NCT04666740 and NCT04548752), olaparib or selumetinib plus durvalumab (NCT04348045). Additionally, the COMBAT/KEYNOTE-202 Trial (NCT02826486) revealed that the ORR was 21.1%, and the triple combination of BL-8040, pembrolizumab, and chemotherapy was safe and well tolerated, but no significant improvement in PFS and OS (38).
Other ICIs can also improve the effect of therapy. TMB is the total number of mutations per coding area of a tumor gene, which can increase the sensitivity to immunotherapy (39). Generally, we defined TMB ≥ 20 mutations/Mb as high TMB, TMB ≤ 10 mutations/Mb as low TMB. Patients with a high TMB also have a better prognosis with immunotherapy. For example, a higher TMB was associated with better response in non-small cell lung cancer patients receiving pembrolizumab (40). A higher TMB had a clinical benefit in malignant melanoma patients receiving either ipilimumab or tremelimumab (41). Additionally, a case report revealed that combined antiangiogenic therapy and immunotherapy is effective for pancreatic cancer with high TMB (42). However, patients with pancreatic cancer generally have a low TMB in comparison to patients with other malignancies (43). Moreover, pancreatic cancer is a tumor with low immunogenicity, which is attributed to low TMB (36).
Conclusion
In this case, the effect of immunotherapy combined with chemotherapy seems to be very effective. We also established a hypothesis that the SMAD4 and TSC2 mutations improved the efficacy of immunotherapy, prolonging the survival of patients. However, very few studies have investigated the relationship between SMAD4 mutation and immunotherapy in pancreatic cancer. Thus, more studies and clinical trials are needed.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
SZ is the guarantor. YY wrote the manuscript. All authors read, provided feedback, and approved the final version.
Funding
The National Natural Science Foundation of China (81372660), Zhejiang Province Public Welfare Technology Application Research Project (2017C33200), and Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
MRI, magnetic resonance imaging; PET, positron emission tomography; CT, computed tomography; NGS, next generation sequencing; TGF-β, transforming growth factor beta; TMB, tumor mutational burden; MSS, microsatellite stable; MSI, microsatellite instability; MSI-H, high levels of microsatellite instability; ICI, immune checkpoint inhibitor; ORR, objective response rate; PFS, progression-free survival; OS, overall survival. | 1000 MILLIGRAM/SQ. METER, WEEKLY | DrugDosageText | CC BY | 34880877 | 20,296,465 | 2021 |
What was the dosage of drug 'PACLITAXEL'? | Successful Immunotherapy for Pancreatic Cancer in a Patient With TSC2 and SMAD4 Mutations: A Case Report.
Pancreatic cancer has a poor prognosis, and it is traditionally treated with chemotherapy. Fortunately, immunotherapy has rapidly changed the landscape of solid tumor treatment, and improving the survival of cancer patients. However, pancreatic cancer is non-immunogenic, and single agent immunotherapies are unfavorable to its prognosis.
Here, we report a case of stage IV pancreatic cancer in a patient with TSC2 and SMAD4 mutations treated with immunotherapy when the disease progressed after multi-line chemotherapy. Next generation sequencing (NGS) confirmed the presence of TSC2 and SMAD4 mutations and microsatellite stability (MSS). When the disease progressed after chemotherapy, a combination strategy was devised consisting of chemotherapy (S-1) and sintilimab. The patient had a partial response to therapy with this regimen, the lesions were significantly reduced and nearly disappeared. In metastatic pancreatic cancer, responses of this magnitude are rarely seen.
This outcome reveals that this combination can be effective in treating metastatic pancreatic cancer, especially in pancreatic cancer patients with SMAD4 and TSC2 mutations. This may help increase the use of this therapy in large-scale clinical research.
pmcIntroduction
Pancreatic cancer has a high incidence and mortality, and its special structure can protect pancreatic cancer cells from chemotherapeutic agents (1, 2). However, pancreatic cancer is non-immunogenic and single agent immunotherapies are unfavorable to the prognosis of patients. Several clinical trials showed that single agent immunotherapies are ineffective for the treatment of advanced pancreatic cancer (3–5). Moreover, there was a clinical trial confirmed that objective response rate (ORR) was 0 for patients receiving single agent immunotherapies (5).
However, the effect of combination therapy is also not optimistic. As for chemotherapy plus immunotherapy, some clinical trials confirmed that the safety profile of combination therapy at standard doses in advanced pancreatic cancer was manageable (6, 7), but there was no significant improvement in progression-free survival (PFS) and overall survival (OS) (6, 8).
Though, the pancreatic cancer has little response rate to immunotherapy, it may be effective for specific patient. For example, several gene mutations can improve the effective of immunotherapy (9), including high levels of microsatellite instability (MSI-H), POLE, POLD1, et al.
Case Presentation
We present the case of a 56-year-old Chinese man who had been smoking and drinking for decades. He was hospitalized for six months with abdominal pain. In September 2019, magnetic resonance imaging (MRI) of the upper abdomen identified a pancreatic head mass, multiple retroperitoneal enlarged lymph nodes, and abnormal enhancement near the inferior vena cava in right lobe of the liver. Ultrasound guided biopsy of the pancreas was performed. Pathology diagnosis was pancreatic ductal adenocarcinoma (stage IV) ( Figures 1A, B ). Next generation sequencing (NGS) confirmed the tumor was microsatellite stability (MSS), and a total of 6 gene mutations, TSC2, CREBBP, HIST1H3I, MAP2K4, SMAD4, and STK11 were detected. Additionally, frame shift mutation occurred in exon 17 of TSC2 gene (32.13%); missense mutation occurred in exon 9 (7.47%) and nonsense mutation occurred in exon 5 (9.49%) of SMAD4 gene. The NGS confirmed that there were no targeted drug-related gene mutations and the tumor mutational burden (TMB) was 7.1 mut/Mb.
Figure 1 (A, B) pancreatic ductal adenocarcinoma. (A) 200X, (B) 400X. The pancreatic head puncture smear showed significant atypical epithelial mass, irregular nuclei, which was consistent with the changes of adenocarcinoma. (C–F) PET/CT images in April 2020. (C) showed a 6.0cm *6.0 cm mass in pancreatic head (arrow); (D) confirmed enlarged lymph nodes in pancreatic head (arrow), and low-density shadows in liver (within cycle); panels (E, F) revealed enlarged multiple lymph nodes in different sizes in retroperitoneum (arrow).
In October 2019, the patient’s primary oncologist started him on AG (gemcitabine and nab-paclitaxel). The gemcitabine (1000mg/m² over 30 minutes, weekly for 2 weeks, every 21 days) and nab-paclitaxel (125mg/m², weekly for 2 weeks, every 21 days) were administered intravenously. However, in the first three cycles and the fifth cycle of chemotherapy, for several reasons (such as COVID-19), he only received chemotherapeutic agents (AG) on the first day. In March 2020, the repeated MRI showed progressive disease. In late March 2020, the patient developed back pain and underwent endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic metal biliary endoprosthesis (EMBE) due to obstructive jaundice. In April 2020, positron emission tomography/computed tomography (PET/CT) revealed a 6.0 cm × 6.0 cm mass in pancreatic head, multiple enlarged lymph nodes in different sizes were found in pancreatic head and retroperitoneum, and multiple low-density shadows in the liver ( Figures 1C–F ).
Based on these findings, the patient was treated with FOLFIRINOX (oxaliplatin, Irinotecan, calcium folinate and 5-Fluorouracil). However, considering that the patient had just undergone surgery, the patient was asked by his doctor to eat S-1 for 14 days (from April 2, 2020 to April 16, 2020) before he received FOLFIRINOX treatment on April 25, 2020. In June 2020, after 4 cycles of chemotherapy, upper-abdomen enhanced CT revealed that the size of pancreatic head lesion was significantly decreased to 2.3 cm × 2.5 cm ( Figure 2A ), more that 50% decrease, and multiple low-density shadows in the liver. The patient was repeated CT about every two months ( Figures 2B, C ). Until October 2020, the CT only revealed a mass in the pancreatic head, and the lesion was slightly low density with peripheral lymph node metastasis.
Figure 2 Enhanced CT images. The pancreatic mass indicated by the arrow on upper-abdomen enhanced CT took in June 2020 (A), in August 2020 (B), in October 2020 (C) and in November 2020 (D). The pancreatic cancer was responded to chemotherapy initially, but the disease was still progressed at later time. After sintilimab combined with S-1 treatment, the pancreatic lesion was significantly reduced in, and nearly disappeared in June 2021 (E). The hepatic metastases indicated by the arrows on upper-abdomen enhanced CT took in October 2020 (F), and in June 2021 (G). The hepatic metastasis was significantly reduced (G).
In October 2020, the patient underwent one cycle of Olaparib by himself, although he did not have the targeted drug-related gene mutation. On October 16, his abdomen enhanced CT scan revealed multiple liver metastases ( Figure 2F ), and the largest measured 2.3 cm. We changed the chemotherapy regimen to AG again (gemcitabine and nab-paclitaxel). In November 2020, the abdomen enhanced CT scan revealed progressive disease ( Figure 2D ), and the size of the pancreatic head lesion was 6.4 cm.
The patient has undergone multi-line chemotherapy, chemotherapy alone could not inhibit the progression of the disease, and there was no standard treatment after two or more lines of systemic chemotherapy. In addition, his Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was 2, he suffered from severe cancer pain all over the body (OxyContin 30mg, every 12 hours) and weight loss, the aspartate transaminase and alanine transaminase were at normal level, and alkaline phosphatase increased slightly (not higher than 2 times the normal value). Thus, we decided to use chemotherapy (S-1) combined with immunotherapy (sintilimab). Considering the economic status of patient, we decided to choose sintilimab (more economical). The sintilimab is a fully human IgG4 monoclonal antibody; it can bind to PD-1, block the interaction of PD-1 with its ligands, and help recover the anti-tumor response of T-cells, and it has been approved to treat relapsed or refractory classical Hodgkin lymphoma, advanced non-small cell lung cancer and metastatic hepatocellular carcinoma. The anti-tumor effect of sintilimab is similar to that of other anti-PD-1/PD-L1 antibodies (10). Sintilimab was administered intravenously (200mg, every 3 weeks); and S-1was orally (40mg, twice a day orally for 2 weeks, every 21 days). The patient started to receive S-1 on November 24, 2020, and sintilimab on November 27, 2020.
The patient did not come to our hospital again until June 2021 ( Figure 3 ). He said he was treated at a local hospital during these seven months, and received a total of 10 cycles of sintilimab combined with S-1. The performance status was better than before (his PS improved to ECOG-PS 1); his severe cancer pain was well controlled (OxyContin 10mg, every 12 hours). The abdomen enhanced CT scan showed that the intrahepatic metastases ( Figure 2G ) and pancreatic head lesion ( Figure 2E ) were significantly reduced (the size of the pancreatic head lesion was 1 cm). By standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1, the patient had a partial response (more than 80% decrease) to therapy with this regimen. Moreover, throughout his treatment, the CA 19-9 level was always normal.
Figure 3 Timeline of the treament. The patient was diagnosed with pancreatic cancer in September 2019, and received chemotherapy (AG) in October 2019. Before receiving immunotherapy in November 2020, the patient had undergone multi-line chemotherapy (including AG, FOLFIRINOX, AG). And until August 2021 (the latest follow-up), the patient was still receiving immunotherapy combined with chemotherapy.
At the latest follow-up (August 2021), the patient still had a partial response to this regimen (S-1 combined with sintilimab), and the duration of partial response was 8 months.
Discussion
Chemotherapy has been the mainstay of treatment for many malignant tumors, including pancreatic cancer. Due to the lack of effective screening tools, most patients lose the opportunity to undergo surgery, which makes chemotherapy the standard treatment. However, chemotherapy has a poor therapeutic effect on pancreatic cancer due to its aggressive nature. Pancreatic cancer is composed of malignant cells and desmoplastic stroma (1). Desmoplastic stoma serves as a physical barrier that protects pancreatic cancer cells and prevent the effective delivery of chemotherapeutic agents (2).
In this case, the chemotherapy was effective for this patient at first. Additionally, after the disease progressed, the immunotherapy combined with chemotherapy had a significant effect. In the past 5 years, immunotherapy has rapidly changed the landscape of solid tumor treatment. What is more, tumor testing can help patients to get a better treatment. The results of a tumor testing making a patient eligible for treatment with immunotherapy, whose disease (advanced pancreatic cancer) progressed after neoadjuvant chemotherapy and adjuvant chemotherapy (11). Recent studies have identified several positive predictive markers for immune checkpoint inhibitors (ICIs), such as high levels of MSI-H, PD-L1 overexpression, high TMB, and gene mutations (9).
TSC2 is a tumor suppressor gene; it negatively regulates the cellular signaling networks that control cellular growth and proliferation (12). The TSC2 protein forms a complex and functions as a tumor suppressor by inhibiting mTORC1 kinase (13). It has been shown that, in TSC2-deficient tumors, the single-agent PD-1 or CTLA-4 blockade, or a combination of them, can inhibit the growth of tumors (14). Additionally, the combination of PD-1 and CTLA-4 antibody treatment or single-agent treatment can increase CD8+ T-cell infiltration in TSC2-deficient human tumors (14), and the level of infiltration is correlated with the degree of response to therapy.
Transforming growth factor beta (TGF-β) is an immune regulator; it can suppress the immune response via many different mechanisms (15). Moreover, it can inhibit tumor growth at the early stages of disease and promote tumor development at the later stages (16). However, the tumor-suppressive role of TGF-β is only effective when the TGF-β signaling pathway is not defective (17). SMAD4 serves as the central mediator of the TGF-β signaling pathway (18), and it is the only common mediator. The TGF-β/SMAD4 signaling pathway plays a tumor suppressive role in early stages of disease, mainly by inducing cell cycle arrest and apoptosis. TGF-β can stimulate regulatory T-cells, which inhibit the function of other lymphocytes (19). PD-1 is highly expressed on tumor infiltrating lymphocytes; it has been shown that human PD-1 expression may under direct transcriptional control by TGF-β, and TGF-β can enhance the expression of PD-1, suppressing anti-tumor immunity (20). TGF-β inhibits CD8+ T-cell effector function through TGF-β signaling pathway (21). Pancreatic cancer cells have lost their tumor-suppressive roles, but they possess tumor-promoting effects induced by increased TGF-β (22). In a tumor microenvironment, TGF-β expression is very high.
In pancreatic cancer, alterations of TGF-β signaling occur through the mutation of the genes involved in the pathway (including SMAD4); this activity is present in 47% of pancreatic cancer patients (23). The loss of SMAD4 will abrogate the canonical TGF-β/SMAD4 signaling pathway (24), and it may make pancreatic cancer more aggressive (25). It has been shown that SMAD4-deleted pancreatic ductal adenocarcinoma cells are sensitive to agents modulating the cell cycle (26). The loss of SMAD4 counteracted TGF-β-induced cell cycle arrest and apoptosis (27). Furthermore, it has been reported that the loss of SMAD4 expression is significantly associated with better survival after resection (28). The inhibition of TGF-β has been reported to have a variety of antitumor effects (29). A TGF-β blockade can reverse the suppressive effects of apoptotic cells on inflammation and adaptive immunity (30). In T-cell excluded mouse models, immune checkpoint-resistant MSS colorectal cancers and liver tumors were rendered susceptible to anti-PD-1/PD-L1 therapy with a TGF-β blockade (31).
Blockade of immune checkpoints by anti-CTLA-4 or anti-PD-1/anti-PD-L1 agents leads to T-cell activation, and it provides an effective approach for tumor immunotherapy (32). And the high PD-L1 expression may have a better clinical benefit. There was a case report showed that blocking the PD-L1 pathway combined with chemotherapy was effective for pancreatic squamous cell carcinoma patients with high PD-L1 expression (33).
Pancreatic cancer is intrinsically non-immunogenic (34). Single agent immunotherapies are unlikely to be successful in treating this type of cancer (35), but immunotherapy combined with chemotherapy has a synergistic effect (36). Chemotherapeutic agents could promote the release of tumor antigens from the cancer cells and reactivate an anti-cancer immune response to suppress tumor growth (37). Besides, according to several ongoing clinical trials, there are other regimens of combination therapy for the treatment of pancreatic cancer, such as BL-8040 (chemokine receptor type 4 inhibitors) and pembrolizumab combined with chemotherapy (NCT02826486), olaparib plus pembrolizumab (NCT04666740 and NCT04548752), olaparib or selumetinib plus durvalumab (NCT04348045). Additionally, the COMBAT/KEYNOTE-202 Trial (NCT02826486) revealed that the ORR was 21.1%, and the triple combination of BL-8040, pembrolizumab, and chemotherapy was safe and well tolerated, but no significant improvement in PFS and OS (38).
Other ICIs can also improve the effect of therapy. TMB is the total number of mutations per coding area of a tumor gene, which can increase the sensitivity to immunotherapy (39). Generally, we defined TMB ≥ 20 mutations/Mb as high TMB, TMB ≤ 10 mutations/Mb as low TMB. Patients with a high TMB also have a better prognosis with immunotherapy. For example, a higher TMB was associated with better response in non-small cell lung cancer patients receiving pembrolizumab (40). A higher TMB had a clinical benefit in malignant melanoma patients receiving either ipilimumab or tremelimumab (41). Additionally, a case report revealed that combined antiangiogenic therapy and immunotherapy is effective for pancreatic cancer with high TMB (42). However, patients with pancreatic cancer generally have a low TMB in comparison to patients with other malignancies (43). Moreover, pancreatic cancer is a tumor with low immunogenicity, which is attributed to low TMB (36).
Conclusion
In this case, the effect of immunotherapy combined with chemotherapy seems to be very effective. We also established a hypothesis that the SMAD4 and TSC2 mutations improved the efficacy of immunotherapy, prolonging the survival of patients. However, very few studies have investigated the relationship between SMAD4 mutation and immunotherapy in pancreatic cancer. Thus, more studies and clinical trials are needed.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
SZ is the guarantor. YY wrote the manuscript. All authors read, provided feedback, and approved the final version.
Funding
The National Natural Science Foundation of China (81372660), Zhejiang Province Public Welfare Technology Application Research Project (2017C33200), and Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
MRI, magnetic resonance imaging; PET, positron emission tomography; CT, computed tomography; NGS, next generation sequencing; TGF-β, transforming growth factor beta; TMB, tumor mutational burden; MSS, microsatellite stable; MSI, microsatellite instability; MSI-H, high levels of microsatellite instability; ICI, immune checkpoint inhibitor; ORR, objective response rate; PFS, progression-free survival; OS, overall survival. | 125 MILLIGRAM/SQ. METER, WEEKLY | DrugDosageText | CC BY | 34880877 | 20,296,465 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy.
To investigate refractory hypercholesterolemia, a female patient and relatives were subjected to whole-genome sequencing. The proband was found to have compound heterozygous substitutions p. Arg446Gln and c.1118+3G>T in ABCG5, one of two genes causing sitosterolemia. When tracing these variants in the full pedigree, all maternally related heterozygotes for the intronic ABCG5 variant exhibited large platelets (over 30 fl), which segregated in an autosomal dominant manner, consistent with macrothrombocytopenia, or large platelet syndrome which may be associated with a bleeding tendency. In vitro cell-line and in vivo rat model experiments supported a pathogenic role for the variant and the macrothrombocytopenia was recapitulated in heterozygous rats and human cell lines exhibiting that single variant. Ezetimibe treatment successfully ameliorated all the symptoms of the proband with sitosterolemia and resolved the macrothrombocytopenia of the treated heterozygote relatives. Subsequently, in follow up these observations, platelet size, and size distribution were measured in 1,180 individuals; 30 were found to be clinically abnormal, three of which carried a single known pathogenic ABCG5 variant (p.Arg446Ter) and two individuals carried novel ABCG5 variants of uncertain significance. In this study, we discovered that identification of large platelets and therefore a possible macrothrombocytopenia diagnosis could easily be inadvertently missed in clinical practice due to variable instrument settings. These findings suggest that ABCG5 heterozygosity may cause macrothrombocytopenia, that Ezetimibe treatment may resolve macrothrombocytopenia in such individuals, and that increased attention to platelet size on complete blood counts can aid in the identification of candidates for ABCG5 genetic testing who might benefit from Ezetimibe treatment.
pmcBackground
Plasma cholesterol homeostasis is maintained by the synthesis, intestinal absorption, and biliary and fecal excretion of sterols. The biosynthesis of cholesterol is a well-defined energy-consuming and feedback-regulated process (Howe et al., 2016). ATP-binding cassette transporters G5 (ABCG5 gene) and G8 (ABCG8 gene) usually form a heterodimer (G5G8) which inhibits the absorption of cholesterol and plant sterols by promoting the efflux of these sterols from enterocytes back into the gut lumen, and the secretions from hepatocytes into bile (Wang et al., 2015; Lee et al., 2016; Sun et al., 2021). In contrast, sterol transporter Niemann–PickC1-Like1 (NPC1L1) promotes intestinal cholesterol absorption and biliary cholesterol re-absorption (Jia et al., 2011). Together, they maintain sterol balance without direct involvement in sterol synthesis.
Homozygous or compound heterozygous variants in either ABCG5 or ABCG8 cause autosomal recessive sitosterolemia (OMIM 210250) (Myrie et al., 1993; Berge et al., 2000), characterized by elevated plasma levels of plant sterols (Bhattacharyya and Connor, 1974; Myrie et al., 2012; Brautbar et al., 2015). However, patients with ABCG5/8 pathogenic variants show significant phenotypic heterogeneity (Wang et al., 2004). The other features also variably include hypercholesterolemia, xanthomas, xanthelasma, and premature atherosclerosis. Affected individuals may also suffer from diverse hematological alterations such as a decreased platelet count, an increased mean platelet volume (large platelets/macrothrombocytosis or macrothrombocytopenia if accompanied by reduced platelet count), and/or hemolytic anemia.
Management of sitosterolemia aims to reduce plasma plant sterol accumulation. Ezetimibe, a small molecule inhibitor of NPC1L1 approved for the treatment of hypercholesterolemia (Suchy et al., 2011), is considered the preferred treatment for sitosterolemia (Salen et al., 2004; Yu et al., 2005; Salen et al., 2006; Lutjohann et al., 2008; Tsubakio-Yamamoto et al., 2010; Altemus et al., 2014; Erkan, 2014; Hu and Tomlinson, 2014; Othman et al., 2015; Yoo, 2016). Studies using knock-out mouse models have successfully shown that Ezetimibe treatment can correct multiple symptoms, including reduction of large platelets and restoration of the platelet count to some extent, caused by pathogenic variants in ABCG5/8; similarly, clinical trials also show improvement in patients with sitosterolemia after Ezetimibe therapy (Salen et al., 2004; Lutjohann et al., 2008; Tsubakio-Yamamoto et al., 2010; Hu and Tomlinson, 2014; Othman et al., 2015). Nevertheless, the clinical improvement in these patients may be attributed at least in part to plasma cholesterol reduction, and the benefits of reduction of plant sterol storage remain unclear (Ajagbe et al., 2015).
Here we described the identification of two variants of ABCG5 in a proband with apparent autosomal recessive hypercholesterolemia recalcitrant to statin therapy who exhibited large platelets without dysfunction of blood coagulation, neither platelet counts nor their functions. Unexpectedly, large platelets (over 30 fl) were a dominant phenotype in family members heterozygous for the c.1118+3G>T variant in ABCG5. Large platelet syndrome describes a group of unique disorders characterized by the presence of abnormally large platelets and is usually accompanied by thrombocytopenia. Thus, it is also termed macrothrombocytopenia. Functional studies showed that variant can cause deletion of exon 8 in human ABCG5, and disruptions of ABCG5/ABCG8 genes recapitulated the occurrence of hypercholesterolemia and large platelets in rats. These variants were ultimately classified as pathogenic and likely pathogenic. Interestingly, the macrothrombocytosis was also successfully treated with Ezetimibe in heterozygotes in the pedigree. Large platelets can be occasionally seen in individuals without other obvious abnormal hematologic findings, and we further sequenced ABCG5 in a large unrelated cohort of individuals with large platelets to see if ABCG5 variant heterozygosity is a common cause; this study was carried out to determine whether a subset of individuals with large platelets might be expected to respond to Ezetimibe treatment, as an example of the potential application of pharmacogenomics that benefits from genetic analysis (Yu and Hu, 2021).
Methods
Proband Description and Blood Sample Collection
A 6-year-old girl with refractory hypercholesterolemia was referred to our institution for the development of a suitable therapeutic regimen. Before the study, atorvastatin had been administered to the patient for more than 2 years, but her plasma total cholesterol level was decreased to only ∼200 mg/dl and large platelets persisted. Additionally, the patient appeared to have atherosclerotic plaque (6 mm × 7 mm) in her left common carotid artery (Figure 1A, right) upon referral. The patient’s initial presenting clinical and laboratory features included profoundly increased levels of total cholesterol (638 mg/dl) and low-density lipoprotein cholesterol (LDL-C, 527 mg/dl); a reduced level of high-density lipoprotein cholesterol (HDL-C, 46 mg/dl) and a slight elevation of plasma β-sitosterol (3.26 mg/dl). Although there was an elevation of β-sitosterol, criteria for the diagnosis of sitosterolemia were initially felt not to be met (Salen et al., 1985). In addition, the patient had abnormally large platelets (Figure 1A, left); over 41% of her platelets had a size over 30 fl. Clinically, Bernard-Soulier syndrome, of which giant platelets are a feature, was excluded as a plausible diagnosis through examination of clotting time and platelet aggregation, which were all normal in the proband (Table 1).
FIGURE 1 Clinical Phenotypes and Identification of Two Novel Mutations of ABCG5 Gene of the proband in a pedigree family. Panel (A) shows the large platelet in the blood smear (left) and the atherosclerotic plaque by B-mode ultrasound measurement from the proband. Panel (B), a pedigree chart shows the phenotype distribution in all family members and the transmission of two novel variants (Var 1 and Var 2) of ABCG5 in the family. Panel (C) shows the size distribution of platelets (PLT) in the proband and her parents. The dash lines represent the platelets’ volume, and the double dash lines indicate 30 fl, in which 40 fl is the up limitation for the normal distribution of PLT. Panel (D) shows the ABCG5 gene model from the NCBI database and the inserted fragments in the constructs for wild type and Var2 mutant in the splicing pattern assay. The arrows indicate the primer pairs used for the detection of the mRNA products which were transcribed from the constructs. Panel (E) shows the PCR amplification results of two products generated from wild-type and Var2 mutant constructs, respectively. The product from the wild-type construct is 295 bp, and the product for the mutant is 81 bp due to deleting exon 8 of the ABCG5 gene. The truncated transcripts were further verified by Sanger sequencing.
TABLE 1 Clinical characteristics of the family members.
Id Normal value of rang
I-1 I-2 I-3 I-4 II-1 II-2 II-3 II-4 III-1
Gender Male Female Male Female Female Male Female Male Female
Age 69 66 58 52 45 40 34 32 9
TC 169.76 213.46 155.07 200.31 212.69 258.7 134.96 97.84 638.06 <200 mg/dl
LDL-C 99 129.93 96.29 123.74 124.9 163.19 71.54 50.66 527.46 ≤120 mg/dl
HDL-C 49.88 61.49 43.7 51.43 68.83 67.29 53.75 39.06 45.63 50–60 mg/dl
β-Sitosterol 1.06 1.44 1.58 1.14 1.3 1.23 1.52 1.49 3.26 0.31∼0.80 mg/dl
PLT 275 324 172 298 363 240 250 217 289 85-303 10^9/L
PDW 10.5 10.9 NaN 15.4 11.4 12.1 NaN NaN 15.7 11∼26.5 fl
MPV 10.2 10.3 NaN 12 10.6 10.8 NaN NaN 12.1 7.6∼13.2 fl
P-LCR 25 26.1 NaN 39.2 28.5 30.1 NaN NaN 41 13∼43%
PT 11 (9–13) 9.4 (9–13) 10 (9–13) 10 (9–13)
APTT 29 (20–40) 26.8 (20–40) 28 (20–40) 27.3 (20–40)
TT 17.1 (14–24) 15 (14–24) 16.7 (14–24) 15 (14–24)
FIB 3.1 (2–4) 3.84 (2–4) 3.62 (2-4) 3.6 (2–4)
PTA 120 (70–150) 106.8 (70–150) 117 (70–150) 116.5 (70–150)
PAgT 61 (35–75) 65.7 (35–75) 63 (35–75) 64.3 (35–75)
Total cholesterol, TC, Low-density lipoprotein cholesterol; LDL-C, High-density lipoprotein cholesterol; HDL-C, Platelet count; PLT, Platelet distribution width; PDW, Mean platelet volume; MPV, Platelet-large cell ratio; P-LCR, prothrombin time; PT, activated partial thromboplastin time; APTT, thrombin time; TT, fibrinogen coagulative time; FIB, prothrombin time activity; PTA, platelet agglutination test, PAgT.
To track genetic variants in the full pedigree, we also collected blood samples from maternal and paternal relatives (I-1,2,3,4, and II-1,4). DNA was extracted from 400 μl whole blood per sample using the (Qiagen, Hilden, Germany), and all blood samples were stored at −80°C before usage. For screening for candidate ABCG5 variants in a general population, we also enrolled individuals over 2 months in 2019, the Second Affiliated Hospital of Nanchang University, Beijing Anzhen Hospital of Capital Medical University, and Peking University Third Hospital. The samples were examined in the Second Affiliated Hospital of Nanchang University. In all, 30 patients had abnormal platelet size distribution and underwent ABCG5 gene sequencing.
Gene Panel Test for Familial Hypercholesterolemia
We designed a custom panel of DNA oligonucleotide primers covering 216 amplicons using the Ion AmpliSeqTM platform (Supplementary Table S1, Life Technology, Thermo Fisher, USA). These amplicons covered all coding exons of four familial hypercholesterolemia (FH) causal genes (APOB, LDLRAP1, LDLR, and PCSK9). Sequencing Libraries were barcoded (IonXpress Barcode Kit, Life Technologies) and equalized (Ion Library Equalizer Kit) to a final concentration of approximately 100 pM. Emulsion PCR was performed using the OneTouch DL instrument, and template-positive Ion Sphere particles were enriched using the OneTouch ES instrument according to the manufacturer’s instructions. Sequencing was performed on a 318 chip on the Ion Torrent PGM following the recommended protocol. Reads were aligned to hg19 and variants were called using the TorrentSuite (version 4.0.2).
Whole Genome Sequencing Analysis and Identification of Pathogenic Variants
WGS was conducted in the proband and her parents. Each sequencing library with an average insert size of 250 bp was loaded into an Illumina HiSeq X ten. Roughly 90 Gb of high-quality data in 150 bp pair-end reads was obtained for each library, reaching an average of 30-fold genome coverage for each individual. The quality evaluation was performed using FastQC software, and sequences from adapters or having low Q-score were removed with cutadapt software (Martin, 2011). The sequencing reads were mapped to the reference human genome (hg19) by the BWA algorithm (Li and Durbin, 2009). PCR duplicates were removed with Picard software. Processed bam files of humans were processed via local indel realignment and base-quality recalibration using the Genome Analysis Tool Kit (GATK) (McKenna et al., 2010). Subsequently, sorted BAM files were used for SNV calling and the UnifiedGenotyper method based on a Bayesian genotype likelihood model was applied with GATK. All detected SNVs were annotated using ANNOVAR. VarSelect in TGex platform was applied to filter for variants in WGS data of the family trio, to identify variants most likely responsible for the phenotypes of the proband (Dahary et al., 2019).
Blood Test and Analysis of Plasma Sterol Levels
The blood lipid measurements were routinely performed by the second Affiliated Hospital of Nanchang University. β-Sitosterol and other plant sterols were analyzed by liquid chromatography-mass spectrometry (AB SCIEX Triple Quad 4500) according to previous studies(Kasama et al., 1987; Hidaka et al., 1990). For each sample, a volume of 20 μl was injected into Agilent Eclipse Plus reversed-phase column (C18, 2.1 × 50 mm). The column temperature was maintained at 35°C. The mobile phase was acetonitrile-methanol (4:1, v/v) at a flow rate of 0.6 ml/min. The mass spectrometer was operated in positive ion polarity mode in the extended dynamic range (1,700 m/z, 2 GHz) with the following parameters: Curtain Gas (GUR) 40 psi; Collision Gas (CAD) 9; IonSpray Voltage (IS) 5,500.0 V; Temperature (TEM) 350°C; Ion Source Gas 1 (GS1) 50 psi; NC 3V. Blood samples from 10 healthy individuals were examined as control samples.
Platelet Size Analysis
Two ml of peripheral blood was collected using standardized tubes (INSEPACK ST serials, Beijing, China) and all tubes were stored at room temperature. Within 30 min, these samples were analyzed on SysmexXE-2100 Haematology System (Sysmex Corporation, Kobe, Japan) for lipid profile and coagulation tests following the methods previously developed protocols (Table 1) (Barsam et al., 2011; Depoorter et al., 2015). Large platelets are identified based on the volume (>30 fl). For each sample, we prepared two blood films dyed by Wright’s dye for platelet morphology analysis using a BX53 microscope (OLYMPUS, Japan). The criteria for large platelets is a diameter greater than 4 microns. All blood films were reviewed by two independent examiners.
Splicing Pattern Assay for ABCG5 Var2
Var2 is located at a splice region of ABCG5, and we performed the splicing pattern assay to verify its functional effect. Genomic DNAs including reference (WT) or ABCG5 variant were isolated from peripheral whole blood of all individuals in the study with Blood Genomic DNA Mini Kit (CWBIO, CW 2087S) and PCR was performed using PrimeSTAR® MaxDNA Polymerase (TAKARA, R045A). The 947 bp PCR fragments of ABCG5 gene, spanning from part of exon 7 (44 bp) to part of exon 9 (37 bp) with exon8 (214 bp) and its flanking intron 7 and 8, were amplified by the primer pair, ABCG5-minigene_Forward (5′-GCGGTACCGCGGAAATGCTTGATTTCTT-3′) with KpnI restriction site and ABCG5-minigene_Reverse (5′-GCCTCGAG TTAAAGGAGGAACAAACCCATGA-3′) with XhoI restriction site. The genomic fragments (both WT and variant, MT) containing the intron of interest were cloned into the pcDNATM-3.1 (+) vector and then all cloned plasmids were verified by sequencing to confirm whether the insertion contained the WT or MT.
HepG2 cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). After seeded in 6-well plates for 24 h, HepG2 cells were transiently transfected with 1ug prepared vectors with the allele of the WT or MT and corresponding empty vectors respectively, using Superfectin II In Vitro siRNA Transfection Reagent (Shanghai Pufei Biotech). After 48 h, total RNA was extracted by TRIzol reagent (Invitrogen) and 1 mg total RNA was used for reverse transcription using PrimeScript RT reagent kit with gDNA eraser (Takara) according to the manufacturer’s instructions. The primer sequences of quantitative RT-PCR were: ABCG5-MGQ_Forward (5′-CGGTTACCCTTGTCCTGAAC-3′) located in exon 7 and ABCG5-MGQ_Reverse (5′-TGCCAGCTTATTTCTCACCA-3′) located in exon 9. Quantitative RT-PCR was performed with SYBR Green dye using ViiA7Real-Time PCR System (Applied Biosystems). The relative mRNA expression was calculated by the comparative Ct method using GAPDH as a control. PCR reactions were performed in triplicate. The RT-PCR products were separated on a 2% agarose gel and detected with Chemidoc Xrs Gel Doc Xr (Bio-Rad Universal Hood Ii 2, USA).
Generation of ABCG5/ABCG8 Double Knockout Rat
ABCG5/ABCG8 double knockout rat model was created by Beijing Biocytogen. In brief, a 19 Kb region was knocked out using a CRISPR/Cas9 system, with two sgRNAs targeting one site in the intron 4 of ABCG5, and the other in the intron 6 of ABCG8. The design was adapted from the protocol developed by Yu L, et al. The sgRNA activity was evaluated by the UCATM (Universal CRISPR Activity Assay), developed by Biocytogen. By zygote microinjection, transferred zygotes of SD rats were obtained and the founders were positively confirmed by PCR product sequencing. The genotyping primers were Forward: 5′-ctaggtccaccaagccatgtgaaca and Reverse: 5′-attttctgggcaccctgtgttccac. The animal study was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University (SYXK-20150001).
Sanger Sequencing of ABCG5
Exon amplification was performed using LA Taq (Takara, Osaka, Japan). Supplementary Table S2 listed all the primers for amplification of 13 exons of ABCG5 extending 50 bp towards both upstream and downstream to cover the splice regions and corresponding PCR protocols for each primer pair. All reactions were performed on a PTC-200 Peltier Thermal Cycler (MJ Research, MA, USA). PCR products were sequenced by Sangon Biotech (Shanghai, China), and the results were manually checked using SeqMan (DNAstar 5.0, WI, USA).
Statistical Analysis
The t-test was used to compare the mean difference of the blood lipid levels in the rat model using R 3.4(R Core Development Team, 2018).
Results
Identification of Compound Heterozygous Variants in ABCG5
This proband had hypercholesterolemia with atypical changes in the β-Sitosterol level in comparison with previous reports (Supplementary Table S3). To identify pathogenic variants responsible for the hypercholesterolemia of the proband, a customized Gene Panel Test was initially performed to screen for variants within all coding regions of four common familial hypercholesterolemia genes: APOB, LDLR, LDLRAP1, and PCSK9. The sequencing results showed that no family member carried any rare coding variants (<1%, MAF in CHB of 1,000 genomes) in these genes. Next, we performed WGS for the proband and her parents (∼30X coverage on average for each person). Two heterozygous variants of the ABCG5 gene were found in the proband, and no other variant was observed in the known genes related to hypercholesterolemia. The proband inherited Var1 (chr2:44050062G/T, NM_022436.3:c.1337G>A, p. Arg446Gln) from her father and Var2 (chr2:44051355T/G, splice region, c.1118+3G>T) from her mother. These two variants (Var1 and Var2) were further verified by Sanger sequencing (Supplementary Figure S1).
Var1 was reported to be a variant of uncertain significance for sitosterolemia in both Clinvar (Accession: VCV000289811) and gnomAD (2-44050062-C-T, allele frequency: 6.74e-5 and no homozygote). While at the same position, p. Arg446Ter (Accession: VCV000030485), has been previously reported as pathogenic for sitosterolemia and hypercholesterolemia (Wang et al., 2014; Buonuomo et al., 2017; Pek et al., 2018). Var2 was not documented in either Clinvar or gnomAD; it was predicted to be a splice site variant. The blood total cholesterol level of the proband was similar to the level in previously reported individuals with biallelic ABCG5 variants, ranging from 116 mg/dl to 870 mg/dl (Supplementary Table S3).
Subsequently, these two variants were examined in all family members. The results showed that these variants were transmitted across all three generations in heterozygous form (Figure 1B). Var1 was specific to the paternal side, and Var2 was only detected in the maternal lineage. However, individual I-1 did not carry any variants in the ABCG5 gene. In addition, all maternal members heterozygous for Var2 exhibited the large platelet phenotype without dysfunction of blood coagulation (Figure 1C; Table 1; Supplementary Figure S2).
Functional Assessment of Var2 Mutation
Since Var2 was predicted to be a splice site variant, we examined if Var2 can result in novel splicing transcripts of ABCG5 (Figure 1D). As shown in Figure 1E, the mRNA transcripts from the reference and Var2 fragments were 295 bp and less than 100 bp, respectively. Subsequent Sanger sequencing verified that this “truncated” transcript was 81 bp and excluded exon 8. Therefore, this result suggests that Var2 leads to deletion of exon 8 of ABCG5 during transcription, and the creation of a premature termination codon triggering nonsense-mediated mRNA decay.
Treatment With Ezetimibe
Before the study, atorvastatin 10 mg/day was first administered to the proband and her plasma LDL-C level gradually decreased to around 200 mg/dl within 2 years (Figure 2A). Although the proband’s serum LDL-C level was reduced to about 150 mg/dl when atorvastatin was increased to 20 mg/day, she experienced severe adverse effects (Supplementary Table S4). By reducing atorvastatin back to 10 mg/day, the proband’s LDL-C level remained around 200 mg/dl.
FIGURE 2 Ezetimibe Corrected the Phenotypes of the Proband. Panel (A) shows the changes in the LDL-C levels under an optimized treatment regimen. Panel (B) shows the disappearance of the aforementioned atherosclerotic plaque revealed by the ultrasound scan after Ezetimibe treatment. Panel (C) shows the comparison of platelet size distributions before and after Ezetimibe treatment in the proband. Panel (D) shows the disappearance of the large platelet in the blood smear of the proband after treatment of Ezetimibe.
Considering the insufficient response to atorvastatin which aims to inhibit cholesterol biosynthesis, we suspected that the proband may have an abnormality in cholesterol excretion instead. At that point, the treating physician suggested stopping cow milk intake (450 ml/day), following a similar infant case with a limited increase in β-Sitosterol where breastfeeding was arrested to ameliorate the symptoms (Rios et al., 2010).
After 1 month, the proband’s LDL-C level was reduced to 130 mg/dl without further decrease. The effect caused by the reduction of cholesterol intake supported the hypothesis of a cholesterol excretion dysfunction since this strategy is not effective for individuals with abnormal cholesterol synthesis. WGS analysis identified compound heterozygous variants in ABCG5 responsible for abnormal cholesterol excretion consistent with the known disorder sitosterolemia, which supported our hypothesis. Following this finding, the physician in our group recommended a combination of atorvastatin (10 mg/day) and Ezetimibe (10 mg/day) be administered to the proband.
Within 2 months, the patient’s LDL-C level was further decreased to an optimal level (<80 mg/dl). After treatment for 39 months, atorvastatin was discontinued but Ezetimibe treatment was continued with no milk intake. Thus far, the patient’s LDL-C level has been maintained at around 80 mg/dl without any obvious adverse effects. An ultrasound scan 2 months following the revised treatment showed that the proband’s atherosclerotic plaque disappeared from her left carotid artery (Figure 2B).
Interestingly, the proband’s macrothrombocytopenia nearly completely resolved within 1 month after the addition of Ezetimibe while the β-Sitosterol level was reduced to normal values (0.83 mg/dl). The size distribution of platelets normalized, and only 25% of platelets remained over 30 fl (Figures 2C,D). ABCG5 functional inactivation leads to relatively active NIPIC, targeting the NIPIC by Ezetimibe was shown to restore the balance of cholesterol absorption and excretion maintained by them. These results suggested that the macrothrombocytopenia of the proband was likely caused by the ABCG5 variant. More unexpectedly, all Var2 heterozygotes in the family had large platelets, and after 1 month of Ezetimibe treatment alone, the macrothrombocytopenia of her maternal uncle (II-2, Figure 2) also disappeared (Supplementary Figure S3).
Disruptions of the ABCG5/ABCG8 genes mimic phenotypes of the proband in double knockout rat.
To further determine if heterozygotes of ABCG5/ABCG8 genes could drive hypercholesterolemia and macrothrombocytopenia phenotypes, we created a double knockout rat (Figure 3A), having a growth curve similar to the WT strain without visible abnormalities (Supplementary Figure S4A) and succesful depletion of ABCG5 and ABCG8 expression in liver and intestine (Supplementary Figure S4B). As expected, the G5G8--/-- rats had a significant elevation of blood lipid levels (Figure 3B, left) with large platelets (4 out of 6 animals) compared with wild-type rats. However, the alterations in blood lipids were not strictly correlated with the occurrence of large platelets (Figure 3B, right), further supporting the observations of phenotypic heterogeneity of ABCG5/ABCG8 variants. In particular, one heterozygous rat (G5G8+ +/- -) also had this biased distribution of platelet size (Figure 3C), similar to the maternal kindred with Var2, suggesting that heterozygotes of this ABCG5 variant might be sufficient to cause macrothrombocytopenia. Considering these functional studies, Var2 may be classified as “Likely pathogenic” according to the standards and guidelines of the American College of Medical Genetics and Genomics (ACMG) (Richards et al., 2015): in this case PS3, our functional studies show a deleterious effect; PM2, absent in population databases. Addtionally, the homozygous KO rats had significantly higher β-Sitosterol level (mean, 7 mg/dl) than WT strain (mean, 2.5 mg/dl) when even being fed by normal diet. We further treated 2 KO rats with Ezetimibe 0.2mg/Kg. Their serum TC reduced from 2.3 and 2.4 mmol/L to 1.7 and 1.9 mmol/L , and β-Sitosterol level reduced from 6.5 and 7.5 mg/dl to 2.6 and 2.7 mg/dl.
FIGURE 3 Disruptions of ABCG5/8 Genes Mimicked the Phenotypes of the Proband in the Double Knockout Rats. Panel (A) shows the strategy for the generation of ABCG5/8 double knockout using the CAS9/sgRNA system. Panel (B) showed significantly increased blood lipid levels (left) and the large platelet (right) in the homozygotes compared with two other groups. For each group, the blood lipid levels and the large platelet were determined from randomly selecting rats. The values of the blood lipid levels are expressed as the mean ± SE. n = 6. *p < 0.05, **p < 0.01. The large platelet was detected in over 80% of homozygotes, and none was found in the wild-type strain. Panel (C) shows a blood smear for three groups of the rat model.
Screening for ABCG5 Variant Carriers in the General Population
We decided to determine whether ABCG5 variants are associated with large platelets in the general population. Routine automated blood cell counting systems differentiate blood cells by their size and do not recognize large platelets as platelets, these instruments may not accurately detect macrothrombocytopenia. The mean platelet volume also does not reflect actual platelet size in the case of large platelets. Platelet count should therefore be determined manually in a calculating chamber or on peripheral blood smears when suspecting the condition. On routine clinical laboratory examination, biased platelet distribution can be observed, with an abnormal “NaN” value instead of specific values. Without other indicators, large platelets may be easily overlooked.
Here, we intended to examine if platelet size could be used to identify ABCG5 heterozygotes (Methods). We collected platelet size distribution results for all individuals having this examination within 2 months in several hospitals. Among 1,180 individuals screened, 30 had evidence of large platelets (>30 fl, Supplementary Figure S5). In ABCG5 sequencing of the 30 individuals (Figure 4, Supplementary Table S5), we identified a known pathogenic variant (p.Arg446Ter, gnomad:2-44050063-G-A; allele frequency:1.70e-4 and no homozygotes) in one individual. In addition, two novel variants, Var3 (hg19-chr2:44039644, NM_022436:c.*610_*611insCCCAGTGATTTTACTGAGGATTA) and Var4 (hg19-chr2:44039650, NM_022436:c.*604_*605insTACAGAGCACCCAGTGATTTTACTGA,hg19), insertions in 3’ UTR region, were also identified in three other individuals, respectively. These are classified as variants of uncertain significance (no record in gnomAD, thus only having PM2 evidence according to ACMG standards and guidelines). Hence, this population-based work along with segregation of an ABCG5 variant in a large pedigree with sitosterolemia identifies heterozygosity for specific ABCG5 variants as an additional genetic cause of macrothrombocytopenia. Our data suggest that 2.5% of individuals requiring complete blood counts may have large platelets, and roughly 10% of those with large platelets may have ABCG5 variants that are causative. Therefore, screening for large platelets may be helpful to identify heterozygotes for ABCG5 pathogenic variants; conversely, sequencing ABCG5 in individuals with large platelets may be useful in identifying patients amenable to Ezetimibe treatment, if it were shown to be effective and beneficial in future large clinical trials.
FIGURE 4 Nine ABCG5 variants in 30 individuals with abnormal platelet size distribution. Details of each variation are in Supplementary Table S4. Genetic variations of them are more commonly seen in the 3′UTR of the gene model. Except for 3 pathogenic and likely pathogenic variations are heterozygotes in affected individuals, other variations are all homozygotes.
Discussion
We identified a proband with profound hypercholesterolemia, recalcitrant to atorvastatin therapy. The pedigree analysis did not support dominant inheritance and gene panel testing for several genes associated with FH was non-diagnostic. ABCG5 Var1 did not behave in a classical dominant way that most other variants responsible for FH lead to abnormal lipid levels of affected individuals when they were young. It is important to note that the increased lipid levels of paternal individuals may be confounded by lifestyles that promote hyperlipidemia. Additionally, this family appears to show an allele dosage effect where heterozygous carriers of a single putative pathogenic variant result in mild signs/symptoms, especially macrothrombocytopenia.
Hematological alterations have long been noticed in individuals with sitosterolemia, such as decreased platelet counts, increased mean platelet volume, and/or hemolytic anemia (Wang et al., 2004; Patel, 2014; Ajagbe et al., 2015). In addition to hypercholesterolemia, the proband had large platelets. Sitosterolemia can cause both phenotypes. Unexpectedly, all heterozygotes for Var2 in the maternal lineage exhibited large platelets without any changes in blood lipid profile. This is the first study to report a sign or symptom caused by heterozygosity for an ABCG5 variant.
It has been long noticed that homozygous mutant mice with disruption of Abcg5 and Abcg8, Del (17Abcg5-Abcg8)1Hobb, have increased mean platelet volume (Yu et al., 2002). Nevertheless, this had not been previously reported in heterozygotes. We generated an ABCG5/8 double knockout rat, which illustrated that heterozygous ABCG5 variants can lead to large platelets independent of hypercholesterolemia. Moreover, this trait was successfully corrected by Ezetimibe treatment in alone both the compound heterozygous proband and heterozygote II-4. Additionally, our preliminary experiment showed that Ezetimibe resolved both hypercholesterolemia and macrothrombocytopenia in two knockout rats. Taken together, Ezetimibe treatment can improve platelet production via unknown mechanisms.
Large platelets are usually accompanied by thrombocytopenia. Thus, it is also termed macrothrombocytopenia. Macrothrombocytopenia is usually due to acquired disorders; inherited large platelet disorders are rare. The mechanisms of large platelet formation and thrombocytopenia are poorly understood. Treatment for acquired versus inherited forms differs. Several different genes have been implicated as causes (Saito et al.). The most common clinical manifestation of inherited large platelets includes bleeding tendency (Mhawech and Saleem, 2000). Platelet count is usually decreased along with their increased size, which explains the abnormal blood coagulation. Overall, Var2 carriers other than the proband seem to be asymptomatic, similar to a few cases exhibiting large platelet syndrome. It is noteworthy that individual I-3 exhibited cerebral ischemic stroke at the age of 58, with normal blood pressure and lipid profile. Particularly, previous studies pointed out the large platelets may increase the stroke risk (O'Malley et al., 1995; Bath et al., 2004). Recently, it has also been reported that heterozygous carriers of ABCG5 variants had a 2-fold increase in the risk of coronary artery disease (Nomura et al., 2020). Therefore, determining the disease risk of Var2 carriers may require future evaluation in cohort studies, as a potential benefit for Ezetimibe treatment in these carriers.
Frequencies of pathogenic variants of ABCG5 should be quite low in the general population; by July 2021, pathogenic or likely pathogenic variants have been reported for 66 cases in ClinVar, and the allele frequency is about 0.04% (126/282856) in gnomAD (2.1.1). The present study, however, found a high prevalence of ABCG5 variants in a general population with large platelets. Screening for large platelets, therefore, may be helpful to identify heterozygotes for ABCG5 pathogenic variants; conversely, sequencing ABCG5 in individuals with large platelets may be useful in identifying patients amenable to Ezetimibe treatment, since a heterozygous family member with large platelets responded to this treatment.
Generally, physicians may only review the average volume/size of platelets, such as mean platelet volume (MPV), examined by the automated blood cell counting systems. But they may commonly ignore an abnormal “NaN” value of MVP in the system report, which stands for a biased platelet size distribution, particularly when patients have normal functions of blood coagulation as our observation in this pedigree. Here we showed the abnormal “NaN” value of MVP stood for the occurrence of large platelets over 30 fl, which can be the only symptom for some carriers of ABCG5 variants. In addition, this volume is equivalent to spheres 4 microns in diameter to identify large platelets, which we adopted at the criteria in the blood film examination. Our study suggested the review of abnormal platelet size distribution may help to identify these carriers more easily. Meanwhile, they may have an increased risk of other complications such as stroke. Further larger studies could incorporate improved methods for detection of large platelets, identification of ABCG5 variants in those with large platelets, the risk of clinical complications in such patients, and the effects of Ezetimibe treatment.
Conclusion
In summary, WGS and plant sterol analysis of a family trio identified sitosterolemia in a proband with recalcitrant hypercholesterolemia and macrothrombocytopenia; she was found to have compound heterozygous variants in the ABGC5 gene. Diagnosis confirmed in this manner guided appropriate therapeutic decisions, leading to clinical improvement. Interestingly, the therapeutic regimen not only reduced the proband’s blood cholesterol level to normal levels but also resolved macrothrombocytopenia. In the course of the evaluation, ABCG5 heterozygosity was identified as a cause of autosomal dominant inherited macrothrombocytopenia; the role of ABCG5 in macrothrombocytopenia and its therapy with Ezetimibe should be further investigated.
We thank the families for their participation in this study.
Data Availability Statement
The detailed methods described above and other measurements/assays for plasma cholesterols and platelets were available in the Supplementary Appendix of the full text of this article. WGS and Gene panel raw data are available from the corresponding author on reasonable request with consent from the patient family. VCF files for variants in ABCG5 genes and the Gene panel are publically available at https://github.com/humangenetest/ABCG5variants.
Ethics Statement
The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University (IRB#2016-3). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. The animal study was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.
Author Contributions
HX, LD, and DZ designed the study, planned experiments. LD, DZ, and JX, analyzed data, and drafted the manuscript. JX, QC, BY, XL, and XW collected the clinical samples, performed the required examinations, and analyzed clinical information. LD, WC, SG, and ZC designed and performed the sequencing analysis of the pedigree. ZC, YX, and KD performed the cell-line functional analysis and analyzed the data for the animal model. HX, LD, RS, DZ, and SS interpreted data and participated in manuscript preparation. All authors reviewed the manuscript and agreed with the final version.
Funding
Supported by the National Natural Science Foundation of China (81260021, 82060112, and 81660041 to LD, 91639106, 81270202, 91339113 to HX); Jiangxi Provincial Department of Science and Technology, China (20122BCB24023 to HX and 20142BCB24001 to KD); 111 Project (Project No: B13003 to DZ).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgene.2021.769699/full#supplementary-material
Click here for additional data file.
Abbreviations
ABCG5, ATP-binding cassette transporters G5; ABCG8, ATP-binding cassette transporters G8; NPC1L1, Niemann–PickC1-Like1; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; WGS, whole genome sequencing; FH, familial hypercholesterolemia; GATK, Genome Analysis Tool Kit; ACMG, American College of Medical Genetics and Genomics; MPV, mean platelet volume; PLT, platelet; fL, femtoliters. | ATORVASTATIN CALCIUM, EZETIMIBE | DrugsGivenReaction | CC BY | 34880906 | 20,467,869 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'. | Remediation of ABCG5-Linked Macrothrombocytopenia With Ezetimibe Therapy.
To investigate refractory hypercholesterolemia, a female patient and relatives were subjected to whole-genome sequencing. The proband was found to have compound heterozygous substitutions p. Arg446Gln and c.1118+3G>T in ABCG5, one of two genes causing sitosterolemia. When tracing these variants in the full pedigree, all maternally related heterozygotes for the intronic ABCG5 variant exhibited large platelets (over 30 fl), which segregated in an autosomal dominant manner, consistent with macrothrombocytopenia, or large platelet syndrome which may be associated with a bleeding tendency. In vitro cell-line and in vivo rat model experiments supported a pathogenic role for the variant and the macrothrombocytopenia was recapitulated in heterozygous rats and human cell lines exhibiting that single variant. Ezetimibe treatment successfully ameliorated all the symptoms of the proband with sitosterolemia and resolved the macrothrombocytopenia of the treated heterozygote relatives. Subsequently, in follow up these observations, platelet size, and size distribution were measured in 1,180 individuals; 30 were found to be clinically abnormal, three of which carried a single known pathogenic ABCG5 variant (p.Arg446Ter) and two individuals carried novel ABCG5 variants of uncertain significance. In this study, we discovered that identification of large platelets and therefore a possible macrothrombocytopenia diagnosis could easily be inadvertently missed in clinical practice due to variable instrument settings. These findings suggest that ABCG5 heterozygosity may cause macrothrombocytopenia, that Ezetimibe treatment may resolve macrothrombocytopenia in such individuals, and that increased attention to platelet size on complete blood counts can aid in the identification of candidates for ABCG5 genetic testing who might benefit from Ezetimibe treatment.
pmcBackground
Plasma cholesterol homeostasis is maintained by the synthesis, intestinal absorption, and biliary and fecal excretion of sterols. The biosynthesis of cholesterol is a well-defined energy-consuming and feedback-regulated process (Howe et al., 2016). ATP-binding cassette transporters G5 (ABCG5 gene) and G8 (ABCG8 gene) usually form a heterodimer (G5G8) which inhibits the absorption of cholesterol and plant sterols by promoting the efflux of these sterols from enterocytes back into the gut lumen, and the secretions from hepatocytes into bile (Wang et al., 2015; Lee et al., 2016; Sun et al., 2021). In contrast, sterol transporter Niemann–PickC1-Like1 (NPC1L1) promotes intestinal cholesterol absorption and biliary cholesterol re-absorption (Jia et al., 2011). Together, they maintain sterol balance without direct involvement in sterol synthesis.
Homozygous or compound heterozygous variants in either ABCG5 or ABCG8 cause autosomal recessive sitosterolemia (OMIM 210250) (Myrie et al., 1993; Berge et al., 2000), characterized by elevated plasma levels of plant sterols (Bhattacharyya and Connor, 1974; Myrie et al., 2012; Brautbar et al., 2015). However, patients with ABCG5/8 pathogenic variants show significant phenotypic heterogeneity (Wang et al., 2004). The other features also variably include hypercholesterolemia, xanthomas, xanthelasma, and premature atherosclerosis. Affected individuals may also suffer from diverse hematological alterations such as a decreased platelet count, an increased mean platelet volume (large platelets/macrothrombocytosis or macrothrombocytopenia if accompanied by reduced platelet count), and/or hemolytic anemia.
Management of sitosterolemia aims to reduce plasma plant sterol accumulation. Ezetimibe, a small molecule inhibitor of NPC1L1 approved for the treatment of hypercholesterolemia (Suchy et al., 2011), is considered the preferred treatment for sitosterolemia (Salen et al., 2004; Yu et al., 2005; Salen et al., 2006; Lutjohann et al., 2008; Tsubakio-Yamamoto et al., 2010; Altemus et al., 2014; Erkan, 2014; Hu and Tomlinson, 2014; Othman et al., 2015; Yoo, 2016). Studies using knock-out mouse models have successfully shown that Ezetimibe treatment can correct multiple symptoms, including reduction of large platelets and restoration of the platelet count to some extent, caused by pathogenic variants in ABCG5/8; similarly, clinical trials also show improvement in patients with sitosterolemia after Ezetimibe therapy (Salen et al., 2004; Lutjohann et al., 2008; Tsubakio-Yamamoto et al., 2010; Hu and Tomlinson, 2014; Othman et al., 2015). Nevertheless, the clinical improvement in these patients may be attributed at least in part to plasma cholesterol reduction, and the benefits of reduction of plant sterol storage remain unclear (Ajagbe et al., 2015).
Here we described the identification of two variants of ABCG5 in a proband with apparent autosomal recessive hypercholesterolemia recalcitrant to statin therapy who exhibited large platelets without dysfunction of blood coagulation, neither platelet counts nor their functions. Unexpectedly, large platelets (over 30 fl) were a dominant phenotype in family members heterozygous for the c.1118+3G>T variant in ABCG5. Large platelet syndrome describes a group of unique disorders characterized by the presence of abnormally large platelets and is usually accompanied by thrombocytopenia. Thus, it is also termed macrothrombocytopenia. Functional studies showed that variant can cause deletion of exon 8 in human ABCG5, and disruptions of ABCG5/ABCG8 genes recapitulated the occurrence of hypercholesterolemia and large platelets in rats. These variants were ultimately classified as pathogenic and likely pathogenic. Interestingly, the macrothrombocytosis was also successfully treated with Ezetimibe in heterozygotes in the pedigree. Large platelets can be occasionally seen in individuals without other obvious abnormal hematologic findings, and we further sequenced ABCG5 in a large unrelated cohort of individuals with large platelets to see if ABCG5 variant heterozygosity is a common cause; this study was carried out to determine whether a subset of individuals with large platelets might be expected to respond to Ezetimibe treatment, as an example of the potential application of pharmacogenomics that benefits from genetic analysis (Yu and Hu, 2021).
Methods
Proband Description and Blood Sample Collection
A 6-year-old girl with refractory hypercholesterolemia was referred to our institution for the development of a suitable therapeutic regimen. Before the study, atorvastatin had been administered to the patient for more than 2 years, but her plasma total cholesterol level was decreased to only ∼200 mg/dl and large platelets persisted. Additionally, the patient appeared to have atherosclerotic plaque (6 mm × 7 mm) in her left common carotid artery (Figure 1A, right) upon referral. The patient’s initial presenting clinical and laboratory features included profoundly increased levels of total cholesterol (638 mg/dl) and low-density lipoprotein cholesterol (LDL-C, 527 mg/dl); a reduced level of high-density lipoprotein cholesterol (HDL-C, 46 mg/dl) and a slight elevation of plasma β-sitosterol (3.26 mg/dl). Although there was an elevation of β-sitosterol, criteria for the diagnosis of sitosterolemia were initially felt not to be met (Salen et al., 1985). In addition, the patient had abnormally large platelets (Figure 1A, left); over 41% of her platelets had a size over 30 fl. Clinically, Bernard-Soulier syndrome, of which giant platelets are a feature, was excluded as a plausible diagnosis through examination of clotting time and platelet aggregation, which were all normal in the proband (Table 1).
FIGURE 1 Clinical Phenotypes and Identification of Two Novel Mutations of ABCG5 Gene of the proband in a pedigree family. Panel (A) shows the large platelet in the blood smear (left) and the atherosclerotic plaque by B-mode ultrasound measurement from the proband. Panel (B), a pedigree chart shows the phenotype distribution in all family members and the transmission of two novel variants (Var 1 and Var 2) of ABCG5 in the family. Panel (C) shows the size distribution of platelets (PLT) in the proband and her parents. The dash lines represent the platelets’ volume, and the double dash lines indicate 30 fl, in which 40 fl is the up limitation for the normal distribution of PLT. Panel (D) shows the ABCG5 gene model from the NCBI database and the inserted fragments in the constructs for wild type and Var2 mutant in the splicing pattern assay. The arrows indicate the primer pairs used for the detection of the mRNA products which were transcribed from the constructs. Panel (E) shows the PCR amplification results of two products generated from wild-type and Var2 mutant constructs, respectively. The product from the wild-type construct is 295 bp, and the product for the mutant is 81 bp due to deleting exon 8 of the ABCG5 gene. The truncated transcripts were further verified by Sanger sequencing.
TABLE 1 Clinical characteristics of the family members.
Id Normal value of rang
I-1 I-2 I-3 I-4 II-1 II-2 II-3 II-4 III-1
Gender Male Female Male Female Female Male Female Male Female
Age 69 66 58 52 45 40 34 32 9
TC 169.76 213.46 155.07 200.31 212.69 258.7 134.96 97.84 638.06 <200 mg/dl
LDL-C 99 129.93 96.29 123.74 124.9 163.19 71.54 50.66 527.46 ≤120 mg/dl
HDL-C 49.88 61.49 43.7 51.43 68.83 67.29 53.75 39.06 45.63 50–60 mg/dl
β-Sitosterol 1.06 1.44 1.58 1.14 1.3 1.23 1.52 1.49 3.26 0.31∼0.80 mg/dl
PLT 275 324 172 298 363 240 250 217 289 85-303 10^9/L
PDW 10.5 10.9 NaN 15.4 11.4 12.1 NaN NaN 15.7 11∼26.5 fl
MPV 10.2 10.3 NaN 12 10.6 10.8 NaN NaN 12.1 7.6∼13.2 fl
P-LCR 25 26.1 NaN 39.2 28.5 30.1 NaN NaN 41 13∼43%
PT 11 (9–13) 9.4 (9–13) 10 (9–13) 10 (9–13)
APTT 29 (20–40) 26.8 (20–40) 28 (20–40) 27.3 (20–40)
TT 17.1 (14–24) 15 (14–24) 16.7 (14–24) 15 (14–24)
FIB 3.1 (2–4) 3.84 (2–4) 3.62 (2-4) 3.6 (2–4)
PTA 120 (70–150) 106.8 (70–150) 117 (70–150) 116.5 (70–150)
PAgT 61 (35–75) 65.7 (35–75) 63 (35–75) 64.3 (35–75)
Total cholesterol, TC, Low-density lipoprotein cholesterol; LDL-C, High-density lipoprotein cholesterol; HDL-C, Platelet count; PLT, Platelet distribution width; PDW, Mean platelet volume; MPV, Platelet-large cell ratio; P-LCR, prothrombin time; PT, activated partial thromboplastin time; APTT, thrombin time; TT, fibrinogen coagulative time; FIB, prothrombin time activity; PTA, platelet agglutination test, PAgT.
To track genetic variants in the full pedigree, we also collected blood samples from maternal and paternal relatives (I-1,2,3,4, and II-1,4). DNA was extracted from 400 μl whole blood per sample using the (Qiagen, Hilden, Germany), and all blood samples were stored at −80°C before usage. For screening for candidate ABCG5 variants in a general population, we also enrolled individuals over 2 months in 2019, the Second Affiliated Hospital of Nanchang University, Beijing Anzhen Hospital of Capital Medical University, and Peking University Third Hospital. The samples were examined in the Second Affiliated Hospital of Nanchang University. In all, 30 patients had abnormal platelet size distribution and underwent ABCG5 gene sequencing.
Gene Panel Test for Familial Hypercholesterolemia
We designed a custom panel of DNA oligonucleotide primers covering 216 amplicons using the Ion AmpliSeqTM platform (Supplementary Table S1, Life Technology, Thermo Fisher, USA). These amplicons covered all coding exons of four familial hypercholesterolemia (FH) causal genes (APOB, LDLRAP1, LDLR, and PCSK9). Sequencing Libraries were barcoded (IonXpress Barcode Kit, Life Technologies) and equalized (Ion Library Equalizer Kit) to a final concentration of approximately 100 pM. Emulsion PCR was performed using the OneTouch DL instrument, and template-positive Ion Sphere particles were enriched using the OneTouch ES instrument according to the manufacturer’s instructions. Sequencing was performed on a 318 chip on the Ion Torrent PGM following the recommended protocol. Reads were aligned to hg19 and variants were called using the TorrentSuite (version 4.0.2).
Whole Genome Sequencing Analysis and Identification of Pathogenic Variants
WGS was conducted in the proband and her parents. Each sequencing library with an average insert size of 250 bp was loaded into an Illumina HiSeq X ten. Roughly 90 Gb of high-quality data in 150 bp pair-end reads was obtained for each library, reaching an average of 30-fold genome coverage for each individual. The quality evaluation was performed using FastQC software, and sequences from adapters or having low Q-score were removed with cutadapt software (Martin, 2011). The sequencing reads were mapped to the reference human genome (hg19) by the BWA algorithm (Li and Durbin, 2009). PCR duplicates were removed with Picard software. Processed bam files of humans were processed via local indel realignment and base-quality recalibration using the Genome Analysis Tool Kit (GATK) (McKenna et al., 2010). Subsequently, sorted BAM files were used for SNV calling and the UnifiedGenotyper method based on a Bayesian genotype likelihood model was applied with GATK. All detected SNVs were annotated using ANNOVAR. VarSelect in TGex platform was applied to filter for variants in WGS data of the family trio, to identify variants most likely responsible for the phenotypes of the proband (Dahary et al., 2019).
Blood Test and Analysis of Plasma Sterol Levels
The blood lipid measurements were routinely performed by the second Affiliated Hospital of Nanchang University. β-Sitosterol and other plant sterols were analyzed by liquid chromatography-mass spectrometry (AB SCIEX Triple Quad 4500) according to previous studies(Kasama et al., 1987; Hidaka et al., 1990). For each sample, a volume of 20 μl was injected into Agilent Eclipse Plus reversed-phase column (C18, 2.1 × 50 mm). The column temperature was maintained at 35°C. The mobile phase was acetonitrile-methanol (4:1, v/v) at a flow rate of 0.6 ml/min. The mass spectrometer was operated in positive ion polarity mode in the extended dynamic range (1,700 m/z, 2 GHz) with the following parameters: Curtain Gas (GUR) 40 psi; Collision Gas (CAD) 9; IonSpray Voltage (IS) 5,500.0 V; Temperature (TEM) 350°C; Ion Source Gas 1 (GS1) 50 psi; NC 3V. Blood samples from 10 healthy individuals were examined as control samples.
Platelet Size Analysis
Two ml of peripheral blood was collected using standardized tubes (INSEPACK ST serials, Beijing, China) and all tubes were stored at room temperature. Within 30 min, these samples were analyzed on SysmexXE-2100 Haematology System (Sysmex Corporation, Kobe, Japan) for lipid profile and coagulation tests following the methods previously developed protocols (Table 1) (Barsam et al., 2011; Depoorter et al., 2015). Large platelets are identified based on the volume (>30 fl). For each sample, we prepared two blood films dyed by Wright’s dye for platelet morphology analysis using a BX53 microscope (OLYMPUS, Japan). The criteria for large platelets is a diameter greater than 4 microns. All blood films were reviewed by two independent examiners.
Splicing Pattern Assay for ABCG5 Var2
Var2 is located at a splice region of ABCG5, and we performed the splicing pattern assay to verify its functional effect. Genomic DNAs including reference (WT) or ABCG5 variant were isolated from peripheral whole blood of all individuals in the study with Blood Genomic DNA Mini Kit (CWBIO, CW 2087S) and PCR was performed using PrimeSTAR® MaxDNA Polymerase (TAKARA, R045A). The 947 bp PCR fragments of ABCG5 gene, spanning from part of exon 7 (44 bp) to part of exon 9 (37 bp) with exon8 (214 bp) and its flanking intron 7 and 8, were amplified by the primer pair, ABCG5-minigene_Forward (5′-GCGGTACCGCGGAAATGCTTGATTTCTT-3′) with KpnI restriction site and ABCG5-minigene_Reverse (5′-GCCTCGAG TTAAAGGAGGAACAAACCCATGA-3′) with XhoI restriction site. The genomic fragments (both WT and variant, MT) containing the intron of interest were cloned into the pcDNATM-3.1 (+) vector and then all cloned plasmids were verified by sequencing to confirm whether the insertion contained the WT or MT.
HepG2 cells were cultured in DMEM (Gibco) supplemented with 10% FBS (Gibco). After seeded in 6-well plates for 24 h, HepG2 cells were transiently transfected with 1ug prepared vectors with the allele of the WT or MT and corresponding empty vectors respectively, using Superfectin II In Vitro siRNA Transfection Reagent (Shanghai Pufei Biotech). After 48 h, total RNA was extracted by TRIzol reagent (Invitrogen) and 1 mg total RNA was used for reverse transcription using PrimeScript RT reagent kit with gDNA eraser (Takara) according to the manufacturer’s instructions. The primer sequences of quantitative RT-PCR were: ABCG5-MGQ_Forward (5′-CGGTTACCCTTGTCCTGAAC-3′) located in exon 7 and ABCG5-MGQ_Reverse (5′-TGCCAGCTTATTTCTCACCA-3′) located in exon 9. Quantitative RT-PCR was performed with SYBR Green dye using ViiA7Real-Time PCR System (Applied Biosystems). The relative mRNA expression was calculated by the comparative Ct method using GAPDH as a control. PCR reactions were performed in triplicate. The RT-PCR products were separated on a 2% agarose gel and detected with Chemidoc Xrs Gel Doc Xr (Bio-Rad Universal Hood Ii 2, USA).
Generation of ABCG5/ABCG8 Double Knockout Rat
ABCG5/ABCG8 double knockout rat model was created by Beijing Biocytogen. In brief, a 19 Kb region was knocked out using a CRISPR/Cas9 system, with two sgRNAs targeting one site in the intron 4 of ABCG5, and the other in the intron 6 of ABCG8. The design was adapted from the protocol developed by Yu L, et al. The sgRNA activity was evaluated by the UCATM (Universal CRISPR Activity Assay), developed by Biocytogen. By zygote microinjection, transferred zygotes of SD rats were obtained and the founders were positively confirmed by PCR product sequencing. The genotyping primers were Forward: 5′-ctaggtccaccaagccatgtgaaca and Reverse: 5′-attttctgggcaccctgtgttccac. The animal study was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University (SYXK-20150001).
Sanger Sequencing of ABCG5
Exon amplification was performed using LA Taq (Takara, Osaka, Japan). Supplementary Table S2 listed all the primers for amplification of 13 exons of ABCG5 extending 50 bp towards both upstream and downstream to cover the splice regions and corresponding PCR protocols for each primer pair. All reactions were performed on a PTC-200 Peltier Thermal Cycler (MJ Research, MA, USA). PCR products were sequenced by Sangon Biotech (Shanghai, China), and the results were manually checked using SeqMan (DNAstar 5.0, WI, USA).
Statistical Analysis
The t-test was used to compare the mean difference of the blood lipid levels in the rat model using R 3.4(R Core Development Team, 2018).
Results
Identification of Compound Heterozygous Variants in ABCG5
This proband had hypercholesterolemia with atypical changes in the β-Sitosterol level in comparison with previous reports (Supplementary Table S3). To identify pathogenic variants responsible for the hypercholesterolemia of the proband, a customized Gene Panel Test was initially performed to screen for variants within all coding regions of four common familial hypercholesterolemia genes: APOB, LDLR, LDLRAP1, and PCSK9. The sequencing results showed that no family member carried any rare coding variants (<1%, MAF in CHB of 1,000 genomes) in these genes. Next, we performed WGS for the proband and her parents (∼30X coverage on average for each person). Two heterozygous variants of the ABCG5 gene were found in the proband, and no other variant was observed in the known genes related to hypercholesterolemia. The proband inherited Var1 (chr2:44050062G/T, NM_022436.3:c.1337G>A, p. Arg446Gln) from her father and Var2 (chr2:44051355T/G, splice region, c.1118+3G>T) from her mother. These two variants (Var1 and Var2) were further verified by Sanger sequencing (Supplementary Figure S1).
Var1 was reported to be a variant of uncertain significance for sitosterolemia in both Clinvar (Accession: VCV000289811) and gnomAD (2-44050062-C-T, allele frequency: 6.74e-5 and no homozygote). While at the same position, p. Arg446Ter (Accession: VCV000030485), has been previously reported as pathogenic for sitosterolemia and hypercholesterolemia (Wang et al., 2014; Buonuomo et al., 2017; Pek et al., 2018). Var2 was not documented in either Clinvar or gnomAD; it was predicted to be a splice site variant. The blood total cholesterol level of the proband was similar to the level in previously reported individuals with biallelic ABCG5 variants, ranging from 116 mg/dl to 870 mg/dl (Supplementary Table S3).
Subsequently, these two variants were examined in all family members. The results showed that these variants were transmitted across all three generations in heterozygous form (Figure 1B). Var1 was specific to the paternal side, and Var2 was only detected in the maternal lineage. However, individual I-1 did not carry any variants in the ABCG5 gene. In addition, all maternal members heterozygous for Var2 exhibited the large platelet phenotype without dysfunction of blood coagulation (Figure 1C; Table 1; Supplementary Figure S2).
Functional Assessment of Var2 Mutation
Since Var2 was predicted to be a splice site variant, we examined if Var2 can result in novel splicing transcripts of ABCG5 (Figure 1D). As shown in Figure 1E, the mRNA transcripts from the reference and Var2 fragments were 295 bp and less than 100 bp, respectively. Subsequent Sanger sequencing verified that this “truncated” transcript was 81 bp and excluded exon 8. Therefore, this result suggests that Var2 leads to deletion of exon 8 of ABCG5 during transcription, and the creation of a premature termination codon triggering nonsense-mediated mRNA decay.
Treatment With Ezetimibe
Before the study, atorvastatin 10 mg/day was first administered to the proband and her plasma LDL-C level gradually decreased to around 200 mg/dl within 2 years (Figure 2A). Although the proband’s serum LDL-C level was reduced to about 150 mg/dl when atorvastatin was increased to 20 mg/day, she experienced severe adverse effects (Supplementary Table S4). By reducing atorvastatin back to 10 mg/day, the proband’s LDL-C level remained around 200 mg/dl.
FIGURE 2 Ezetimibe Corrected the Phenotypes of the Proband. Panel (A) shows the changes in the LDL-C levels under an optimized treatment regimen. Panel (B) shows the disappearance of the aforementioned atherosclerotic plaque revealed by the ultrasound scan after Ezetimibe treatment. Panel (C) shows the comparison of platelet size distributions before and after Ezetimibe treatment in the proband. Panel (D) shows the disappearance of the large platelet in the blood smear of the proband after treatment of Ezetimibe.
Considering the insufficient response to atorvastatin which aims to inhibit cholesterol biosynthesis, we suspected that the proband may have an abnormality in cholesterol excretion instead. At that point, the treating physician suggested stopping cow milk intake (450 ml/day), following a similar infant case with a limited increase in β-Sitosterol where breastfeeding was arrested to ameliorate the symptoms (Rios et al., 2010).
After 1 month, the proband’s LDL-C level was reduced to 130 mg/dl without further decrease. The effect caused by the reduction of cholesterol intake supported the hypothesis of a cholesterol excretion dysfunction since this strategy is not effective for individuals with abnormal cholesterol synthesis. WGS analysis identified compound heterozygous variants in ABCG5 responsible for abnormal cholesterol excretion consistent with the known disorder sitosterolemia, which supported our hypothesis. Following this finding, the physician in our group recommended a combination of atorvastatin (10 mg/day) and Ezetimibe (10 mg/day) be administered to the proband.
Within 2 months, the patient’s LDL-C level was further decreased to an optimal level (<80 mg/dl). After treatment for 39 months, atorvastatin was discontinued but Ezetimibe treatment was continued with no milk intake. Thus far, the patient’s LDL-C level has been maintained at around 80 mg/dl without any obvious adverse effects. An ultrasound scan 2 months following the revised treatment showed that the proband’s atherosclerotic plaque disappeared from her left carotid artery (Figure 2B).
Interestingly, the proband’s macrothrombocytopenia nearly completely resolved within 1 month after the addition of Ezetimibe while the β-Sitosterol level was reduced to normal values (0.83 mg/dl). The size distribution of platelets normalized, and only 25% of platelets remained over 30 fl (Figures 2C,D). ABCG5 functional inactivation leads to relatively active NIPIC, targeting the NIPIC by Ezetimibe was shown to restore the balance of cholesterol absorption and excretion maintained by them. These results suggested that the macrothrombocytopenia of the proband was likely caused by the ABCG5 variant. More unexpectedly, all Var2 heterozygotes in the family had large platelets, and after 1 month of Ezetimibe treatment alone, the macrothrombocytopenia of her maternal uncle (II-2, Figure 2) also disappeared (Supplementary Figure S3).
Disruptions of the ABCG5/ABCG8 genes mimic phenotypes of the proband in double knockout rat.
To further determine if heterozygotes of ABCG5/ABCG8 genes could drive hypercholesterolemia and macrothrombocytopenia phenotypes, we created a double knockout rat (Figure 3A), having a growth curve similar to the WT strain without visible abnormalities (Supplementary Figure S4A) and succesful depletion of ABCG5 and ABCG8 expression in liver and intestine (Supplementary Figure S4B). As expected, the G5G8--/-- rats had a significant elevation of blood lipid levels (Figure 3B, left) with large platelets (4 out of 6 animals) compared with wild-type rats. However, the alterations in blood lipids were not strictly correlated with the occurrence of large platelets (Figure 3B, right), further supporting the observations of phenotypic heterogeneity of ABCG5/ABCG8 variants. In particular, one heterozygous rat (G5G8+ +/- -) also had this biased distribution of platelet size (Figure 3C), similar to the maternal kindred with Var2, suggesting that heterozygotes of this ABCG5 variant might be sufficient to cause macrothrombocytopenia. Considering these functional studies, Var2 may be classified as “Likely pathogenic” according to the standards and guidelines of the American College of Medical Genetics and Genomics (ACMG) (Richards et al., 2015): in this case PS3, our functional studies show a deleterious effect; PM2, absent in population databases. Addtionally, the homozygous KO rats had significantly higher β-Sitosterol level (mean, 7 mg/dl) than WT strain (mean, 2.5 mg/dl) when even being fed by normal diet. We further treated 2 KO rats with Ezetimibe 0.2mg/Kg. Their serum TC reduced from 2.3 and 2.4 mmol/L to 1.7 and 1.9 mmol/L , and β-Sitosterol level reduced from 6.5 and 7.5 mg/dl to 2.6 and 2.7 mg/dl.
FIGURE 3 Disruptions of ABCG5/8 Genes Mimicked the Phenotypes of the Proband in the Double Knockout Rats. Panel (A) shows the strategy for the generation of ABCG5/8 double knockout using the CAS9/sgRNA system. Panel (B) showed significantly increased blood lipid levels (left) and the large platelet (right) in the homozygotes compared with two other groups. For each group, the blood lipid levels and the large platelet were determined from randomly selecting rats. The values of the blood lipid levels are expressed as the mean ± SE. n = 6. *p < 0.05, **p < 0.01. The large platelet was detected in over 80% of homozygotes, and none was found in the wild-type strain. Panel (C) shows a blood smear for three groups of the rat model.
Screening for ABCG5 Variant Carriers in the General Population
We decided to determine whether ABCG5 variants are associated with large platelets in the general population. Routine automated blood cell counting systems differentiate blood cells by their size and do not recognize large platelets as platelets, these instruments may not accurately detect macrothrombocytopenia. The mean platelet volume also does not reflect actual platelet size in the case of large platelets. Platelet count should therefore be determined manually in a calculating chamber or on peripheral blood smears when suspecting the condition. On routine clinical laboratory examination, biased platelet distribution can be observed, with an abnormal “NaN” value instead of specific values. Without other indicators, large platelets may be easily overlooked.
Here, we intended to examine if platelet size could be used to identify ABCG5 heterozygotes (Methods). We collected platelet size distribution results for all individuals having this examination within 2 months in several hospitals. Among 1,180 individuals screened, 30 had evidence of large platelets (>30 fl, Supplementary Figure S5). In ABCG5 sequencing of the 30 individuals (Figure 4, Supplementary Table S5), we identified a known pathogenic variant (p.Arg446Ter, gnomad:2-44050063-G-A; allele frequency:1.70e-4 and no homozygotes) in one individual. In addition, two novel variants, Var3 (hg19-chr2:44039644, NM_022436:c.*610_*611insCCCAGTGATTTTACTGAGGATTA) and Var4 (hg19-chr2:44039650, NM_022436:c.*604_*605insTACAGAGCACCCAGTGATTTTACTGA,hg19), insertions in 3’ UTR region, were also identified in three other individuals, respectively. These are classified as variants of uncertain significance (no record in gnomAD, thus only having PM2 evidence according to ACMG standards and guidelines). Hence, this population-based work along with segregation of an ABCG5 variant in a large pedigree with sitosterolemia identifies heterozygosity for specific ABCG5 variants as an additional genetic cause of macrothrombocytopenia. Our data suggest that 2.5% of individuals requiring complete blood counts may have large platelets, and roughly 10% of those with large platelets may have ABCG5 variants that are causative. Therefore, screening for large platelets may be helpful to identify heterozygotes for ABCG5 pathogenic variants; conversely, sequencing ABCG5 in individuals with large platelets may be useful in identifying patients amenable to Ezetimibe treatment, if it were shown to be effective and beneficial in future large clinical trials.
FIGURE 4 Nine ABCG5 variants in 30 individuals with abnormal platelet size distribution. Details of each variation are in Supplementary Table S4. Genetic variations of them are more commonly seen in the 3′UTR of the gene model. Except for 3 pathogenic and likely pathogenic variations are heterozygotes in affected individuals, other variations are all homozygotes.
Discussion
We identified a proband with profound hypercholesterolemia, recalcitrant to atorvastatin therapy. The pedigree analysis did not support dominant inheritance and gene panel testing for several genes associated with FH was non-diagnostic. ABCG5 Var1 did not behave in a classical dominant way that most other variants responsible for FH lead to abnormal lipid levels of affected individuals when they were young. It is important to note that the increased lipid levels of paternal individuals may be confounded by lifestyles that promote hyperlipidemia. Additionally, this family appears to show an allele dosage effect where heterozygous carriers of a single putative pathogenic variant result in mild signs/symptoms, especially macrothrombocytopenia.
Hematological alterations have long been noticed in individuals with sitosterolemia, such as decreased platelet counts, increased mean platelet volume, and/or hemolytic anemia (Wang et al., 2004; Patel, 2014; Ajagbe et al., 2015). In addition to hypercholesterolemia, the proband had large platelets. Sitosterolemia can cause both phenotypes. Unexpectedly, all heterozygotes for Var2 in the maternal lineage exhibited large platelets without any changes in blood lipid profile. This is the first study to report a sign or symptom caused by heterozygosity for an ABCG5 variant.
It has been long noticed that homozygous mutant mice with disruption of Abcg5 and Abcg8, Del (17Abcg5-Abcg8)1Hobb, have increased mean platelet volume (Yu et al., 2002). Nevertheless, this had not been previously reported in heterozygotes. We generated an ABCG5/8 double knockout rat, which illustrated that heterozygous ABCG5 variants can lead to large platelets independent of hypercholesterolemia. Moreover, this trait was successfully corrected by Ezetimibe treatment in alone both the compound heterozygous proband and heterozygote II-4. Additionally, our preliminary experiment showed that Ezetimibe resolved both hypercholesterolemia and macrothrombocytopenia in two knockout rats. Taken together, Ezetimibe treatment can improve platelet production via unknown mechanisms.
Large platelets are usually accompanied by thrombocytopenia. Thus, it is also termed macrothrombocytopenia. Macrothrombocytopenia is usually due to acquired disorders; inherited large platelet disorders are rare. The mechanisms of large platelet formation and thrombocytopenia are poorly understood. Treatment for acquired versus inherited forms differs. Several different genes have been implicated as causes (Saito et al.). The most common clinical manifestation of inherited large platelets includes bleeding tendency (Mhawech and Saleem, 2000). Platelet count is usually decreased along with their increased size, which explains the abnormal blood coagulation. Overall, Var2 carriers other than the proband seem to be asymptomatic, similar to a few cases exhibiting large platelet syndrome. It is noteworthy that individual I-3 exhibited cerebral ischemic stroke at the age of 58, with normal blood pressure and lipid profile. Particularly, previous studies pointed out the large platelets may increase the stroke risk (O'Malley et al., 1995; Bath et al., 2004). Recently, it has also been reported that heterozygous carriers of ABCG5 variants had a 2-fold increase in the risk of coronary artery disease (Nomura et al., 2020). Therefore, determining the disease risk of Var2 carriers may require future evaluation in cohort studies, as a potential benefit for Ezetimibe treatment in these carriers.
Frequencies of pathogenic variants of ABCG5 should be quite low in the general population; by July 2021, pathogenic or likely pathogenic variants have been reported for 66 cases in ClinVar, and the allele frequency is about 0.04% (126/282856) in gnomAD (2.1.1). The present study, however, found a high prevalence of ABCG5 variants in a general population with large platelets. Screening for large platelets, therefore, may be helpful to identify heterozygotes for ABCG5 pathogenic variants; conversely, sequencing ABCG5 in individuals with large platelets may be useful in identifying patients amenable to Ezetimibe treatment, since a heterozygous family member with large platelets responded to this treatment.
Generally, physicians may only review the average volume/size of platelets, such as mean platelet volume (MPV), examined by the automated blood cell counting systems. But they may commonly ignore an abnormal “NaN” value of MVP in the system report, which stands for a biased platelet size distribution, particularly when patients have normal functions of blood coagulation as our observation in this pedigree. Here we showed the abnormal “NaN” value of MVP stood for the occurrence of large platelets over 30 fl, which can be the only symptom for some carriers of ABCG5 variants. In addition, this volume is equivalent to spheres 4 microns in diameter to identify large platelets, which we adopted at the criteria in the blood film examination. Our study suggested the review of abnormal platelet size distribution may help to identify these carriers more easily. Meanwhile, they may have an increased risk of other complications such as stroke. Further larger studies could incorporate improved methods for detection of large platelets, identification of ABCG5 variants in those with large platelets, the risk of clinical complications in such patients, and the effects of Ezetimibe treatment.
Conclusion
In summary, WGS and plant sterol analysis of a family trio identified sitosterolemia in a proband with recalcitrant hypercholesterolemia and macrothrombocytopenia; she was found to have compound heterozygous variants in the ABGC5 gene. Diagnosis confirmed in this manner guided appropriate therapeutic decisions, leading to clinical improvement. Interestingly, the therapeutic regimen not only reduced the proband’s blood cholesterol level to normal levels but also resolved macrothrombocytopenia. In the course of the evaluation, ABCG5 heterozygosity was identified as a cause of autosomal dominant inherited macrothrombocytopenia; the role of ABCG5 in macrothrombocytopenia and its therapy with Ezetimibe should be further investigated.
We thank the families for their participation in this study.
Data Availability Statement
The detailed methods described above and other measurements/assays for plasma cholesterols and platelets were available in the Supplementary Appendix of the full text of this article. WGS and Gene panel raw data are available from the corresponding author on reasonable request with consent from the patient family. VCF files for variants in ABCG5 genes and the Gene panel are publically available at https://github.com/humangenetest/ABCG5variants.
Ethics Statement
The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University (IRB#2016-3). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. The animal study was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.
Author Contributions
HX, LD, and DZ designed the study, planned experiments. LD, DZ, and JX, analyzed data, and drafted the manuscript. JX, QC, BY, XL, and XW collected the clinical samples, performed the required examinations, and analyzed clinical information. LD, WC, SG, and ZC designed and performed the sequencing analysis of the pedigree. ZC, YX, and KD performed the cell-line functional analysis and analyzed the data for the animal model. HX, LD, RS, DZ, and SS interpreted data and participated in manuscript preparation. All authors reviewed the manuscript and agreed with the final version.
Funding
Supported by the National Natural Science Foundation of China (81260021, 82060112, and 81660041 to LD, 91639106, 81270202, 91339113 to HX); Jiangxi Provincial Department of Science and Technology, China (20122BCB24023 to HX and 20142BCB24001 to KD); 111 Project (Project No: B13003 to DZ).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgene.2021.769699/full#supplementary-material
Click here for additional data file.
Abbreviations
ABCG5, ATP-binding cassette transporters G5; ABCG8, ATP-binding cassette transporters G8; NPC1L1, Niemann–PickC1-Like1; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; WGS, whole genome sequencing; FH, familial hypercholesterolemia; GATK, Genome Analysis Tool Kit; ACMG, American College of Medical Genetics and Genomics; MPV, mean platelet volume; PLT, platelet; fL, femtoliters. | ATORVASTATIN | DrugsGivenReaction | CC BY | 34880906 | 20,497,668 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal distension'. | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | GIMERACIL\OTERACIL\TEGAFUR, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ascites'. | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | GIMERACIL\OTERACIL\TEGAFUR, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic cirrhosis'. | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | GIMERACIL\OTERACIL\TEGAFUR, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant ascites'. | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | GIMERACIL\OTERACIL\TEGAFUR, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 34881031 | 20,816,334 | 2022-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pleural effusion'. | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | GIMERACIL\OTERACIL\TEGAFUR, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 34881031 | 20,816,334 | 2022-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pseudocirrhosis'. | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | GIMERACIL\OTERACIL\TEGAFUR, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Varices oesophageal'. | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | GIMERACIL\OTERACIL\TEGAFUR, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
What was the administration route of drug 'GIMERACIL\OTERACIL\TEGAFUR'? | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | Oral | DrugAdministrationRoute | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
What was the outcome of reaction 'Abdominal distension'? | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | Recovered | ReactionOutcome | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
What was the outcome of reaction 'Ascites'? | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | Recovered | ReactionOutcome | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
What was the outcome of reaction 'Hepatic cirrhosis'? | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | Recovered | ReactionOutcome | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
What was the outcome of reaction 'Malignant ascites'? | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | Recovered | ReactionOutcome | CC BY-NC-ND | 34881031 | 20,816,334 | 2022-01 |
What was the outcome of reaction 'Pseudocirrhosis'? | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | Recovered | ReactionOutcome | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
What was the outcome of reaction 'Varices oesophageal'? | Pseudocirrhosis after chemotherapy for gastric cancer with diffuse liver metastases: A case report.
Pseudocirrhosis is a rare but important complication of metastatic cancer. We herein present the case of a patient with pseudocirrhosis occurring after a complete response to chemotherapy for metastatic gastric cancer was achieved. A 72-year-old man was diagnosed with gastric adenocarcinoma with multiple liver metastases. The patient's general condition was good, with an Eastern Cooperative Oncology Group performance status of 1. Chemotherapy with oxaliplatin and S-1 was initiated and, after four cycles, the patient noticed sudden abdominal distension. Despite the marked regression of the liver metastases, massive ascites, segmental atrophy and esophageal varices developed, findings consistent with pseudocirrhosis. The patient achieved complete response for the primary and metastatic lesions. Following endoscopic ligation of the varices, he underwent subsequent chemotherapy with S-1 only and management of his ascites for 6 months. At 12 months after initial chemotherapy, the patient appeared to be disease-free. In conclusion, clinicians should be aware of the possibility of pseudocirrhosis in cases of cancer metastasis to the liver, including metastatic gastric cancer.
pmcIntroduction
Although rare, pseudocirrhosis is an important complication of metastatic cancer. The radiological term pseudocirrhosis has been used to describe the development of diffuse hepatic nodules in patients with cancer metastasis to the liver (1). Pseudocirrhosis presents with morphological changes similar to those of true liver cirrhosis, including lobular hepatic contour, a retracted capsular surface, segmental atrophy and an enlarged caudate lobe (2). Similar to cirrhosis, portal hypertension that results in ascites and esophageal varices are often encountered in patients with pseudocirrhosis (3-8). Pseudocirrhosis occurs most frequently in patients with breast cancer metastasizing to the liver (5-7,9-11), but it is uncommon with other malignancies, although it has been occasionally reported in association with thyroid (3), pancreatic (12), esophageal (13), small-cell lung (14), colon (15) and gastric cancer (16). We herein report the rare case of a patient with metastatic gastric cancer who developed pseudocirrhosis after achieving complete response to chemotherapy.
Case report
A 72-year-old man was referred to the Gifu Municipal Hospital (Kashimacho, Japan) in March 2019 with anorexia, feeling of abdominal distension and general malaise. The patient was subjected to upper gastrointestinal endoscopy and was diagnosed with advanced gastric cancer type 2, a classification used in Japan to grossly describe gastric cancer in which ulcer localization is visible to the naked eye, in the greater curvature of the stomach by (Fig. 1A). Histological examination of the biopsy samples revealed well-differentiated adenocarcinoma. Blood chemistry testing revealed the following (Table I): Albumin 3.5 mg/dl (normal range, 4.1-5.1 mg/dl), aspartate aminotransferase 263 IU/l (normal range; 13-30 IU/l), alanine aminotransferase 115 IU/l (normal range, 10-42 IU/l), lactate dehydrogenase 1769 U/l (normal range, 124-222 U/l) and total bilirubin 1.8 mg/dl (normal range, 0.4-1.5 mg/dl). The carcinoembryonic antigen level was normal (3.7 ng/ml; normal range, 0-5 ng/ml), but that of carbohydrate antigen 19-9 (CA19-9) was highly elevated at 42.5 U/ml (normal range, 0-37 U/ml). Abdominal CT examination revealed the presence of multiple liver metastases (Fig. 1B). The patient's oral intake was good, and his Eastern Cooperative Oncology Group performance status was 1. Therefore, he received chemotherapy with S-1 (orally at 40 mg/m2 twice a day for 2 weeks combined with 130 mg/m2 oxaliplatin administered on day 1 every 3 weeks).
After 4 cycles of chemotherapy, the patient suddenly developed abdominal distention. CT examination revealed a nodular liver contour and liver volume loss, accompanied by marked regression of the liver metastases. Massive ascites and pleural effusion were also present (Fig. 2A). Radiologically, these findings mimicked those of liver cirrhosis, but the liver enzyme levels were normal, and the CA19-9 level had decreased to 11.0 U/ml (Table I). The patient did not report excessive alcohol intake, and the serological examinations performed to investigate viral and autoimmune etiologies of cirrhosis were negative. Cytology of the transudative ascites revealed no malignant cells. Repeat upper gastrointestinal endoscopy revealed esophageal varices (red color sign) and a red scar at the site of the primary tumor (Fig. 2B); furthermore, the sample obtained by biopsy of the lesion was free of tumor cells. Positron emission tomography-CT revealed no abnormal fluorodeoxyglucose accumulation in the stomach or liver (Fig. 2C). Thus, the patient was diagnosed with pseudocirrhosis. Treatment with abdominal paracentesis and diuretics (furosemide and spironolactone) was initiated for his worsening abdominal distension and peripheral edema. The patient also underwent two sessions of endoscopic ligation of his esophageal varices with curative intent. The patient was discharged after his ascites was reduced to a manageable level, and chemotherapy was reinitiated with S-1 alone at 40 mg/m2 orally twice daily for 4 weeks. CT examination at 6 months after the initial treatment revealed total remission of the liver metastases and disappearance of the ascites (Fig. 3A). Therefore, the response to treatment was deemed as complete. At 12 months after the initial treatment, CT examination revealed no evidence of recurrence or metastasis. Another upper gastrointestinal endoscopic examination revealed the presence of a scar at the primary tumor site (Fig. 3B), and no tumor cells were detected following biopsy of the lesion. The patient was maintained on S-1 monotherapy, and the complete response was confirmed in April 2020 (12 months after the initial chemotherapy).
Discussion
Pseudocirrhosis is a term used to describe a complication of cancer with multiple liver metastases, and its radiological appearance is similar to that of cirrhosis (17). However, there is no examination that can definitively distinguish pseudocirrhosis from cirrhosis, and the typical histopathological findings of cirrhosis are lacking. The precise mechanism underlying the development of pseudocirrhosis remains unclear. However, it is currently attributed to two etiologies, either a process related to hepatic metastases, or toxicity resulting from systemic therapy (5,6,11). In the former, chemotherapy can induce hepatic retraction with a lobular contour from either an increase or decrease in the size of the subjacent tumor (2,9). In the latter, pseudocirrhosis can occur with or without prior systemic chemotherapy. Hepatic histology in this case may exhibit extensive tumor infiltration and desmoplastic fibrosis (5,6,11).
The only known case to date of pseudocirrhosis arising from metastatic gastric cancer was reported by Mitani et al (16). The majority of other reports on pseudocirrhosis are associated with hepatic metastasis of breast cancer (2,4-11,18). Furthermore, although there have been some case reports of pseudocirrhosis in various primary cancers with liver metastases (3,12-17,19), these reports suggested no correlation with the specific type of cancer.
Nodular regenerative hyperplasia, which presents as a widespread transformation of normal hepatic parenchyma into regenerative nodules with little or no bridging fibrosis, may also be associated with the development of pseudocirrhosis (2). There are some reports that pseudocirrhosis occurs when using oxaliplatin for gastric, colon, or pancreatic cancer (12,15,16), and oxaliplatin is well known to cause nodular regenerative hyperplasia. However, the chemotherapeutic agents that can worsen pseudocirrhosis remain unclear, and no chemotherapeutic agent has yet been identified as the sole culprit (4,19).
Adike et al (18) reported abdominal distention with ascites as the most common initial presentation of pseudocirrhosis. In addition, certain severe complications, such as hepatic encephalopathy and variceal bleeding, may occasionally result in a fatal outcome (3-8), which indicates the clinical significance of pseudocirrhosis, as well as classic cirrhosis, and the importance of early detection and appropriate management (16).
In conclusion, pseudocirrhosis may occur during the achievement of a chemotherapeutic response in metastatic gastric or breast cancer. Thus, clinicians must be aware of this entity and recognize the onset of pseudocirrhosis in order to administer appropriate treatment in a timely manner, even when the patients are receiving chemotherapy for gastric cancer.
Acknowledgements
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TSh and TT analyzed and interpreted the data, wrote the manuscript and confirm the authenticity of the raw data. TSh, TT, TSa, MO, SF, SK, KM, KY, YS, SO and MY evaluated the patient and participated in his therapy. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of the case details and any associated images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Imaging prior to chemotherapy. (A) Endoscopic examination revealed advanced gastric cancer, type 2, located in the lesser curvature. (B) Initial abdominal CT examination revealed multiple metastatic lesions throughout the liver.
Figure 2 Imaging after four treatment cycles. (A) CT examination revealed marked regression of the liver metastases with accompanying nodular liver contour, loss of liver volume, massive ascites and pleural effusion, findings suggestive of pseudocirrhosis. (B) Endoscopic examination revealed esophageal varices, with a red scar at the site of the primary tumor. (C) Positron emission tomography-CT examination revealed no abnormal accumulation of fluorodeoxyglucose in the stomach or liver.
Figure 3 Imaging examination at 6 and 12 months post-treatment. (A) CT examination performed 6 months after the initial treatment revealed disappearance of the liver metastases and ascites. (B) CT examination performed 12 months after the initial treatment revealed no evidence of recurrence or metastasis.
Table I Changes in the blood tests following chemotherapy.
Blood test Prior to treatment After 1 treatment cycle After 4 treatment cycles 12 months after initial treatment
Aspartate aminotransferase (IU/l) 263 57 54 37
Alanine aminotransferase (IU/l) 115 30 39 20
Lactate dehydrogenase (IU/l) 1,769 - 295 195
Total bilirubin (mg/dl) 1.8 0.9 2.0 1.3
Carcinoembryonic antigen (ng/ml) 3.7 4.4 7.2 5.6
Carbohydrate antigen 19-9 (U/ml) 42.4 12.4 11.0 11.1 | Recovered | ReactionOutcome | CC BY-NC-ND | 34881031 | 20,742,764 | 2022-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Copper deficiency'. | Mimicking Myelodysplastic Syndrome: Importance of Differential Diagnosis.
Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation.
pmc1. Introduction
Myelodysplastic syndrome (MDS) is a hematological malignancy that presents with pancytopenia, ineffective hematopoiesis, and cytogenetic abnormalities; the condition is considered incurable without an allogeneic stem cell transplant (allo-HCT) [1]. The diagnosis is made through bone marrow biopsy evaluation and requires appropriate exclusion of other causes of cytopenias, e.g., nutritional deficiencies, drug toxicities, infection, and autoimmune disease [2]. Several conditions can mimic MDS with potentially catastrophic consequences should the patient proceed towards allo-HCT [3]. In this report, we describe a case of copper deficiency initially diagnosed as MDS to emphasize the need to rule out nutritional deficiency in the workup of patients with suspected MDS. IRB submission was deferred per institutional policy for case series including less than 3 patients.
2. Case Report
A 61-year-old female with a history of alcoholism, vitamin B12 deficiency, and remote gastric bypass was referred to hematology with a two-month history of shortness of breath and cytopenias. She admitted to consuming 2–4 alcoholic drinks weekly and had just recently resumed B12 supplementation. Complete blood count revealed a severe macrocytic anemia (6.6 g/dL), MCV (108 fl), and neutropenia (ANC 520/μL). She had an elevated vitamin B12 level reflective of recent intramuscular supplementation (Table 1). Bone marrow biopsy was performed and revealed a hypercellular marrow for age (75%) and dyserythropoiesis but without cytogenetic and dysplastic changes characteristic of MDS. However, early MDS could not be ruled out. Despite two months of B12 supplementation, her anemia and leukopenia did not improve, and she required further transfusion. Direct Coombs testing, lactate dehydrogenase, reticulocyte count, haptoglobin, and methylmalonic acid testing revealed no significant abnormalities. Daily prednisone (40 mg) was started as empiric treatment for potential occult autoimmune condition with no efficacy. The patient's anemia continued to worsen (5.7 g/dL) requiring further transfusion with progressive neutropenia. Additionally, she developed bilateral foot paresthesias, which were felt to be due to Raynaud's phenomena. A repeat bone marrow biopsy now revealed a hypocellular bone marrow (20–30%) with erythroid hyperplasia and dyserythropoiesis. A presumptive diagnosis of MDS (R–IPSS 3) was made, and the patient was referred for allo-HCT evaluation.
At time of consultation, the patient reported taking a daily zinc supplement for several years for a previously diagnosed deficiency. The combined history of gastric bypass and high zinc intake raised suspicion for copper deficiency, and additional labs were drawn. Both serum ceruloplasmin (<3 mg/dL) and copper (10 μg/dL) were below the lower limits of diagnostic testing, and serum zinc (151 μg/dL) was elevated. Hematopathology review of the second bone marrow biopsy showed vacuolated precursors and ring sideroblasts commonly seen in copper deficiency (Figure 1). Accordingly, the patient was started on IV cupric chloride (2 g) daily for 5 days and then once weekly for four weeks. At one-month follow-up, the patient's anemia improved and leukopenia resolved (Table 1). Although her energy level improved, her paresthesia remained.
3. Discussion
Copper deficiency is a rare nutritional condition that results in reversible hematologic findings—anemia and neutropenia—and often irreversible neurologic manifestations—optic neuropathy, paresthesia, and spasticity [4]. The most common etiologies of copper deficiency in the United States are gastric bypass surgery, excessive zinc intake, and celiac disease [4, 5]. Since the majority of copper is absorbed in the stomach and duodenum, gastric bypass surgery significantly increases risk of copper deficiency [4, 6]. The utility of prophylactic oral copper supplementation or serum copper monitoring in bariatric surgery patients is well established [6, 7]. Zinc primarily upregulates expression of metallothionein in enterocytes, which binds copper to a greater extent than zinc, thereby sequestering copper within the intestinal tract [4, 8].
While our patient had risk factors for development of copper deficiency, her age and clinical presentation were suggestive of MDS [9]. The early signs of insufficiency of hematopoiesis seen in copper deficiency—cytopenias and dysplastic changes—mimic those seen in clonal expansion driven diseases such as MDS—a condition encountered more frequently [10, 11]. Although not pathognomonic for copper deficiency, intracytoplasmic vacuoles in precursor cells and ring sideroblasts are subtle findings often observed on bone marrow biopsy as found in this patient; cytogenetic changes are not found in copper deficiency [10, 12]. Although the mechanism of copper deficiency anemia is unclear, copper is a vital coenzyme in the function of hephaestin—responsible for the oxidation of dietary iron—and ceruloplasmin—responsible for the transfer of iron from macrophages/monocytes to plasma [4, 13].
4. Conclusion
In this report, we highlight the clinical progression of occult copper deficiency. Although our patient's copper deficiency was initially misdiagnosed, prompt treatment with IV cupric chloride ameliorated the hematological and constitutional symptoms of low copper. Since delayed treatment of copper deficiency can result in permanent neurological impairment, clinicians should promptly rule out copper deficiency in patients being evaluated for MDS, especially if presenting with neurological symptoms [4, 14]. The steady rise of bariatric surgeries performed to curb the obesity epidemic will likely increase the prevalence of nutritional deficiencies, including copper deficiency [15]. Most importantly, early diagnosis can alleviate symptoms and spare patients' toxicities associated with chemotherapeutic agents or allo-HCT.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Disclosure
This study was performed as part of employment or enrollment at the Medical College of Wisconsin.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 (a-b) Wright Giemsa-stained bone marrow aspirate smear slide (l000x magnification) showing neutrophil precursors (a) and an erythroid precursor (b) bottom with cytoplasmic vacuoles. (c) Prussian blue-stained bone marrow aspirate smear slide (l000x magnification) showing ring sideroblasts.
Table 1 Laboratory values.
Initial presentation +2 months +4 months allo-HCT consult 1 month postcopper replacement
WBC, K/µL 1.3 1.4 0.8 4.3
ANC, K/µL 0.7 0.4 0.29 3.3
MCV 108 96 97 93
Hgb, g/dL 6.6 7.1 7.3 11.6
PLT, K/µL 222 191 144 157
Vit B12 (211–911) >2000 — 507 —
Copper (80–155) — — <10 107
Ceruloplasmin (17–54) — — <3 —
WBC, white blood cell; ANC, absolute neutrophil count; MCV, mean corpuscular volume; Hgb, hemoglobin; PLT, platelet; Vit, vitamin. Bolded values are abnormal. | CYANOCOBALAMIN, PREDNISONE, ZINC | DrugsGivenReaction | CC BY | 34881068 | 20,511,654 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancytopenia'. | Mimicking Myelodysplastic Syndrome: Importance of Differential Diagnosis.
Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation.
pmc1. Introduction
Myelodysplastic syndrome (MDS) is a hematological malignancy that presents with pancytopenia, ineffective hematopoiesis, and cytogenetic abnormalities; the condition is considered incurable without an allogeneic stem cell transplant (allo-HCT) [1]. The diagnosis is made through bone marrow biopsy evaluation and requires appropriate exclusion of other causes of cytopenias, e.g., nutritional deficiencies, drug toxicities, infection, and autoimmune disease [2]. Several conditions can mimic MDS with potentially catastrophic consequences should the patient proceed towards allo-HCT [3]. In this report, we describe a case of copper deficiency initially diagnosed as MDS to emphasize the need to rule out nutritional deficiency in the workup of patients with suspected MDS. IRB submission was deferred per institutional policy for case series including less than 3 patients.
2. Case Report
A 61-year-old female with a history of alcoholism, vitamin B12 deficiency, and remote gastric bypass was referred to hematology with a two-month history of shortness of breath and cytopenias. She admitted to consuming 2–4 alcoholic drinks weekly and had just recently resumed B12 supplementation. Complete blood count revealed a severe macrocytic anemia (6.6 g/dL), MCV (108 fl), and neutropenia (ANC 520/μL). She had an elevated vitamin B12 level reflective of recent intramuscular supplementation (Table 1). Bone marrow biopsy was performed and revealed a hypercellular marrow for age (75%) and dyserythropoiesis but without cytogenetic and dysplastic changes characteristic of MDS. However, early MDS could not be ruled out. Despite two months of B12 supplementation, her anemia and leukopenia did not improve, and she required further transfusion. Direct Coombs testing, lactate dehydrogenase, reticulocyte count, haptoglobin, and methylmalonic acid testing revealed no significant abnormalities. Daily prednisone (40 mg) was started as empiric treatment for potential occult autoimmune condition with no efficacy. The patient's anemia continued to worsen (5.7 g/dL) requiring further transfusion with progressive neutropenia. Additionally, she developed bilateral foot paresthesias, which were felt to be due to Raynaud's phenomena. A repeat bone marrow biopsy now revealed a hypocellular bone marrow (20–30%) with erythroid hyperplasia and dyserythropoiesis. A presumptive diagnosis of MDS (R–IPSS 3) was made, and the patient was referred for allo-HCT evaluation.
At time of consultation, the patient reported taking a daily zinc supplement for several years for a previously diagnosed deficiency. The combined history of gastric bypass and high zinc intake raised suspicion for copper deficiency, and additional labs were drawn. Both serum ceruloplasmin (<3 mg/dL) and copper (10 μg/dL) were below the lower limits of diagnostic testing, and serum zinc (151 μg/dL) was elevated. Hematopathology review of the second bone marrow biopsy showed vacuolated precursors and ring sideroblasts commonly seen in copper deficiency (Figure 1). Accordingly, the patient was started on IV cupric chloride (2 g) daily for 5 days and then once weekly for four weeks. At one-month follow-up, the patient's anemia improved and leukopenia resolved (Table 1). Although her energy level improved, her paresthesia remained.
3. Discussion
Copper deficiency is a rare nutritional condition that results in reversible hematologic findings—anemia and neutropenia—and often irreversible neurologic manifestations—optic neuropathy, paresthesia, and spasticity [4]. The most common etiologies of copper deficiency in the United States are gastric bypass surgery, excessive zinc intake, and celiac disease [4, 5]. Since the majority of copper is absorbed in the stomach and duodenum, gastric bypass surgery significantly increases risk of copper deficiency [4, 6]. The utility of prophylactic oral copper supplementation or serum copper monitoring in bariatric surgery patients is well established [6, 7]. Zinc primarily upregulates expression of metallothionein in enterocytes, which binds copper to a greater extent than zinc, thereby sequestering copper within the intestinal tract [4, 8].
While our patient had risk factors for development of copper deficiency, her age and clinical presentation were suggestive of MDS [9]. The early signs of insufficiency of hematopoiesis seen in copper deficiency—cytopenias and dysplastic changes—mimic those seen in clonal expansion driven diseases such as MDS—a condition encountered more frequently [10, 11]. Although not pathognomonic for copper deficiency, intracytoplasmic vacuoles in precursor cells and ring sideroblasts are subtle findings often observed on bone marrow biopsy as found in this patient; cytogenetic changes are not found in copper deficiency [10, 12]. Although the mechanism of copper deficiency anemia is unclear, copper is a vital coenzyme in the function of hephaestin—responsible for the oxidation of dietary iron—and ceruloplasmin—responsible for the transfer of iron from macrophages/monocytes to plasma [4, 13].
4. Conclusion
In this report, we highlight the clinical progression of occult copper deficiency. Although our patient's copper deficiency was initially misdiagnosed, prompt treatment with IV cupric chloride ameliorated the hematological and constitutional symptoms of low copper. Since delayed treatment of copper deficiency can result in permanent neurological impairment, clinicians should promptly rule out copper deficiency in patients being evaluated for MDS, especially if presenting with neurological symptoms [4, 14]. The steady rise of bariatric surgeries performed to curb the obesity epidemic will likely increase the prevalence of nutritional deficiencies, including copper deficiency [15]. Most importantly, early diagnosis can alleviate symptoms and spare patients' toxicities associated with chemotherapeutic agents or allo-HCT.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Disclosure
This study was performed as part of employment or enrollment at the Medical College of Wisconsin.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 (a-b) Wright Giemsa-stained bone marrow aspirate smear slide (l000x magnification) showing neutrophil precursors (a) and an erythroid precursor (b) bottom with cytoplasmic vacuoles. (c) Prussian blue-stained bone marrow aspirate smear slide (l000x magnification) showing ring sideroblasts.
Table 1 Laboratory values.
Initial presentation +2 months +4 months allo-HCT consult 1 month postcopper replacement
WBC, K/µL 1.3 1.4 0.8 4.3
ANC, K/µL 0.7 0.4 0.29 3.3
MCV 108 96 97 93
Hgb, g/dL 6.6 7.1 7.3 11.6
PLT, K/µL 222 191 144 157
Vit B12 (211–911) >2000 — 507 —
Copper (80–155) — — <10 107
Ceruloplasmin (17–54) — — <3 —
WBC, white blood cell; ANC, absolute neutrophil count; MCV, mean corpuscular volume; Hgb, hemoglobin; PLT, platelet; Vit, vitamin. Bolded values are abnormal. | CYANOCOBALAMIN, PREDNISONE, ZINC | DrugsGivenReaction | CC BY | 34881068 | 20,511,654 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Paraesthesia'. | Mimicking Myelodysplastic Syndrome: Importance of Differential Diagnosis.
Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation.
pmc1. Introduction
Myelodysplastic syndrome (MDS) is a hematological malignancy that presents with pancytopenia, ineffective hematopoiesis, and cytogenetic abnormalities; the condition is considered incurable without an allogeneic stem cell transplant (allo-HCT) [1]. The diagnosis is made through bone marrow biopsy evaluation and requires appropriate exclusion of other causes of cytopenias, e.g., nutritional deficiencies, drug toxicities, infection, and autoimmune disease [2]. Several conditions can mimic MDS with potentially catastrophic consequences should the patient proceed towards allo-HCT [3]. In this report, we describe a case of copper deficiency initially diagnosed as MDS to emphasize the need to rule out nutritional deficiency in the workup of patients with suspected MDS. IRB submission was deferred per institutional policy for case series including less than 3 patients.
2. Case Report
A 61-year-old female with a history of alcoholism, vitamin B12 deficiency, and remote gastric bypass was referred to hematology with a two-month history of shortness of breath and cytopenias. She admitted to consuming 2–4 alcoholic drinks weekly and had just recently resumed B12 supplementation. Complete blood count revealed a severe macrocytic anemia (6.6 g/dL), MCV (108 fl), and neutropenia (ANC 520/μL). She had an elevated vitamin B12 level reflective of recent intramuscular supplementation (Table 1). Bone marrow biopsy was performed and revealed a hypercellular marrow for age (75%) and dyserythropoiesis but without cytogenetic and dysplastic changes characteristic of MDS. However, early MDS could not be ruled out. Despite two months of B12 supplementation, her anemia and leukopenia did not improve, and she required further transfusion. Direct Coombs testing, lactate dehydrogenase, reticulocyte count, haptoglobin, and methylmalonic acid testing revealed no significant abnormalities. Daily prednisone (40 mg) was started as empiric treatment for potential occult autoimmune condition with no efficacy. The patient's anemia continued to worsen (5.7 g/dL) requiring further transfusion with progressive neutropenia. Additionally, she developed bilateral foot paresthesias, which were felt to be due to Raynaud's phenomena. A repeat bone marrow biopsy now revealed a hypocellular bone marrow (20–30%) with erythroid hyperplasia and dyserythropoiesis. A presumptive diagnosis of MDS (R–IPSS 3) was made, and the patient was referred for allo-HCT evaluation.
At time of consultation, the patient reported taking a daily zinc supplement for several years for a previously diagnosed deficiency. The combined history of gastric bypass and high zinc intake raised suspicion for copper deficiency, and additional labs were drawn. Both serum ceruloplasmin (<3 mg/dL) and copper (10 μg/dL) were below the lower limits of diagnostic testing, and serum zinc (151 μg/dL) was elevated. Hematopathology review of the second bone marrow biopsy showed vacuolated precursors and ring sideroblasts commonly seen in copper deficiency (Figure 1). Accordingly, the patient was started on IV cupric chloride (2 g) daily for 5 days and then once weekly for four weeks. At one-month follow-up, the patient's anemia improved and leukopenia resolved (Table 1). Although her energy level improved, her paresthesia remained.
3. Discussion
Copper deficiency is a rare nutritional condition that results in reversible hematologic findings—anemia and neutropenia—and often irreversible neurologic manifestations—optic neuropathy, paresthesia, and spasticity [4]. The most common etiologies of copper deficiency in the United States are gastric bypass surgery, excessive zinc intake, and celiac disease [4, 5]. Since the majority of copper is absorbed in the stomach and duodenum, gastric bypass surgery significantly increases risk of copper deficiency [4, 6]. The utility of prophylactic oral copper supplementation or serum copper monitoring in bariatric surgery patients is well established [6, 7]. Zinc primarily upregulates expression of metallothionein in enterocytes, which binds copper to a greater extent than zinc, thereby sequestering copper within the intestinal tract [4, 8].
While our patient had risk factors for development of copper deficiency, her age and clinical presentation were suggestive of MDS [9]. The early signs of insufficiency of hematopoiesis seen in copper deficiency—cytopenias and dysplastic changes—mimic those seen in clonal expansion driven diseases such as MDS—a condition encountered more frequently [10, 11]. Although not pathognomonic for copper deficiency, intracytoplasmic vacuoles in precursor cells and ring sideroblasts are subtle findings often observed on bone marrow biopsy as found in this patient; cytogenetic changes are not found in copper deficiency [10, 12]. Although the mechanism of copper deficiency anemia is unclear, copper is a vital coenzyme in the function of hephaestin—responsible for the oxidation of dietary iron—and ceruloplasmin—responsible for the transfer of iron from macrophages/monocytes to plasma [4, 13].
4. Conclusion
In this report, we highlight the clinical progression of occult copper deficiency. Although our patient's copper deficiency was initially misdiagnosed, prompt treatment with IV cupric chloride ameliorated the hematological and constitutional symptoms of low copper. Since delayed treatment of copper deficiency can result in permanent neurological impairment, clinicians should promptly rule out copper deficiency in patients being evaluated for MDS, especially if presenting with neurological symptoms [4, 14]. The steady rise of bariatric surgeries performed to curb the obesity epidemic will likely increase the prevalence of nutritional deficiencies, including copper deficiency [15]. Most importantly, early diagnosis can alleviate symptoms and spare patients' toxicities associated with chemotherapeutic agents or allo-HCT.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Disclosure
This study was performed as part of employment or enrollment at the Medical College of Wisconsin.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 (a-b) Wright Giemsa-stained bone marrow aspirate smear slide (l000x magnification) showing neutrophil precursors (a) and an erythroid precursor (b) bottom with cytoplasmic vacuoles. (c) Prussian blue-stained bone marrow aspirate smear slide (l000x magnification) showing ring sideroblasts.
Table 1 Laboratory values.
Initial presentation +2 months +4 months allo-HCT consult 1 month postcopper replacement
WBC, K/µL 1.3 1.4 0.8 4.3
ANC, K/µL 0.7 0.4 0.29 3.3
MCV 108 96 97 93
Hgb, g/dL 6.6 7.1 7.3 11.6
PLT, K/µL 222 191 144 157
Vit B12 (211–911) >2000 — 507 —
Copper (80–155) — — <10 107
Ceruloplasmin (17–54) — — <3 —
WBC, white blood cell; ANC, absolute neutrophil count; MCV, mean corpuscular volume; Hgb, hemoglobin; PLT, platelet; Vit, vitamin. Bolded values are abnormal. | CYANOCOBALAMIN, PREDNISONE, ZINC | DrugsGivenReaction | CC BY | 34881068 | 20,511,654 | 2021 |
What was the administration route of drug 'CYANOCOBALAMIN'? | Mimicking Myelodysplastic Syndrome: Importance of Differential Diagnosis.
Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation.
pmc1. Introduction
Myelodysplastic syndrome (MDS) is a hematological malignancy that presents with pancytopenia, ineffective hematopoiesis, and cytogenetic abnormalities; the condition is considered incurable without an allogeneic stem cell transplant (allo-HCT) [1]. The diagnosis is made through bone marrow biopsy evaluation and requires appropriate exclusion of other causes of cytopenias, e.g., nutritional deficiencies, drug toxicities, infection, and autoimmune disease [2]. Several conditions can mimic MDS with potentially catastrophic consequences should the patient proceed towards allo-HCT [3]. In this report, we describe a case of copper deficiency initially diagnosed as MDS to emphasize the need to rule out nutritional deficiency in the workup of patients with suspected MDS. IRB submission was deferred per institutional policy for case series including less than 3 patients.
2. Case Report
A 61-year-old female with a history of alcoholism, vitamin B12 deficiency, and remote gastric bypass was referred to hematology with a two-month history of shortness of breath and cytopenias. She admitted to consuming 2–4 alcoholic drinks weekly and had just recently resumed B12 supplementation. Complete blood count revealed a severe macrocytic anemia (6.6 g/dL), MCV (108 fl), and neutropenia (ANC 520/μL). She had an elevated vitamin B12 level reflective of recent intramuscular supplementation (Table 1). Bone marrow biopsy was performed and revealed a hypercellular marrow for age (75%) and dyserythropoiesis but without cytogenetic and dysplastic changes characteristic of MDS. However, early MDS could not be ruled out. Despite two months of B12 supplementation, her anemia and leukopenia did not improve, and she required further transfusion. Direct Coombs testing, lactate dehydrogenase, reticulocyte count, haptoglobin, and methylmalonic acid testing revealed no significant abnormalities. Daily prednisone (40 mg) was started as empiric treatment for potential occult autoimmune condition with no efficacy. The patient's anemia continued to worsen (5.7 g/dL) requiring further transfusion with progressive neutropenia. Additionally, she developed bilateral foot paresthesias, which were felt to be due to Raynaud's phenomena. A repeat bone marrow biopsy now revealed a hypocellular bone marrow (20–30%) with erythroid hyperplasia and dyserythropoiesis. A presumptive diagnosis of MDS (R–IPSS 3) was made, and the patient was referred for allo-HCT evaluation.
At time of consultation, the patient reported taking a daily zinc supplement for several years for a previously diagnosed deficiency. The combined history of gastric bypass and high zinc intake raised suspicion for copper deficiency, and additional labs were drawn. Both serum ceruloplasmin (<3 mg/dL) and copper (10 μg/dL) were below the lower limits of diagnostic testing, and serum zinc (151 μg/dL) was elevated. Hematopathology review of the second bone marrow biopsy showed vacuolated precursors and ring sideroblasts commonly seen in copper deficiency (Figure 1). Accordingly, the patient was started on IV cupric chloride (2 g) daily for 5 days and then once weekly for four weeks. At one-month follow-up, the patient's anemia improved and leukopenia resolved (Table 1). Although her energy level improved, her paresthesia remained.
3. Discussion
Copper deficiency is a rare nutritional condition that results in reversible hematologic findings—anemia and neutropenia—and often irreversible neurologic manifestations—optic neuropathy, paresthesia, and spasticity [4]. The most common etiologies of copper deficiency in the United States are gastric bypass surgery, excessive zinc intake, and celiac disease [4, 5]. Since the majority of copper is absorbed in the stomach and duodenum, gastric bypass surgery significantly increases risk of copper deficiency [4, 6]. The utility of prophylactic oral copper supplementation or serum copper monitoring in bariatric surgery patients is well established [6, 7]. Zinc primarily upregulates expression of metallothionein in enterocytes, which binds copper to a greater extent than zinc, thereby sequestering copper within the intestinal tract [4, 8].
While our patient had risk factors for development of copper deficiency, her age and clinical presentation were suggestive of MDS [9]. The early signs of insufficiency of hematopoiesis seen in copper deficiency—cytopenias and dysplastic changes—mimic those seen in clonal expansion driven diseases such as MDS—a condition encountered more frequently [10, 11]. Although not pathognomonic for copper deficiency, intracytoplasmic vacuoles in precursor cells and ring sideroblasts are subtle findings often observed on bone marrow biopsy as found in this patient; cytogenetic changes are not found in copper deficiency [10, 12]. Although the mechanism of copper deficiency anemia is unclear, copper is a vital coenzyme in the function of hephaestin—responsible for the oxidation of dietary iron—and ceruloplasmin—responsible for the transfer of iron from macrophages/monocytes to plasma [4, 13].
4. Conclusion
In this report, we highlight the clinical progression of occult copper deficiency. Although our patient's copper deficiency was initially misdiagnosed, prompt treatment with IV cupric chloride ameliorated the hematological and constitutional symptoms of low copper. Since delayed treatment of copper deficiency can result in permanent neurological impairment, clinicians should promptly rule out copper deficiency in patients being evaluated for MDS, especially if presenting with neurological symptoms [4, 14]. The steady rise of bariatric surgeries performed to curb the obesity epidemic will likely increase the prevalence of nutritional deficiencies, including copper deficiency [15]. Most importantly, early diagnosis can alleviate symptoms and spare patients' toxicities associated with chemotherapeutic agents or allo-HCT.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Disclosure
This study was performed as part of employment or enrollment at the Medical College of Wisconsin.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 (a-b) Wright Giemsa-stained bone marrow aspirate smear slide (l000x magnification) showing neutrophil precursors (a) and an erythroid precursor (b) bottom with cytoplasmic vacuoles. (c) Prussian blue-stained bone marrow aspirate smear slide (l000x magnification) showing ring sideroblasts.
Table 1 Laboratory values.
Initial presentation +2 months +4 months allo-HCT consult 1 month postcopper replacement
WBC, K/µL 1.3 1.4 0.8 4.3
ANC, K/µL 0.7 0.4 0.29 3.3
MCV 108 96 97 93
Hgb, g/dL 6.6 7.1 7.3 11.6
PLT, K/µL 222 191 144 157
Vit B12 (211–911) >2000 — 507 —
Copper (80–155) — — <10 107
Ceruloplasmin (17–54) — — <3 —
WBC, white blood cell; ANC, absolute neutrophil count; MCV, mean corpuscular volume; Hgb, hemoglobin; PLT, platelet; Vit, vitamin. Bolded values are abnormal. | Intramuscular | DrugAdministrationRoute | CC BY | 34881068 | 20,511,654 | 2021 |
What was the dosage of drug 'ZINC'? | Mimicking Myelodysplastic Syndrome: Importance of Differential Diagnosis.
Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation.
pmc1. Introduction
Myelodysplastic syndrome (MDS) is a hematological malignancy that presents with pancytopenia, ineffective hematopoiesis, and cytogenetic abnormalities; the condition is considered incurable without an allogeneic stem cell transplant (allo-HCT) [1]. The diagnosis is made through bone marrow biopsy evaluation and requires appropriate exclusion of other causes of cytopenias, e.g., nutritional deficiencies, drug toxicities, infection, and autoimmune disease [2]. Several conditions can mimic MDS with potentially catastrophic consequences should the patient proceed towards allo-HCT [3]. In this report, we describe a case of copper deficiency initially diagnosed as MDS to emphasize the need to rule out nutritional deficiency in the workup of patients with suspected MDS. IRB submission was deferred per institutional policy for case series including less than 3 patients.
2. Case Report
A 61-year-old female with a history of alcoholism, vitamin B12 deficiency, and remote gastric bypass was referred to hematology with a two-month history of shortness of breath and cytopenias. She admitted to consuming 2–4 alcoholic drinks weekly and had just recently resumed B12 supplementation. Complete blood count revealed a severe macrocytic anemia (6.6 g/dL), MCV (108 fl), and neutropenia (ANC 520/μL). She had an elevated vitamin B12 level reflective of recent intramuscular supplementation (Table 1). Bone marrow biopsy was performed and revealed a hypercellular marrow for age (75%) and dyserythropoiesis but without cytogenetic and dysplastic changes characteristic of MDS. However, early MDS could not be ruled out. Despite two months of B12 supplementation, her anemia and leukopenia did not improve, and she required further transfusion. Direct Coombs testing, lactate dehydrogenase, reticulocyte count, haptoglobin, and methylmalonic acid testing revealed no significant abnormalities. Daily prednisone (40 mg) was started as empiric treatment for potential occult autoimmune condition with no efficacy. The patient's anemia continued to worsen (5.7 g/dL) requiring further transfusion with progressive neutropenia. Additionally, she developed bilateral foot paresthesias, which were felt to be due to Raynaud's phenomena. A repeat bone marrow biopsy now revealed a hypocellular bone marrow (20–30%) with erythroid hyperplasia and dyserythropoiesis. A presumptive diagnosis of MDS (R–IPSS 3) was made, and the patient was referred for allo-HCT evaluation.
At time of consultation, the patient reported taking a daily zinc supplement for several years for a previously diagnosed deficiency. The combined history of gastric bypass and high zinc intake raised suspicion for copper deficiency, and additional labs were drawn. Both serum ceruloplasmin (<3 mg/dL) and copper (10 μg/dL) were below the lower limits of diagnostic testing, and serum zinc (151 μg/dL) was elevated. Hematopathology review of the second bone marrow biopsy showed vacuolated precursors and ring sideroblasts commonly seen in copper deficiency (Figure 1). Accordingly, the patient was started on IV cupric chloride (2 g) daily for 5 days and then once weekly for four weeks. At one-month follow-up, the patient's anemia improved and leukopenia resolved (Table 1). Although her energy level improved, her paresthesia remained.
3. Discussion
Copper deficiency is a rare nutritional condition that results in reversible hematologic findings—anemia and neutropenia—and often irreversible neurologic manifestations—optic neuropathy, paresthesia, and spasticity [4]. The most common etiologies of copper deficiency in the United States are gastric bypass surgery, excessive zinc intake, and celiac disease [4, 5]. Since the majority of copper is absorbed in the stomach and duodenum, gastric bypass surgery significantly increases risk of copper deficiency [4, 6]. The utility of prophylactic oral copper supplementation or serum copper monitoring in bariatric surgery patients is well established [6, 7]. Zinc primarily upregulates expression of metallothionein in enterocytes, which binds copper to a greater extent than zinc, thereby sequestering copper within the intestinal tract [4, 8].
While our patient had risk factors for development of copper deficiency, her age and clinical presentation were suggestive of MDS [9]. The early signs of insufficiency of hematopoiesis seen in copper deficiency—cytopenias and dysplastic changes—mimic those seen in clonal expansion driven diseases such as MDS—a condition encountered more frequently [10, 11]. Although not pathognomonic for copper deficiency, intracytoplasmic vacuoles in precursor cells and ring sideroblasts are subtle findings often observed on bone marrow biopsy as found in this patient; cytogenetic changes are not found in copper deficiency [10, 12]. Although the mechanism of copper deficiency anemia is unclear, copper is a vital coenzyme in the function of hephaestin—responsible for the oxidation of dietary iron—and ceruloplasmin—responsible for the transfer of iron from macrophages/monocytes to plasma [4, 13].
4. Conclusion
In this report, we highlight the clinical progression of occult copper deficiency. Although our patient's copper deficiency was initially misdiagnosed, prompt treatment with IV cupric chloride ameliorated the hematological and constitutional symptoms of low copper. Since delayed treatment of copper deficiency can result in permanent neurological impairment, clinicians should promptly rule out copper deficiency in patients being evaluated for MDS, especially if presenting with neurological symptoms [4, 14]. The steady rise of bariatric surgeries performed to curb the obesity epidemic will likely increase the prevalence of nutritional deficiencies, including copper deficiency [15]. Most importantly, early diagnosis can alleviate symptoms and spare patients' toxicities associated with chemotherapeutic agents or allo-HCT.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Disclosure
This study was performed as part of employment or enrollment at the Medical College of Wisconsin.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 (a-b) Wright Giemsa-stained bone marrow aspirate smear slide (l000x magnification) showing neutrophil precursors (a) and an erythroid precursor (b) bottom with cytoplasmic vacuoles. (c) Prussian blue-stained bone marrow aspirate smear slide (l000x magnification) showing ring sideroblasts.
Table 1 Laboratory values.
Initial presentation +2 months +4 months allo-HCT consult 1 month postcopper replacement
WBC, K/µL 1.3 1.4 0.8 4.3
ANC, K/µL 0.7 0.4 0.29 3.3
MCV 108 96 97 93
Hgb, g/dL 6.6 7.1 7.3 11.6
PLT, K/µL 222 191 144 157
Vit B12 (211–911) >2000 — 507 —
Copper (80–155) — — <10 107
Ceruloplasmin (17–54) — — <3 —
WBC, white blood cell; ANC, absolute neutrophil count; MCV, mean corpuscular volume; Hgb, hemoglobin; PLT, platelet; Vit, vitamin. Bolded values are abnormal. | TAKEN DAILY FOR MANY YEARS | DrugDosageText | CC BY | 34881068 | 20,511,654 | 2021 |
What was the outcome of reaction 'Copper deficiency'? | Mimicking Myelodysplastic Syndrome: Importance of Differential Diagnosis.
Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation.
pmc1. Introduction
Myelodysplastic syndrome (MDS) is a hematological malignancy that presents with pancytopenia, ineffective hematopoiesis, and cytogenetic abnormalities; the condition is considered incurable without an allogeneic stem cell transplant (allo-HCT) [1]. The diagnosis is made through bone marrow biopsy evaluation and requires appropriate exclusion of other causes of cytopenias, e.g., nutritional deficiencies, drug toxicities, infection, and autoimmune disease [2]. Several conditions can mimic MDS with potentially catastrophic consequences should the patient proceed towards allo-HCT [3]. In this report, we describe a case of copper deficiency initially diagnosed as MDS to emphasize the need to rule out nutritional deficiency in the workup of patients with suspected MDS. IRB submission was deferred per institutional policy for case series including less than 3 patients.
2. Case Report
A 61-year-old female with a history of alcoholism, vitamin B12 deficiency, and remote gastric bypass was referred to hematology with a two-month history of shortness of breath and cytopenias. She admitted to consuming 2–4 alcoholic drinks weekly and had just recently resumed B12 supplementation. Complete blood count revealed a severe macrocytic anemia (6.6 g/dL), MCV (108 fl), and neutropenia (ANC 520/μL). She had an elevated vitamin B12 level reflective of recent intramuscular supplementation (Table 1). Bone marrow biopsy was performed and revealed a hypercellular marrow for age (75%) and dyserythropoiesis but without cytogenetic and dysplastic changes characteristic of MDS. However, early MDS could not be ruled out. Despite two months of B12 supplementation, her anemia and leukopenia did not improve, and she required further transfusion. Direct Coombs testing, lactate dehydrogenase, reticulocyte count, haptoglobin, and methylmalonic acid testing revealed no significant abnormalities. Daily prednisone (40 mg) was started as empiric treatment for potential occult autoimmune condition with no efficacy. The patient's anemia continued to worsen (5.7 g/dL) requiring further transfusion with progressive neutropenia. Additionally, she developed bilateral foot paresthesias, which were felt to be due to Raynaud's phenomena. A repeat bone marrow biopsy now revealed a hypocellular bone marrow (20–30%) with erythroid hyperplasia and dyserythropoiesis. A presumptive diagnosis of MDS (R–IPSS 3) was made, and the patient was referred for allo-HCT evaluation.
At time of consultation, the patient reported taking a daily zinc supplement for several years for a previously diagnosed deficiency. The combined history of gastric bypass and high zinc intake raised suspicion for copper deficiency, and additional labs were drawn. Both serum ceruloplasmin (<3 mg/dL) and copper (10 μg/dL) were below the lower limits of diagnostic testing, and serum zinc (151 μg/dL) was elevated. Hematopathology review of the second bone marrow biopsy showed vacuolated precursors and ring sideroblasts commonly seen in copper deficiency (Figure 1). Accordingly, the patient was started on IV cupric chloride (2 g) daily for 5 days and then once weekly for four weeks. At one-month follow-up, the patient's anemia improved and leukopenia resolved (Table 1). Although her energy level improved, her paresthesia remained.
3. Discussion
Copper deficiency is a rare nutritional condition that results in reversible hematologic findings—anemia and neutropenia—and often irreversible neurologic manifestations—optic neuropathy, paresthesia, and spasticity [4]. The most common etiologies of copper deficiency in the United States are gastric bypass surgery, excessive zinc intake, and celiac disease [4, 5]. Since the majority of copper is absorbed in the stomach and duodenum, gastric bypass surgery significantly increases risk of copper deficiency [4, 6]. The utility of prophylactic oral copper supplementation or serum copper monitoring in bariatric surgery patients is well established [6, 7]. Zinc primarily upregulates expression of metallothionein in enterocytes, which binds copper to a greater extent than zinc, thereby sequestering copper within the intestinal tract [4, 8].
While our patient had risk factors for development of copper deficiency, her age and clinical presentation were suggestive of MDS [9]. The early signs of insufficiency of hematopoiesis seen in copper deficiency—cytopenias and dysplastic changes—mimic those seen in clonal expansion driven diseases such as MDS—a condition encountered more frequently [10, 11]. Although not pathognomonic for copper deficiency, intracytoplasmic vacuoles in precursor cells and ring sideroblasts are subtle findings often observed on bone marrow biopsy as found in this patient; cytogenetic changes are not found in copper deficiency [10, 12]. Although the mechanism of copper deficiency anemia is unclear, copper is a vital coenzyme in the function of hephaestin—responsible for the oxidation of dietary iron—and ceruloplasmin—responsible for the transfer of iron from macrophages/monocytes to plasma [4, 13].
4. Conclusion
In this report, we highlight the clinical progression of occult copper deficiency. Although our patient's copper deficiency was initially misdiagnosed, prompt treatment with IV cupric chloride ameliorated the hematological and constitutional symptoms of low copper. Since delayed treatment of copper deficiency can result in permanent neurological impairment, clinicians should promptly rule out copper deficiency in patients being evaluated for MDS, especially if presenting with neurological symptoms [4, 14]. The steady rise of bariatric surgeries performed to curb the obesity epidemic will likely increase the prevalence of nutritional deficiencies, including copper deficiency [15]. Most importantly, early diagnosis can alleviate symptoms and spare patients' toxicities associated with chemotherapeutic agents or allo-HCT.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Disclosure
This study was performed as part of employment or enrollment at the Medical College of Wisconsin.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 (a-b) Wright Giemsa-stained bone marrow aspirate smear slide (l000x magnification) showing neutrophil precursors (a) and an erythroid precursor (b) bottom with cytoplasmic vacuoles. (c) Prussian blue-stained bone marrow aspirate smear slide (l000x magnification) showing ring sideroblasts.
Table 1 Laboratory values.
Initial presentation +2 months +4 months allo-HCT consult 1 month postcopper replacement
WBC, K/µL 1.3 1.4 0.8 4.3
ANC, K/µL 0.7 0.4 0.29 3.3
MCV 108 96 97 93
Hgb, g/dL 6.6 7.1 7.3 11.6
PLT, K/µL 222 191 144 157
Vit B12 (211–911) >2000 — 507 —
Copper (80–155) — — <10 107
Ceruloplasmin (17–54) — — <3 —
WBC, white blood cell; ANC, absolute neutrophil count; MCV, mean corpuscular volume; Hgb, hemoglobin; PLT, platelet; Vit, vitamin. Bolded values are abnormal. | Recovering | ReactionOutcome | CC BY | 34881068 | 20,511,654 | 2021 |
What was the outcome of reaction 'Pancytopenia'? | Mimicking Myelodysplastic Syndrome: Importance of Differential Diagnosis.
Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation.
pmc1. Introduction
Myelodysplastic syndrome (MDS) is a hematological malignancy that presents with pancytopenia, ineffective hematopoiesis, and cytogenetic abnormalities; the condition is considered incurable without an allogeneic stem cell transplant (allo-HCT) [1]. The diagnosis is made through bone marrow biopsy evaluation and requires appropriate exclusion of other causes of cytopenias, e.g., nutritional deficiencies, drug toxicities, infection, and autoimmune disease [2]. Several conditions can mimic MDS with potentially catastrophic consequences should the patient proceed towards allo-HCT [3]. In this report, we describe a case of copper deficiency initially diagnosed as MDS to emphasize the need to rule out nutritional deficiency in the workup of patients with suspected MDS. IRB submission was deferred per institutional policy for case series including less than 3 patients.
2. Case Report
A 61-year-old female with a history of alcoholism, vitamin B12 deficiency, and remote gastric bypass was referred to hematology with a two-month history of shortness of breath and cytopenias. She admitted to consuming 2–4 alcoholic drinks weekly and had just recently resumed B12 supplementation. Complete blood count revealed a severe macrocytic anemia (6.6 g/dL), MCV (108 fl), and neutropenia (ANC 520/μL). She had an elevated vitamin B12 level reflective of recent intramuscular supplementation (Table 1). Bone marrow biopsy was performed and revealed a hypercellular marrow for age (75%) and dyserythropoiesis but without cytogenetic and dysplastic changes characteristic of MDS. However, early MDS could not be ruled out. Despite two months of B12 supplementation, her anemia and leukopenia did not improve, and she required further transfusion. Direct Coombs testing, lactate dehydrogenase, reticulocyte count, haptoglobin, and methylmalonic acid testing revealed no significant abnormalities. Daily prednisone (40 mg) was started as empiric treatment for potential occult autoimmune condition with no efficacy. The patient's anemia continued to worsen (5.7 g/dL) requiring further transfusion with progressive neutropenia. Additionally, she developed bilateral foot paresthesias, which were felt to be due to Raynaud's phenomena. A repeat bone marrow biopsy now revealed a hypocellular bone marrow (20–30%) with erythroid hyperplasia and dyserythropoiesis. A presumptive diagnosis of MDS (R–IPSS 3) was made, and the patient was referred for allo-HCT evaluation.
At time of consultation, the patient reported taking a daily zinc supplement for several years for a previously diagnosed deficiency. The combined history of gastric bypass and high zinc intake raised suspicion for copper deficiency, and additional labs were drawn. Both serum ceruloplasmin (<3 mg/dL) and copper (10 μg/dL) were below the lower limits of diagnostic testing, and serum zinc (151 μg/dL) was elevated. Hematopathology review of the second bone marrow biopsy showed vacuolated precursors and ring sideroblasts commonly seen in copper deficiency (Figure 1). Accordingly, the patient was started on IV cupric chloride (2 g) daily for 5 days and then once weekly for four weeks. At one-month follow-up, the patient's anemia improved and leukopenia resolved (Table 1). Although her energy level improved, her paresthesia remained.
3. Discussion
Copper deficiency is a rare nutritional condition that results in reversible hematologic findings—anemia and neutropenia—and often irreversible neurologic manifestations—optic neuropathy, paresthesia, and spasticity [4]. The most common etiologies of copper deficiency in the United States are gastric bypass surgery, excessive zinc intake, and celiac disease [4, 5]. Since the majority of copper is absorbed in the stomach and duodenum, gastric bypass surgery significantly increases risk of copper deficiency [4, 6]. The utility of prophylactic oral copper supplementation or serum copper monitoring in bariatric surgery patients is well established [6, 7]. Zinc primarily upregulates expression of metallothionein in enterocytes, which binds copper to a greater extent than zinc, thereby sequestering copper within the intestinal tract [4, 8].
While our patient had risk factors for development of copper deficiency, her age and clinical presentation were suggestive of MDS [9]. The early signs of insufficiency of hematopoiesis seen in copper deficiency—cytopenias and dysplastic changes—mimic those seen in clonal expansion driven diseases such as MDS—a condition encountered more frequently [10, 11]. Although not pathognomonic for copper deficiency, intracytoplasmic vacuoles in precursor cells and ring sideroblasts are subtle findings often observed on bone marrow biopsy as found in this patient; cytogenetic changes are not found in copper deficiency [10, 12]. Although the mechanism of copper deficiency anemia is unclear, copper is a vital coenzyme in the function of hephaestin—responsible for the oxidation of dietary iron—and ceruloplasmin—responsible for the transfer of iron from macrophages/monocytes to plasma [4, 13].
4. Conclusion
In this report, we highlight the clinical progression of occult copper deficiency. Although our patient's copper deficiency was initially misdiagnosed, prompt treatment with IV cupric chloride ameliorated the hematological and constitutional symptoms of low copper. Since delayed treatment of copper deficiency can result in permanent neurological impairment, clinicians should promptly rule out copper deficiency in patients being evaluated for MDS, especially if presenting with neurological symptoms [4, 14]. The steady rise of bariatric surgeries performed to curb the obesity epidemic will likely increase the prevalence of nutritional deficiencies, including copper deficiency [15]. Most importantly, early diagnosis can alleviate symptoms and spare patients' toxicities associated with chemotherapeutic agents or allo-HCT.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Disclosure
This study was performed as part of employment or enrollment at the Medical College of Wisconsin.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 (a-b) Wright Giemsa-stained bone marrow aspirate smear slide (l000x magnification) showing neutrophil precursors (a) and an erythroid precursor (b) bottom with cytoplasmic vacuoles. (c) Prussian blue-stained bone marrow aspirate smear slide (l000x magnification) showing ring sideroblasts.
Table 1 Laboratory values.
Initial presentation +2 months +4 months allo-HCT consult 1 month postcopper replacement
WBC, K/µL 1.3 1.4 0.8 4.3
ANC, K/µL 0.7 0.4 0.29 3.3
MCV 108 96 97 93
Hgb, g/dL 6.6 7.1 7.3 11.6
PLT, K/µL 222 191 144 157
Vit B12 (211–911) >2000 — 507 —
Copper (80–155) — — <10 107
Ceruloplasmin (17–54) — — <3 —
WBC, white blood cell; ANC, absolute neutrophil count; MCV, mean corpuscular volume; Hgb, hemoglobin; PLT, platelet; Vit, vitamin. Bolded values are abnormal. | Recovering | ReactionOutcome | CC BY | 34881068 | 20,511,654 | 2021 |
What was the outcome of reaction 'Paraesthesia'? | Mimicking Myelodysplastic Syndrome: Importance of Differential Diagnosis.
Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation.
pmc1. Introduction
Myelodysplastic syndrome (MDS) is a hematological malignancy that presents with pancytopenia, ineffective hematopoiesis, and cytogenetic abnormalities; the condition is considered incurable without an allogeneic stem cell transplant (allo-HCT) [1]. The diagnosis is made through bone marrow biopsy evaluation and requires appropriate exclusion of other causes of cytopenias, e.g., nutritional deficiencies, drug toxicities, infection, and autoimmune disease [2]. Several conditions can mimic MDS with potentially catastrophic consequences should the patient proceed towards allo-HCT [3]. In this report, we describe a case of copper deficiency initially diagnosed as MDS to emphasize the need to rule out nutritional deficiency in the workup of patients with suspected MDS. IRB submission was deferred per institutional policy for case series including less than 3 patients.
2. Case Report
A 61-year-old female with a history of alcoholism, vitamin B12 deficiency, and remote gastric bypass was referred to hematology with a two-month history of shortness of breath and cytopenias. She admitted to consuming 2–4 alcoholic drinks weekly and had just recently resumed B12 supplementation. Complete blood count revealed a severe macrocytic anemia (6.6 g/dL), MCV (108 fl), and neutropenia (ANC 520/μL). She had an elevated vitamin B12 level reflective of recent intramuscular supplementation (Table 1). Bone marrow biopsy was performed and revealed a hypercellular marrow for age (75%) and dyserythropoiesis but without cytogenetic and dysplastic changes characteristic of MDS. However, early MDS could not be ruled out. Despite two months of B12 supplementation, her anemia and leukopenia did not improve, and she required further transfusion. Direct Coombs testing, lactate dehydrogenase, reticulocyte count, haptoglobin, and methylmalonic acid testing revealed no significant abnormalities. Daily prednisone (40 mg) was started as empiric treatment for potential occult autoimmune condition with no efficacy. The patient's anemia continued to worsen (5.7 g/dL) requiring further transfusion with progressive neutropenia. Additionally, she developed bilateral foot paresthesias, which were felt to be due to Raynaud's phenomena. A repeat bone marrow biopsy now revealed a hypocellular bone marrow (20–30%) with erythroid hyperplasia and dyserythropoiesis. A presumptive diagnosis of MDS (R–IPSS 3) was made, and the patient was referred for allo-HCT evaluation.
At time of consultation, the patient reported taking a daily zinc supplement for several years for a previously diagnosed deficiency. The combined history of gastric bypass and high zinc intake raised suspicion for copper deficiency, and additional labs were drawn. Both serum ceruloplasmin (<3 mg/dL) and copper (10 μg/dL) were below the lower limits of diagnostic testing, and serum zinc (151 μg/dL) was elevated. Hematopathology review of the second bone marrow biopsy showed vacuolated precursors and ring sideroblasts commonly seen in copper deficiency (Figure 1). Accordingly, the patient was started on IV cupric chloride (2 g) daily for 5 days and then once weekly for four weeks. At one-month follow-up, the patient's anemia improved and leukopenia resolved (Table 1). Although her energy level improved, her paresthesia remained.
3. Discussion
Copper deficiency is a rare nutritional condition that results in reversible hematologic findings—anemia and neutropenia—and often irreversible neurologic manifestations—optic neuropathy, paresthesia, and spasticity [4]. The most common etiologies of copper deficiency in the United States are gastric bypass surgery, excessive zinc intake, and celiac disease [4, 5]. Since the majority of copper is absorbed in the stomach and duodenum, gastric bypass surgery significantly increases risk of copper deficiency [4, 6]. The utility of prophylactic oral copper supplementation or serum copper monitoring in bariatric surgery patients is well established [6, 7]. Zinc primarily upregulates expression of metallothionein in enterocytes, which binds copper to a greater extent than zinc, thereby sequestering copper within the intestinal tract [4, 8].
While our patient had risk factors for development of copper deficiency, her age and clinical presentation were suggestive of MDS [9]. The early signs of insufficiency of hematopoiesis seen in copper deficiency—cytopenias and dysplastic changes—mimic those seen in clonal expansion driven diseases such as MDS—a condition encountered more frequently [10, 11]. Although not pathognomonic for copper deficiency, intracytoplasmic vacuoles in precursor cells and ring sideroblasts are subtle findings often observed on bone marrow biopsy as found in this patient; cytogenetic changes are not found in copper deficiency [10, 12]. Although the mechanism of copper deficiency anemia is unclear, copper is a vital coenzyme in the function of hephaestin—responsible for the oxidation of dietary iron—and ceruloplasmin—responsible for the transfer of iron from macrophages/monocytes to plasma [4, 13].
4. Conclusion
In this report, we highlight the clinical progression of occult copper deficiency. Although our patient's copper deficiency was initially misdiagnosed, prompt treatment with IV cupric chloride ameliorated the hematological and constitutional symptoms of low copper. Since delayed treatment of copper deficiency can result in permanent neurological impairment, clinicians should promptly rule out copper deficiency in patients being evaluated for MDS, especially if presenting with neurological symptoms [4, 14]. The steady rise of bariatric surgeries performed to curb the obesity epidemic will likely increase the prevalence of nutritional deficiencies, including copper deficiency [15]. Most importantly, early diagnosis can alleviate symptoms and spare patients' toxicities associated with chemotherapeutic agents or allo-HCT.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Disclosure
This study was performed as part of employment or enrollment at the Medical College of Wisconsin.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 (a-b) Wright Giemsa-stained bone marrow aspirate smear slide (l000x magnification) showing neutrophil precursors (a) and an erythroid precursor (b) bottom with cytoplasmic vacuoles. (c) Prussian blue-stained bone marrow aspirate smear slide (l000x magnification) showing ring sideroblasts.
Table 1 Laboratory values.
Initial presentation +2 months +4 months allo-HCT consult 1 month postcopper replacement
WBC, K/µL 1.3 1.4 0.8 4.3
ANC, K/µL 0.7 0.4 0.29 3.3
MCV 108 96 97 93
Hgb, g/dL 6.6 7.1 7.3 11.6
PLT, K/µL 222 191 144 157
Vit B12 (211–911) >2000 — 507 —
Copper (80–155) — — <10 107
Ceruloplasmin (17–54) — — <3 —
WBC, white blood cell; ANC, absolute neutrophil count; MCV, mean corpuscular volume; Hgb, hemoglobin; PLT, platelet; Vit, vitamin. Bolded values are abnormal. | Not recovered | ReactionOutcome | CC BY | 34881068 | 20,511,654 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Parvovirus B19 Infection due to over Immunosuppression in Kidney Transplant Recipients: Case Reports and Literature Review.
Parvovirus B19 (PB19) is a single-stranded DNA virus that belongs to the Erythrovirus genus within the Parvoviridae family. Clinical presentations associated with PB19 infection vary greatly, depending on the infected individual's age and hematologic and immunologic status. The limited data available regarding consensus on screening algorithms and indications in donors and recipients prior to kidney transplantation makes diagnosis and management challenging. We presented 3 cases of pure red cell aplasia due to parvovirus B19 after kidney transplant. These patients were diagnosed with severe normocytic, normochromic anemia (hemoglobin below 60 g/L) in the 1st 6 months posttransplant. A complete anemia work-up revealed low reticulocyte count and was otherwise inconclusive. All patients were diagnosed with pure red cell aplasia due to parvovirus B19. Two patients improved after receiving intravenous immunoglobulin 2 gm/kg given over 4 doses. Unfortunately, they relapse after few weeks and required additional doses of intravenous immunoglobulin in conjugation with reduction of their immunosuppressive medication. The third patient improved after holding mycophenolate mofetil (MMF) and did not require intravenous immunoglobulin. Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in confirming the diagnosis. Intravenous immunoglobulin (IVIG) can be an effective treatment in immunocompromised patients with primary or relapsed PB19 infection in conjunction with minimizing immunosuppressive medication. Further research and consideration are required to determine appropriate and targeted screening in donors and recipients in the peritransplantation period.
pmc1. Introduction
Parvovirus (Erythrovirus) B19 (PB19) is a common human infection worldwide. It belongs to the Erythrovirus genus within the Parvoviridae family [1]. PB19 transmission occurs by different routes that include respiratory transmission, vertically from mother to fetus, transfusion of blood or blood-derived products, or organ transplantation [2]. After PB19 infection, immunocompetent individuals are considered immune. However, reinfection has been suspected in some cases [2]. During active infection, the virus binds to globoside (P antigen) receptors that are present in erythroid precursor cells. The virus infects, replicates in, and then, lyses erythroid progenitor cells [2]. This will lead to pure red cell aplasia on bone marrow examination by revealing the presence of giant pronormoblasts which can help the diagnostic process [3].
2. Clinical Presentation
Clinical manifestations depend on host's hematological status and immune responses [1]. There is a wide spectrum of clinical findings in immunocompetent patients with PB19 infection. Most individuals who have serologic evidence of prior infection do not recall ever having any specific symptoms classically associated with PB19. The brief period of red cell aplasia is generally subclinical in otherwise healthy individuals, in children and adults with chronic hemolytic anemia (e.g., sickle cell disease or hereditary spherocytosis); the short-term pure red cell aplasia associated with PB19 infection leads to acute worsening of anemia, termed an “aplastic crisis,” often necessitating blood transfusion. In children, PB19 can manifest in erythema infectiosum, also known as the “fifth” disease, which presents as rash, fever, malaise, and polyarthropathy. In pregnancy, PB19 infection is associated with hydrops fetalis [4].
In solid organ transplant recipients, PB19 infection occurs on average 7 weeks (range, 1 week–8 years) after transplantation. Up to 65% of transplant recipients with PB19 infection present within the first 3 months following transplantation [5]. Anemia is an expected finding of this infection in solid organ transplantation. Fever presents in only 25% while arthralgia occurs in 6% of transplant recipients. Leucopenia and thrombocytopenia are seen in 33% and 18%, respectively, which is similar to noninfected transplant recipient's rates. Notably, skin rash is seen more frequently in hematopoietic stem cell transplant as opposed to solid organ transplant recipients (33% vs. 6%) [5]. Tissue-invasive disease was reported in 11% of transplant recipients, manifesting as hepatitis, myocarditis, pneumonitis, collapsing glomerulopathy, encephalitis, or vasculitis [6–9].
While not common, relapsing PB19-related anemia has been observed in 33% of patients treated with IVIG for primary PB19 infection. The risk of relapse is higher in patients with primary PB19 infection and patients who received antithymocyte globulin (ATG) for induction therapy [10].
3. Diagnosis
Diagnosis is based on the detection of PB19 IgG or IgM antibodies or PB19 DNA in blood or tissue samples by polymerase chain reaction (PCR). Bone marrow study may show giant pronormoblasts with prominent nuclear inclusions, which is characteristic of PB19 infection (Figure 1).
4. Management in Transplant Recipients
Management of presumed or confirmed PB19 infection in transplant recipients includes reduction of immunosuppressive medication. Some case reports have shown recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [12]. While intravenous immunoglobulin (IVIG) has also been used to treat PB19 infection in many transplant recipients, with successful resolution of viremia [5, 13, 14], some other patients experienced long-lasting resolution of the infection without receiving IVIG [5]. Although the optimal dose of IVIG and the frequency of administration are not well studied, a dose of 400 mg/kg/day for 5 days has been recommended in some studies [5].
5. Case Presentation
5.1. Case 1
A 43-year-old man had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to IgA nephropathy. The induction agent used at the time of transplantation was ATG 4.5 mg/kg. Afterwards, he received immunosuppressive maintenance therapy that consisted of mycophenolate mofetil (MMF) 1000 mg twice daily, tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
After the transplant, hemoglobin remained stable in the range of 100-120 g/L until 4-month posttransplantation when the patient started to complain of dizziness and shortness of breath on exertion. Blood work at that time showed hemoglobin level of 58 mg/L that was normocytic and normochromic with normal morphology on the blood smear. The patient's reticulocyte count was inappropriately low at 3 × 109/L (normal range 10 − 86 × 109/L). Vitamin B12 and iron indices were normal, and the hemolytic screen was negative. PCR for Cytomegalovirus (CMV), BK virus, and Epstein-Barr virus (EBV) was negative. Serology for PB19 showed a negative IgG and an indeterminate IgM antibody level. The patient was transfused 2 units of red blood cells and discharged home on erythropoietin stimulating agent. MMF dose also reduced to 500 mg twice daily upon discharge.
Unfortunately, the patient was readmitted 2 weeks later with the same complaints and a hemoglobin level of 56 g/L. The reticulocyte count was persistently low at 5 × 109/L. PB19 serology was repeated and showed negative IgG and an indeterminate IgM. The patient received transfusion of 2 units of RBCs and PB19 PCR also positive this time. Patient started on IVIG (0.5 g/kg) for a total of 4 doses. MMF discontinued on this admission and patient discharge after completing IVIG course on prednisolone and tacrolimus only. On discharge, the patient's symptoms had improved, and hemoglobin was 87 g/L. Patients followed monthly in posttransplant clinic, and hemoglobin normalized after 1 month. MMF resumed at 500 mg bid after 4 months, and hemoglobin remained above 125 g/L during 3 years follow-up with no further relapse.
5.2. Case 2
A 26-year-old female had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to Alport syndrome. The induction agent used at the time of transplantation was ATG 4.2 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
The patient developed severe symptomatic, normocytic, and normochromic anemia (hemoglobin 55 g/L) 6 months after transplantation with normal platelet and white cell count. A complete anemia work-up showed low reticulocyte count; otherwise, inconclusive. Her severe anemia persisted for over 2 weeks despite packed blood cell transfusion, adjustment of immunosuppressant medications, and administration of erythropoietin stimulating agent. PB19 PCR was sent few days after admission and came back positive. MMF was held, and 2 gm/kg of IVIG was given over 4 doses. She was discharged few days after completing the IVIG course with better hemoglobin (90 g/L). The patient was seen after 2 weeks in the clinic with almost normalized hemoglobin (124 g/L). Hence, MMF 500 mg twice daily was restarted. 5 weeks later, the patient presented again to the emergency department with fatigability and shortness of breath and a hemoglobin level of 52 g/L. Another course of IVIG treatment was initiated. She received a total of 2 gm/kg over 4 doses, and MMF was held again. PB19 PCR came back positive yet again. After treatment, she improved and was discharged home. The hemoglobin level normalized after few weeks. Hence, MMF 500 mg BID was restarted. For the third time, the patient represented with severe anemia requiring blood transfusion. She was given IVIG 2 gm/kg again and discharge with a plan to discontinue MMF permanently. Her hemoglobin remained stable during the subsequent 2 years of follow-up with no further relapse.
5.3. Case 3
A 24-year-old female had a combined diseased donor kidney and liver transplant. The induction agent used at the time of transplantation was ATG 4 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
One month after discharge, the patient presented to the clinic with a hemoglobin drop reaching 61 g/L. The anemia was normocytic and normochromic with low reticulocyte. A complete anemia workup was inconclusive. The patient was already on an erythropoietin stimulating agent. PB19 PCR test was sent and came back positive. Patient was also found to have BK viremia with 11000 copies detected via PCR. MMF was discontinued, and she was followed in transplant clinic weekly. Her hemoglobin improved and reached 123 g/L after 4 weeks and she did not require IVIG. BK viremia resolved after 2 months as well. Her hemoglobin remains stable during the subsequent 2-year follow-up period. The MMF was never resumed.
6. Discussion
Kidney transplant recipients are highly susceptible to infections such as PB19 [15]. This is due to the use of potent immunosuppressive agents such as ATG to prevent early acute rejection and because of the effect of sustained long-term immunosuppression to prevent graft loss. In this case series, we are presenting 3 cases presented with symptomatic, normocytic, and normochromic anemia with normal platelet and white cell count. They have positive PB19 PCR. Although posttransplant anemia could be related to medication such as ATG and MMF, this is unlikely in our cases because these medications mainly cause leucopenia and thrombocytopenia as well, in addition to positive PB19 PCR in our cases that suggest pure red cell aplasia due to PB19 infection.
PB19 infection in transplanted patients often leads to pure red cell aplasia by attacking erythroid progenitor cells in the bone marrow [16]. Induction with ATG was found to have a higher risk for PB19 infection compared to the other induction agents [17]. Maintenance regimen also plays a role in the risk for PB19 infection as one study showed substitution of tacrolimus with cyclosporine was followed by resolution of anemia and viral clearance [11]. The presence of viral coinfection with PB19 such as CMV and human herpesvirus 6 has also been reported. In our case series, the noted patients' risk factors for PB19 infection and relapse included induction with ATG and having negative IgG on PB19 serology testing suggesting a primary infection, and not reactivation. Similar to other case reports, one of our patients also has a coinfection with BK virus [18].
PB19 infection is likely underdiagnosed in organ transplant recipients, and a high index of suspicion is necessary to allow for prompt identification of PB19 infection among renal transplant recipients with anemia of unclear etiology.
Our case series further suggests that the treatment of PB19 relies on the reduction of immunosuppression and IVIG administration. There is no clear evidence to support the best practice for adjusting the immunosuppressive medication. Some case reports showed recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [11]. In our cases, we discontinue MMF in all 3 cases by the end. These cases suggest that treatment with IVIG is effective in treating primary infection and relapse, but holding antimetabolite immunosuppressive drugs is essential in treating such cases and preventing further relapses, although we do not know when should we resume it.
7. Conclusion
Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in establishing the diagnosis. IVIG may be an effective treatment in immunocompromised patients with primary and relapsing PB19 infection. Minimizing or holding antimetabolite immunosuppressive drugs plays a vital role in treating and preventing PB19 relapse. Further research and consideration are required to determine an appropriate screening protocol for donors and recipients in the peritransplantation period.
Data Availability
The detailed case data used to support the findings are available from the corresponding author upon request.
Ethical Approval
The study was approved by the King Abdullah International Medical Research Center (KAIMRC) ethical committee with Memo Ref. No. IRBC/01095/21.
Consent
Written informed consent was obtained from the patients for being included in this case report publication.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
A Altheaby, M Alotaibi, N Alajlan, and A Alshareef wrote the proposal and collect the data for 3 cases. M Alruwaymi, Ghaleb Aboalsamh, and M F Shaheen wrote the manuscript. A Altheaby, M Alzunitan, and Z Arabi did all editing and reviewing of the manuscript.
Figure 1 May–Grünwald–Giemsa staining of bone marrow aspirate showing the classical feature of PRCA, namely, a red inclusion in the nucleus of giant pronormoblasts (arrow) [11]. | MYCOPHENOLATE MOFETIL, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY | 34881070 | 20,206,212 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Parvovirus B19 infection'. | Parvovirus B19 Infection due to over Immunosuppression in Kidney Transplant Recipients: Case Reports and Literature Review.
Parvovirus B19 (PB19) is a single-stranded DNA virus that belongs to the Erythrovirus genus within the Parvoviridae family. Clinical presentations associated with PB19 infection vary greatly, depending on the infected individual's age and hematologic and immunologic status. The limited data available regarding consensus on screening algorithms and indications in donors and recipients prior to kidney transplantation makes diagnosis and management challenging. We presented 3 cases of pure red cell aplasia due to parvovirus B19 after kidney transplant. These patients were diagnosed with severe normocytic, normochromic anemia (hemoglobin below 60 g/L) in the 1st 6 months posttransplant. A complete anemia work-up revealed low reticulocyte count and was otherwise inconclusive. All patients were diagnosed with pure red cell aplasia due to parvovirus B19. Two patients improved after receiving intravenous immunoglobulin 2 gm/kg given over 4 doses. Unfortunately, they relapse after few weeks and required additional doses of intravenous immunoglobulin in conjugation with reduction of their immunosuppressive medication. The third patient improved after holding mycophenolate mofetil (MMF) and did not require intravenous immunoglobulin. Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in confirming the diagnosis. Intravenous immunoglobulin (IVIG) can be an effective treatment in immunocompromised patients with primary or relapsed PB19 infection in conjunction with minimizing immunosuppressive medication. Further research and consideration are required to determine appropriate and targeted screening in donors and recipients in the peritransplantation period.
pmc1. Introduction
Parvovirus (Erythrovirus) B19 (PB19) is a common human infection worldwide. It belongs to the Erythrovirus genus within the Parvoviridae family [1]. PB19 transmission occurs by different routes that include respiratory transmission, vertically from mother to fetus, transfusion of blood or blood-derived products, or organ transplantation [2]. After PB19 infection, immunocompetent individuals are considered immune. However, reinfection has been suspected in some cases [2]. During active infection, the virus binds to globoside (P antigen) receptors that are present in erythroid precursor cells. The virus infects, replicates in, and then, lyses erythroid progenitor cells [2]. This will lead to pure red cell aplasia on bone marrow examination by revealing the presence of giant pronormoblasts which can help the diagnostic process [3].
2. Clinical Presentation
Clinical manifestations depend on host's hematological status and immune responses [1]. There is a wide spectrum of clinical findings in immunocompetent patients with PB19 infection. Most individuals who have serologic evidence of prior infection do not recall ever having any specific symptoms classically associated with PB19. The brief period of red cell aplasia is generally subclinical in otherwise healthy individuals, in children and adults with chronic hemolytic anemia (e.g., sickle cell disease or hereditary spherocytosis); the short-term pure red cell aplasia associated with PB19 infection leads to acute worsening of anemia, termed an “aplastic crisis,” often necessitating blood transfusion. In children, PB19 can manifest in erythema infectiosum, also known as the “fifth” disease, which presents as rash, fever, malaise, and polyarthropathy. In pregnancy, PB19 infection is associated with hydrops fetalis [4].
In solid organ transplant recipients, PB19 infection occurs on average 7 weeks (range, 1 week–8 years) after transplantation. Up to 65% of transplant recipients with PB19 infection present within the first 3 months following transplantation [5]. Anemia is an expected finding of this infection in solid organ transplantation. Fever presents in only 25% while arthralgia occurs in 6% of transplant recipients. Leucopenia and thrombocytopenia are seen in 33% and 18%, respectively, which is similar to noninfected transplant recipient's rates. Notably, skin rash is seen more frequently in hematopoietic stem cell transplant as opposed to solid organ transplant recipients (33% vs. 6%) [5]. Tissue-invasive disease was reported in 11% of transplant recipients, manifesting as hepatitis, myocarditis, pneumonitis, collapsing glomerulopathy, encephalitis, or vasculitis [6–9].
While not common, relapsing PB19-related anemia has been observed in 33% of patients treated with IVIG for primary PB19 infection. The risk of relapse is higher in patients with primary PB19 infection and patients who received antithymocyte globulin (ATG) for induction therapy [10].
3. Diagnosis
Diagnosis is based on the detection of PB19 IgG or IgM antibodies or PB19 DNA in blood or tissue samples by polymerase chain reaction (PCR). Bone marrow study may show giant pronormoblasts with prominent nuclear inclusions, which is characteristic of PB19 infection (Figure 1).
4. Management in Transplant Recipients
Management of presumed or confirmed PB19 infection in transplant recipients includes reduction of immunosuppressive medication. Some case reports have shown recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [12]. While intravenous immunoglobulin (IVIG) has also been used to treat PB19 infection in many transplant recipients, with successful resolution of viremia [5, 13, 14], some other patients experienced long-lasting resolution of the infection without receiving IVIG [5]. Although the optimal dose of IVIG and the frequency of administration are not well studied, a dose of 400 mg/kg/day for 5 days has been recommended in some studies [5].
5. Case Presentation
5.1. Case 1
A 43-year-old man had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to IgA nephropathy. The induction agent used at the time of transplantation was ATG 4.5 mg/kg. Afterwards, he received immunosuppressive maintenance therapy that consisted of mycophenolate mofetil (MMF) 1000 mg twice daily, tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
After the transplant, hemoglobin remained stable in the range of 100-120 g/L until 4-month posttransplantation when the patient started to complain of dizziness and shortness of breath on exertion. Blood work at that time showed hemoglobin level of 58 mg/L that was normocytic and normochromic with normal morphology on the blood smear. The patient's reticulocyte count was inappropriately low at 3 × 109/L (normal range 10 − 86 × 109/L). Vitamin B12 and iron indices were normal, and the hemolytic screen was negative. PCR for Cytomegalovirus (CMV), BK virus, and Epstein-Barr virus (EBV) was negative. Serology for PB19 showed a negative IgG and an indeterminate IgM antibody level. The patient was transfused 2 units of red blood cells and discharged home on erythropoietin stimulating agent. MMF dose also reduced to 500 mg twice daily upon discharge.
Unfortunately, the patient was readmitted 2 weeks later with the same complaints and a hemoglobin level of 56 g/L. The reticulocyte count was persistently low at 5 × 109/L. PB19 serology was repeated and showed negative IgG and an indeterminate IgM. The patient received transfusion of 2 units of RBCs and PB19 PCR also positive this time. Patient started on IVIG (0.5 g/kg) for a total of 4 doses. MMF discontinued on this admission and patient discharge after completing IVIG course on prednisolone and tacrolimus only. On discharge, the patient's symptoms had improved, and hemoglobin was 87 g/L. Patients followed monthly in posttransplant clinic, and hemoglobin normalized after 1 month. MMF resumed at 500 mg bid after 4 months, and hemoglobin remained above 125 g/L during 3 years follow-up with no further relapse.
5.2. Case 2
A 26-year-old female had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to Alport syndrome. The induction agent used at the time of transplantation was ATG 4.2 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
The patient developed severe symptomatic, normocytic, and normochromic anemia (hemoglobin 55 g/L) 6 months after transplantation with normal platelet and white cell count. A complete anemia work-up showed low reticulocyte count; otherwise, inconclusive. Her severe anemia persisted for over 2 weeks despite packed blood cell transfusion, adjustment of immunosuppressant medications, and administration of erythropoietin stimulating agent. PB19 PCR was sent few days after admission and came back positive. MMF was held, and 2 gm/kg of IVIG was given over 4 doses. She was discharged few days after completing the IVIG course with better hemoglobin (90 g/L). The patient was seen after 2 weeks in the clinic with almost normalized hemoglobin (124 g/L). Hence, MMF 500 mg twice daily was restarted. 5 weeks later, the patient presented again to the emergency department with fatigability and shortness of breath and a hemoglobin level of 52 g/L. Another course of IVIG treatment was initiated. She received a total of 2 gm/kg over 4 doses, and MMF was held again. PB19 PCR came back positive yet again. After treatment, she improved and was discharged home. The hemoglobin level normalized after few weeks. Hence, MMF 500 mg BID was restarted. For the third time, the patient represented with severe anemia requiring blood transfusion. She was given IVIG 2 gm/kg again and discharge with a plan to discontinue MMF permanently. Her hemoglobin remained stable during the subsequent 2 years of follow-up with no further relapse.
5.3. Case 3
A 24-year-old female had a combined diseased donor kidney and liver transplant. The induction agent used at the time of transplantation was ATG 4 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
One month after discharge, the patient presented to the clinic with a hemoglobin drop reaching 61 g/L. The anemia was normocytic and normochromic with low reticulocyte. A complete anemia workup was inconclusive. The patient was already on an erythropoietin stimulating agent. PB19 PCR test was sent and came back positive. Patient was also found to have BK viremia with 11000 copies detected via PCR. MMF was discontinued, and she was followed in transplant clinic weekly. Her hemoglobin improved and reached 123 g/L after 4 weeks and she did not require IVIG. BK viremia resolved after 2 months as well. Her hemoglobin remains stable during the subsequent 2-year follow-up period. The MMF was never resumed.
6. Discussion
Kidney transplant recipients are highly susceptible to infections such as PB19 [15]. This is due to the use of potent immunosuppressive agents such as ATG to prevent early acute rejection and because of the effect of sustained long-term immunosuppression to prevent graft loss. In this case series, we are presenting 3 cases presented with symptomatic, normocytic, and normochromic anemia with normal platelet and white cell count. They have positive PB19 PCR. Although posttransplant anemia could be related to medication such as ATG and MMF, this is unlikely in our cases because these medications mainly cause leucopenia and thrombocytopenia as well, in addition to positive PB19 PCR in our cases that suggest pure red cell aplasia due to PB19 infection.
PB19 infection in transplanted patients often leads to pure red cell aplasia by attacking erythroid progenitor cells in the bone marrow [16]. Induction with ATG was found to have a higher risk for PB19 infection compared to the other induction agents [17]. Maintenance regimen also plays a role in the risk for PB19 infection as one study showed substitution of tacrolimus with cyclosporine was followed by resolution of anemia and viral clearance [11]. The presence of viral coinfection with PB19 such as CMV and human herpesvirus 6 has also been reported. In our case series, the noted patients' risk factors for PB19 infection and relapse included induction with ATG and having negative IgG on PB19 serology testing suggesting a primary infection, and not reactivation. Similar to other case reports, one of our patients also has a coinfection with BK virus [18].
PB19 infection is likely underdiagnosed in organ transplant recipients, and a high index of suspicion is necessary to allow for prompt identification of PB19 infection among renal transplant recipients with anemia of unclear etiology.
Our case series further suggests that the treatment of PB19 relies on the reduction of immunosuppression and IVIG administration. There is no clear evidence to support the best practice for adjusting the immunosuppressive medication. Some case reports showed recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [11]. In our cases, we discontinue MMF in all 3 cases by the end. These cases suggest that treatment with IVIG is effective in treating primary infection and relapse, but holding antimetabolite immunosuppressive drugs is essential in treating such cases and preventing further relapses, although we do not know when should we resume it.
7. Conclusion
Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in establishing the diagnosis. IVIG may be an effective treatment in immunocompromised patients with primary and relapsing PB19 infection. Minimizing or holding antimetabolite immunosuppressive drugs plays a vital role in treating and preventing PB19 relapse. Further research and consideration are required to determine an appropriate screening protocol for donors and recipients in the peritransplantation period.
Data Availability
The detailed case data used to support the findings are available from the corresponding author upon request.
Ethical Approval
The study was approved by the King Abdullah International Medical Research Center (KAIMRC) ethical committee with Memo Ref. No. IRBC/01095/21.
Consent
Written informed consent was obtained from the patients for being included in this case report publication.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
A Altheaby, M Alotaibi, N Alajlan, and A Alshareef wrote the proposal and collect the data for 3 cases. M Alruwaymi, Ghaleb Aboalsamh, and M F Shaheen wrote the manuscript. A Altheaby, M Alzunitan, and Z Arabi did all editing and reviewing of the manuscript.
Figure 1 May–Grünwald–Giemsa staining of bone marrow aspirate showing the classical feature of PRCA, namely, a red inclusion in the nucleus of giant pronormoblasts (arrow) [11]. | MYCOPHENOLATE MOFETIL, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY | 34881070 | 20,206,212 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Polyomavirus viraemia'. | Parvovirus B19 Infection due to over Immunosuppression in Kidney Transplant Recipients: Case Reports and Literature Review.
Parvovirus B19 (PB19) is a single-stranded DNA virus that belongs to the Erythrovirus genus within the Parvoviridae family. Clinical presentations associated with PB19 infection vary greatly, depending on the infected individual's age and hematologic and immunologic status. The limited data available regarding consensus on screening algorithms and indications in donors and recipients prior to kidney transplantation makes diagnosis and management challenging. We presented 3 cases of pure red cell aplasia due to parvovirus B19 after kidney transplant. These patients were diagnosed with severe normocytic, normochromic anemia (hemoglobin below 60 g/L) in the 1st 6 months posttransplant. A complete anemia work-up revealed low reticulocyte count and was otherwise inconclusive. All patients were diagnosed with pure red cell aplasia due to parvovirus B19. Two patients improved after receiving intravenous immunoglobulin 2 gm/kg given over 4 doses. Unfortunately, they relapse after few weeks and required additional doses of intravenous immunoglobulin in conjugation with reduction of their immunosuppressive medication. The third patient improved after holding mycophenolate mofetil (MMF) and did not require intravenous immunoglobulin. Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in confirming the diagnosis. Intravenous immunoglobulin (IVIG) can be an effective treatment in immunocompromised patients with primary or relapsed PB19 infection in conjunction with minimizing immunosuppressive medication. Further research and consideration are required to determine appropriate and targeted screening in donors and recipients in the peritransplantation period.
pmc1. Introduction
Parvovirus (Erythrovirus) B19 (PB19) is a common human infection worldwide. It belongs to the Erythrovirus genus within the Parvoviridae family [1]. PB19 transmission occurs by different routes that include respiratory transmission, vertically from mother to fetus, transfusion of blood or blood-derived products, or organ transplantation [2]. After PB19 infection, immunocompetent individuals are considered immune. However, reinfection has been suspected in some cases [2]. During active infection, the virus binds to globoside (P antigen) receptors that are present in erythroid precursor cells. The virus infects, replicates in, and then, lyses erythroid progenitor cells [2]. This will lead to pure red cell aplasia on bone marrow examination by revealing the presence of giant pronormoblasts which can help the diagnostic process [3].
2. Clinical Presentation
Clinical manifestations depend on host's hematological status and immune responses [1]. There is a wide spectrum of clinical findings in immunocompetent patients with PB19 infection. Most individuals who have serologic evidence of prior infection do not recall ever having any specific symptoms classically associated with PB19. The brief period of red cell aplasia is generally subclinical in otherwise healthy individuals, in children and adults with chronic hemolytic anemia (e.g., sickle cell disease or hereditary spherocytosis); the short-term pure red cell aplasia associated with PB19 infection leads to acute worsening of anemia, termed an “aplastic crisis,” often necessitating blood transfusion. In children, PB19 can manifest in erythema infectiosum, also known as the “fifth” disease, which presents as rash, fever, malaise, and polyarthropathy. In pregnancy, PB19 infection is associated with hydrops fetalis [4].
In solid organ transplant recipients, PB19 infection occurs on average 7 weeks (range, 1 week–8 years) after transplantation. Up to 65% of transplant recipients with PB19 infection present within the first 3 months following transplantation [5]. Anemia is an expected finding of this infection in solid organ transplantation. Fever presents in only 25% while arthralgia occurs in 6% of transplant recipients. Leucopenia and thrombocytopenia are seen in 33% and 18%, respectively, which is similar to noninfected transplant recipient's rates. Notably, skin rash is seen more frequently in hematopoietic stem cell transplant as opposed to solid organ transplant recipients (33% vs. 6%) [5]. Tissue-invasive disease was reported in 11% of transplant recipients, manifesting as hepatitis, myocarditis, pneumonitis, collapsing glomerulopathy, encephalitis, or vasculitis [6–9].
While not common, relapsing PB19-related anemia has been observed in 33% of patients treated with IVIG for primary PB19 infection. The risk of relapse is higher in patients with primary PB19 infection and patients who received antithymocyte globulin (ATG) for induction therapy [10].
3. Diagnosis
Diagnosis is based on the detection of PB19 IgG or IgM antibodies or PB19 DNA in blood or tissue samples by polymerase chain reaction (PCR). Bone marrow study may show giant pronormoblasts with prominent nuclear inclusions, which is characteristic of PB19 infection (Figure 1).
4. Management in Transplant Recipients
Management of presumed or confirmed PB19 infection in transplant recipients includes reduction of immunosuppressive medication. Some case reports have shown recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [12]. While intravenous immunoglobulin (IVIG) has also been used to treat PB19 infection in many transplant recipients, with successful resolution of viremia [5, 13, 14], some other patients experienced long-lasting resolution of the infection without receiving IVIG [5]. Although the optimal dose of IVIG and the frequency of administration are not well studied, a dose of 400 mg/kg/day for 5 days has been recommended in some studies [5].
5. Case Presentation
5.1. Case 1
A 43-year-old man had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to IgA nephropathy. The induction agent used at the time of transplantation was ATG 4.5 mg/kg. Afterwards, he received immunosuppressive maintenance therapy that consisted of mycophenolate mofetil (MMF) 1000 mg twice daily, tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
After the transplant, hemoglobin remained stable in the range of 100-120 g/L until 4-month posttransplantation when the patient started to complain of dizziness and shortness of breath on exertion. Blood work at that time showed hemoglobin level of 58 mg/L that was normocytic and normochromic with normal morphology on the blood smear. The patient's reticulocyte count was inappropriately low at 3 × 109/L (normal range 10 − 86 × 109/L). Vitamin B12 and iron indices were normal, and the hemolytic screen was negative. PCR for Cytomegalovirus (CMV), BK virus, and Epstein-Barr virus (EBV) was negative. Serology for PB19 showed a negative IgG and an indeterminate IgM antibody level. The patient was transfused 2 units of red blood cells and discharged home on erythropoietin stimulating agent. MMF dose also reduced to 500 mg twice daily upon discharge.
Unfortunately, the patient was readmitted 2 weeks later with the same complaints and a hemoglobin level of 56 g/L. The reticulocyte count was persistently low at 5 × 109/L. PB19 serology was repeated and showed negative IgG and an indeterminate IgM. The patient received transfusion of 2 units of RBCs and PB19 PCR also positive this time. Patient started on IVIG (0.5 g/kg) for a total of 4 doses. MMF discontinued on this admission and patient discharge after completing IVIG course on prednisolone and tacrolimus only. On discharge, the patient's symptoms had improved, and hemoglobin was 87 g/L. Patients followed monthly in posttransplant clinic, and hemoglobin normalized after 1 month. MMF resumed at 500 mg bid after 4 months, and hemoglobin remained above 125 g/L during 3 years follow-up with no further relapse.
5.2. Case 2
A 26-year-old female had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to Alport syndrome. The induction agent used at the time of transplantation was ATG 4.2 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
The patient developed severe symptomatic, normocytic, and normochromic anemia (hemoglobin 55 g/L) 6 months after transplantation with normal platelet and white cell count. A complete anemia work-up showed low reticulocyte count; otherwise, inconclusive. Her severe anemia persisted for over 2 weeks despite packed blood cell transfusion, adjustment of immunosuppressant medications, and administration of erythropoietin stimulating agent. PB19 PCR was sent few days after admission and came back positive. MMF was held, and 2 gm/kg of IVIG was given over 4 doses. She was discharged few days after completing the IVIG course with better hemoglobin (90 g/L). The patient was seen after 2 weeks in the clinic with almost normalized hemoglobin (124 g/L). Hence, MMF 500 mg twice daily was restarted. 5 weeks later, the patient presented again to the emergency department with fatigability and shortness of breath and a hemoglobin level of 52 g/L. Another course of IVIG treatment was initiated. She received a total of 2 gm/kg over 4 doses, and MMF was held again. PB19 PCR came back positive yet again. After treatment, she improved and was discharged home. The hemoglobin level normalized after few weeks. Hence, MMF 500 mg BID was restarted. For the third time, the patient represented with severe anemia requiring blood transfusion. She was given IVIG 2 gm/kg again and discharge with a plan to discontinue MMF permanently. Her hemoglobin remained stable during the subsequent 2 years of follow-up with no further relapse.
5.3. Case 3
A 24-year-old female had a combined diseased donor kidney and liver transplant. The induction agent used at the time of transplantation was ATG 4 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
One month after discharge, the patient presented to the clinic with a hemoglobin drop reaching 61 g/L. The anemia was normocytic and normochromic with low reticulocyte. A complete anemia workup was inconclusive. The patient was already on an erythropoietin stimulating agent. PB19 PCR test was sent and came back positive. Patient was also found to have BK viremia with 11000 copies detected via PCR. MMF was discontinued, and she was followed in transplant clinic weekly. Her hemoglobin improved and reached 123 g/L after 4 weeks and she did not require IVIG. BK viremia resolved after 2 months as well. Her hemoglobin remains stable during the subsequent 2-year follow-up period. The MMF was never resumed.
6. Discussion
Kidney transplant recipients are highly susceptible to infections such as PB19 [15]. This is due to the use of potent immunosuppressive agents such as ATG to prevent early acute rejection and because of the effect of sustained long-term immunosuppression to prevent graft loss. In this case series, we are presenting 3 cases presented with symptomatic, normocytic, and normochromic anemia with normal platelet and white cell count. They have positive PB19 PCR. Although posttransplant anemia could be related to medication such as ATG and MMF, this is unlikely in our cases because these medications mainly cause leucopenia and thrombocytopenia as well, in addition to positive PB19 PCR in our cases that suggest pure red cell aplasia due to PB19 infection.
PB19 infection in transplanted patients often leads to pure red cell aplasia by attacking erythroid progenitor cells in the bone marrow [16]. Induction with ATG was found to have a higher risk for PB19 infection compared to the other induction agents [17]. Maintenance regimen also plays a role in the risk for PB19 infection as one study showed substitution of tacrolimus with cyclosporine was followed by resolution of anemia and viral clearance [11]. The presence of viral coinfection with PB19 such as CMV and human herpesvirus 6 has also been reported. In our case series, the noted patients' risk factors for PB19 infection and relapse included induction with ATG and having negative IgG on PB19 serology testing suggesting a primary infection, and not reactivation. Similar to other case reports, one of our patients also has a coinfection with BK virus [18].
PB19 infection is likely underdiagnosed in organ transplant recipients, and a high index of suspicion is necessary to allow for prompt identification of PB19 infection among renal transplant recipients with anemia of unclear etiology.
Our case series further suggests that the treatment of PB19 relies on the reduction of immunosuppression and IVIG administration. There is no clear evidence to support the best practice for adjusting the immunosuppressive medication. Some case reports showed recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [11]. In our cases, we discontinue MMF in all 3 cases by the end. These cases suggest that treatment with IVIG is effective in treating primary infection and relapse, but holding antimetabolite immunosuppressive drugs is essential in treating such cases and preventing further relapses, although we do not know when should we resume it.
7. Conclusion
Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in establishing the diagnosis. IVIG may be an effective treatment in immunocompromised patients with primary and relapsing PB19 infection. Minimizing or holding antimetabolite immunosuppressive drugs plays a vital role in treating and preventing PB19 relapse. Further research and consideration are required to determine an appropriate screening protocol for donors and recipients in the peritransplantation period.
Data Availability
The detailed case data used to support the findings are available from the corresponding author upon request.
Ethical Approval
The study was approved by the King Abdullah International Medical Research Center (KAIMRC) ethical committee with Memo Ref. No. IRBC/01095/21.
Consent
Written informed consent was obtained from the patients for being included in this case report publication.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
A Altheaby, M Alotaibi, N Alajlan, and A Alshareef wrote the proposal and collect the data for 3 cases. M Alruwaymi, Ghaleb Aboalsamh, and M F Shaheen wrote the manuscript. A Altheaby, M Alzunitan, and Z Arabi did all editing and reviewing of the manuscript.
Figure 1 May–Grünwald–Giemsa staining of bone marrow aspirate showing the classical feature of PRCA, namely, a red inclusion in the nucleus of giant pronormoblasts (arrow) [11]. | MYCOPHENOLATE MOFETIL, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY | 34881070 | 20,206,212 | 2021 |
What was the outcome of reaction 'Anaemia'? | Parvovirus B19 Infection due to over Immunosuppression in Kidney Transplant Recipients: Case Reports and Literature Review.
Parvovirus B19 (PB19) is a single-stranded DNA virus that belongs to the Erythrovirus genus within the Parvoviridae family. Clinical presentations associated with PB19 infection vary greatly, depending on the infected individual's age and hematologic and immunologic status. The limited data available regarding consensus on screening algorithms and indications in donors and recipients prior to kidney transplantation makes diagnosis and management challenging. We presented 3 cases of pure red cell aplasia due to parvovirus B19 after kidney transplant. These patients were diagnosed with severe normocytic, normochromic anemia (hemoglobin below 60 g/L) in the 1st 6 months posttransplant. A complete anemia work-up revealed low reticulocyte count and was otherwise inconclusive. All patients were diagnosed with pure red cell aplasia due to parvovirus B19. Two patients improved after receiving intravenous immunoglobulin 2 gm/kg given over 4 doses. Unfortunately, they relapse after few weeks and required additional doses of intravenous immunoglobulin in conjugation with reduction of their immunosuppressive medication. The third patient improved after holding mycophenolate mofetil (MMF) and did not require intravenous immunoglobulin. Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in confirming the diagnosis. Intravenous immunoglobulin (IVIG) can be an effective treatment in immunocompromised patients with primary or relapsed PB19 infection in conjunction with minimizing immunosuppressive medication. Further research and consideration are required to determine appropriate and targeted screening in donors and recipients in the peritransplantation period.
pmc1. Introduction
Parvovirus (Erythrovirus) B19 (PB19) is a common human infection worldwide. It belongs to the Erythrovirus genus within the Parvoviridae family [1]. PB19 transmission occurs by different routes that include respiratory transmission, vertically from mother to fetus, transfusion of blood or blood-derived products, or organ transplantation [2]. After PB19 infection, immunocompetent individuals are considered immune. However, reinfection has been suspected in some cases [2]. During active infection, the virus binds to globoside (P antigen) receptors that are present in erythroid precursor cells. The virus infects, replicates in, and then, lyses erythroid progenitor cells [2]. This will lead to pure red cell aplasia on bone marrow examination by revealing the presence of giant pronormoblasts which can help the diagnostic process [3].
2. Clinical Presentation
Clinical manifestations depend on host's hematological status and immune responses [1]. There is a wide spectrum of clinical findings in immunocompetent patients with PB19 infection. Most individuals who have serologic evidence of prior infection do not recall ever having any specific symptoms classically associated with PB19. The brief period of red cell aplasia is generally subclinical in otherwise healthy individuals, in children and adults with chronic hemolytic anemia (e.g., sickle cell disease or hereditary spherocytosis); the short-term pure red cell aplasia associated with PB19 infection leads to acute worsening of anemia, termed an “aplastic crisis,” often necessitating blood transfusion. In children, PB19 can manifest in erythema infectiosum, also known as the “fifth” disease, which presents as rash, fever, malaise, and polyarthropathy. In pregnancy, PB19 infection is associated with hydrops fetalis [4].
In solid organ transplant recipients, PB19 infection occurs on average 7 weeks (range, 1 week–8 years) after transplantation. Up to 65% of transplant recipients with PB19 infection present within the first 3 months following transplantation [5]. Anemia is an expected finding of this infection in solid organ transplantation. Fever presents in only 25% while arthralgia occurs in 6% of transplant recipients. Leucopenia and thrombocytopenia are seen in 33% and 18%, respectively, which is similar to noninfected transplant recipient's rates. Notably, skin rash is seen more frequently in hematopoietic stem cell transplant as opposed to solid organ transplant recipients (33% vs. 6%) [5]. Tissue-invasive disease was reported in 11% of transplant recipients, manifesting as hepatitis, myocarditis, pneumonitis, collapsing glomerulopathy, encephalitis, or vasculitis [6–9].
While not common, relapsing PB19-related anemia has been observed in 33% of patients treated with IVIG for primary PB19 infection. The risk of relapse is higher in patients with primary PB19 infection and patients who received antithymocyte globulin (ATG) for induction therapy [10].
3. Diagnosis
Diagnosis is based on the detection of PB19 IgG or IgM antibodies or PB19 DNA in blood or tissue samples by polymerase chain reaction (PCR). Bone marrow study may show giant pronormoblasts with prominent nuclear inclusions, which is characteristic of PB19 infection (Figure 1).
4. Management in Transplant Recipients
Management of presumed or confirmed PB19 infection in transplant recipients includes reduction of immunosuppressive medication. Some case reports have shown recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [12]. While intravenous immunoglobulin (IVIG) has also been used to treat PB19 infection in many transplant recipients, with successful resolution of viremia [5, 13, 14], some other patients experienced long-lasting resolution of the infection without receiving IVIG [5]. Although the optimal dose of IVIG and the frequency of administration are not well studied, a dose of 400 mg/kg/day for 5 days has been recommended in some studies [5].
5. Case Presentation
5.1. Case 1
A 43-year-old man had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to IgA nephropathy. The induction agent used at the time of transplantation was ATG 4.5 mg/kg. Afterwards, he received immunosuppressive maintenance therapy that consisted of mycophenolate mofetil (MMF) 1000 mg twice daily, tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
After the transplant, hemoglobin remained stable in the range of 100-120 g/L until 4-month posttransplantation when the patient started to complain of dizziness and shortness of breath on exertion. Blood work at that time showed hemoglobin level of 58 mg/L that was normocytic and normochromic with normal morphology on the blood smear. The patient's reticulocyte count was inappropriately low at 3 × 109/L (normal range 10 − 86 × 109/L). Vitamin B12 and iron indices were normal, and the hemolytic screen was negative. PCR for Cytomegalovirus (CMV), BK virus, and Epstein-Barr virus (EBV) was negative. Serology for PB19 showed a negative IgG and an indeterminate IgM antibody level. The patient was transfused 2 units of red blood cells and discharged home on erythropoietin stimulating agent. MMF dose also reduced to 500 mg twice daily upon discharge.
Unfortunately, the patient was readmitted 2 weeks later with the same complaints and a hemoglobin level of 56 g/L. The reticulocyte count was persistently low at 5 × 109/L. PB19 serology was repeated and showed negative IgG and an indeterminate IgM. The patient received transfusion of 2 units of RBCs and PB19 PCR also positive this time. Patient started on IVIG (0.5 g/kg) for a total of 4 doses. MMF discontinued on this admission and patient discharge after completing IVIG course on prednisolone and tacrolimus only. On discharge, the patient's symptoms had improved, and hemoglobin was 87 g/L. Patients followed monthly in posttransplant clinic, and hemoglobin normalized after 1 month. MMF resumed at 500 mg bid after 4 months, and hemoglobin remained above 125 g/L during 3 years follow-up with no further relapse.
5.2. Case 2
A 26-year-old female had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to Alport syndrome. The induction agent used at the time of transplantation was ATG 4.2 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
The patient developed severe symptomatic, normocytic, and normochromic anemia (hemoglobin 55 g/L) 6 months after transplantation with normal platelet and white cell count. A complete anemia work-up showed low reticulocyte count; otherwise, inconclusive. Her severe anemia persisted for over 2 weeks despite packed blood cell transfusion, adjustment of immunosuppressant medications, and administration of erythropoietin stimulating agent. PB19 PCR was sent few days after admission and came back positive. MMF was held, and 2 gm/kg of IVIG was given over 4 doses. She was discharged few days after completing the IVIG course with better hemoglobin (90 g/L). The patient was seen after 2 weeks in the clinic with almost normalized hemoglobin (124 g/L). Hence, MMF 500 mg twice daily was restarted. 5 weeks later, the patient presented again to the emergency department with fatigability and shortness of breath and a hemoglobin level of 52 g/L. Another course of IVIG treatment was initiated. She received a total of 2 gm/kg over 4 doses, and MMF was held again. PB19 PCR came back positive yet again. After treatment, she improved and was discharged home. The hemoglobin level normalized after few weeks. Hence, MMF 500 mg BID was restarted. For the third time, the patient represented with severe anemia requiring blood transfusion. She was given IVIG 2 gm/kg again and discharge with a plan to discontinue MMF permanently. Her hemoglobin remained stable during the subsequent 2 years of follow-up with no further relapse.
5.3. Case 3
A 24-year-old female had a combined diseased donor kidney and liver transplant. The induction agent used at the time of transplantation was ATG 4 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
One month after discharge, the patient presented to the clinic with a hemoglobin drop reaching 61 g/L. The anemia was normocytic and normochromic with low reticulocyte. A complete anemia workup was inconclusive. The patient was already on an erythropoietin stimulating agent. PB19 PCR test was sent and came back positive. Patient was also found to have BK viremia with 11000 copies detected via PCR. MMF was discontinued, and she was followed in transplant clinic weekly. Her hemoglobin improved and reached 123 g/L after 4 weeks and she did not require IVIG. BK viremia resolved after 2 months as well. Her hemoglobin remains stable during the subsequent 2-year follow-up period. The MMF was never resumed.
6. Discussion
Kidney transplant recipients are highly susceptible to infections such as PB19 [15]. This is due to the use of potent immunosuppressive agents such as ATG to prevent early acute rejection and because of the effect of sustained long-term immunosuppression to prevent graft loss. In this case series, we are presenting 3 cases presented with symptomatic, normocytic, and normochromic anemia with normal platelet and white cell count. They have positive PB19 PCR. Although posttransplant anemia could be related to medication such as ATG and MMF, this is unlikely in our cases because these medications mainly cause leucopenia and thrombocytopenia as well, in addition to positive PB19 PCR in our cases that suggest pure red cell aplasia due to PB19 infection.
PB19 infection in transplanted patients often leads to pure red cell aplasia by attacking erythroid progenitor cells in the bone marrow [16]. Induction with ATG was found to have a higher risk for PB19 infection compared to the other induction agents [17]. Maintenance regimen also plays a role in the risk for PB19 infection as one study showed substitution of tacrolimus with cyclosporine was followed by resolution of anemia and viral clearance [11]. The presence of viral coinfection with PB19 such as CMV and human herpesvirus 6 has also been reported. In our case series, the noted patients' risk factors for PB19 infection and relapse included induction with ATG and having negative IgG on PB19 serology testing suggesting a primary infection, and not reactivation. Similar to other case reports, one of our patients also has a coinfection with BK virus [18].
PB19 infection is likely underdiagnosed in organ transplant recipients, and a high index of suspicion is necessary to allow for prompt identification of PB19 infection among renal transplant recipients with anemia of unclear etiology.
Our case series further suggests that the treatment of PB19 relies on the reduction of immunosuppression and IVIG administration. There is no clear evidence to support the best practice for adjusting the immunosuppressive medication. Some case reports showed recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [11]. In our cases, we discontinue MMF in all 3 cases by the end. These cases suggest that treatment with IVIG is effective in treating primary infection and relapse, but holding antimetabolite immunosuppressive drugs is essential in treating such cases and preventing further relapses, although we do not know when should we resume it.
7. Conclusion
Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in establishing the diagnosis. IVIG may be an effective treatment in immunocompromised patients with primary and relapsing PB19 infection. Minimizing or holding antimetabolite immunosuppressive drugs plays a vital role in treating and preventing PB19 relapse. Further research and consideration are required to determine an appropriate screening protocol for donors and recipients in the peritransplantation period.
Data Availability
The detailed case data used to support the findings are available from the corresponding author upon request.
Ethical Approval
The study was approved by the King Abdullah International Medical Research Center (KAIMRC) ethical committee with Memo Ref. No. IRBC/01095/21.
Consent
Written informed consent was obtained from the patients for being included in this case report publication.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
A Altheaby, M Alotaibi, N Alajlan, and A Alshareef wrote the proposal and collect the data for 3 cases. M Alruwaymi, Ghaleb Aboalsamh, and M F Shaheen wrote the manuscript. A Altheaby, M Alzunitan, and Z Arabi did all editing and reviewing of the manuscript.
Figure 1 May–Grünwald–Giemsa staining of bone marrow aspirate showing the classical feature of PRCA, namely, a red inclusion in the nucleus of giant pronormoblasts (arrow) [11]. | Recovered | ReactionOutcome | CC BY | 34881070 | 20,206,212 | 2021 |
What was the outcome of reaction 'Parvovirus B19 infection'? | Parvovirus B19 Infection due to over Immunosuppression in Kidney Transplant Recipients: Case Reports and Literature Review.
Parvovirus B19 (PB19) is a single-stranded DNA virus that belongs to the Erythrovirus genus within the Parvoviridae family. Clinical presentations associated with PB19 infection vary greatly, depending on the infected individual's age and hematologic and immunologic status. The limited data available regarding consensus on screening algorithms and indications in donors and recipients prior to kidney transplantation makes diagnosis and management challenging. We presented 3 cases of pure red cell aplasia due to parvovirus B19 after kidney transplant. These patients were diagnosed with severe normocytic, normochromic anemia (hemoglobin below 60 g/L) in the 1st 6 months posttransplant. A complete anemia work-up revealed low reticulocyte count and was otherwise inconclusive. All patients were diagnosed with pure red cell aplasia due to parvovirus B19. Two patients improved after receiving intravenous immunoglobulin 2 gm/kg given over 4 doses. Unfortunately, they relapse after few weeks and required additional doses of intravenous immunoglobulin in conjugation with reduction of their immunosuppressive medication. The third patient improved after holding mycophenolate mofetil (MMF) and did not require intravenous immunoglobulin. Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in confirming the diagnosis. Intravenous immunoglobulin (IVIG) can be an effective treatment in immunocompromised patients with primary or relapsed PB19 infection in conjunction with minimizing immunosuppressive medication. Further research and consideration are required to determine appropriate and targeted screening in donors and recipients in the peritransplantation period.
pmc1. Introduction
Parvovirus (Erythrovirus) B19 (PB19) is a common human infection worldwide. It belongs to the Erythrovirus genus within the Parvoviridae family [1]. PB19 transmission occurs by different routes that include respiratory transmission, vertically from mother to fetus, transfusion of blood or blood-derived products, or organ transplantation [2]. After PB19 infection, immunocompetent individuals are considered immune. However, reinfection has been suspected in some cases [2]. During active infection, the virus binds to globoside (P antigen) receptors that are present in erythroid precursor cells. The virus infects, replicates in, and then, lyses erythroid progenitor cells [2]. This will lead to pure red cell aplasia on bone marrow examination by revealing the presence of giant pronormoblasts which can help the diagnostic process [3].
2. Clinical Presentation
Clinical manifestations depend on host's hematological status and immune responses [1]. There is a wide spectrum of clinical findings in immunocompetent patients with PB19 infection. Most individuals who have serologic evidence of prior infection do not recall ever having any specific symptoms classically associated with PB19. The brief period of red cell aplasia is generally subclinical in otherwise healthy individuals, in children and adults with chronic hemolytic anemia (e.g., sickle cell disease or hereditary spherocytosis); the short-term pure red cell aplasia associated with PB19 infection leads to acute worsening of anemia, termed an “aplastic crisis,” often necessitating blood transfusion. In children, PB19 can manifest in erythema infectiosum, also known as the “fifth” disease, which presents as rash, fever, malaise, and polyarthropathy. In pregnancy, PB19 infection is associated with hydrops fetalis [4].
In solid organ transplant recipients, PB19 infection occurs on average 7 weeks (range, 1 week–8 years) after transplantation. Up to 65% of transplant recipients with PB19 infection present within the first 3 months following transplantation [5]. Anemia is an expected finding of this infection in solid organ transplantation. Fever presents in only 25% while arthralgia occurs in 6% of transplant recipients. Leucopenia and thrombocytopenia are seen in 33% and 18%, respectively, which is similar to noninfected transplant recipient's rates. Notably, skin rash is seen more frequently in hematopoietic stem cell transplant as opposed to solid organ transplant recipients (33% vs. 6%) [5]. Tissue-invasive disease was reported in 11% of transplant recipients, manifesting as hepatitis, myocarditis, pneumonitis, collapsing glomerulopathy, encephalitis, or vasculitis [6–9].
While not common, relapsing PB19-related anemia has been observed in 33% of patients treated with IVIG for primary PB19 infection. The risk of relapse is higher in patients with primary PB19 infection and patients who received antithymocyte globulin (ATG) for induction therapy [10].
3. Diagnosis
Diagnosis is based on the detection of PB19 IgG or IgM antibodies or PB19 DNA in blood or tissue samples by polymerase chain reaction (PCR). Bone marrow study may show giant pronormoblasts with prominent nuclear inclusions, which is characteristic of PB19 infection (Figure 1).
4. Management in Transplant Recipients
Management of presumed or confirmed PB19 infection in transplant recipients includes reduction of immunosuppressive medication. Some case reports have shown recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [12]. While intravenous immunoglobulin (IVIG) has also been used to treat PB19 infection in many transplant recipients, with successful resolution of viremia [5, 13, 14], some other patients experienced long-lasting resolution of the infection without receiving IVIG [5]. Although the optimal dose of IVIG and the frequency of administration are not well studied, a dose of 400 mg/kg/day for 5 days has been recommended in some studies [5].
5. Case Presentation
5.1. Case 1
A 43-year-old man had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to IgA nephropathy. The induction agent used at the time of transplantation was ATG 4.5 mg/kg. Afterwards, he received immunosuppressive maintenance therapy that consisted of mycophenolate mofetil (MMF) 1000 mg twice daily, tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
After the transplant, hemoglobin remained stable in the range of 100-120 g/L until 4-month posttransplantation when the patient started to complain of dizziness and shortness of breath on exertion. Blood work at that time showed hemoglobin level of 58 mg/L that was normocytic and normochromic with normal morphology on the blood smear. The patient's reticulocyte count was inappropriately low at 3 × 109/L (normal range 10 − 86 × 109/L). Vitamin B12 and iron indices were normal, and the hemolytic screen was negative. PCR for Cytomegalovirus (CMV), BK virus, and Epstein-Barr virus (EBV) was negative. Serology for PB19 showed a negative IgG and an indeterminate IgM antibody level. The patient was transfused 2 units of red blood cells and discharged home on erythropoietin stimulating agent. MMF dose also reduced to 500 mg twice daily upon discharge.
Unfortunately, the patient was readmitted 2 weeks later with the same complaints and a hemoglobin level of 56 g/L. The reticulocyte count was persistently low at 5 × 109/L. PB19 serology was repeated and showed negative IgG and an indeterminate IgM. The patient received transfusion of 2 units of RBCs and PB19 PCR also positive this time. Patient started on IVIG (0.5 g/kg) for a total of 4 doses. MMF discontinued on this admission and patient discharge after completing IVIG course on prednisolone and tacrolimus only. On discharge, the patient's symptoms had improved, and hemoglobin was 87 g/L. Patients followed monthly in posttransplant clinic, and hemoglobin normalized after 1 month. MMF resumed at 500 mg bid after 4 months, and hemoglobin remained above 125 g/L during 3 years follow-up with no further relapse.
5.2. Case 2
A 26-year-old female had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to Alport syndrome. The induction agent used at the time of transplantation was ATG 4.2 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
The patient developed severe symptomatic, normocytic, and normochromic anemia (hemoglobin 55 g/L) 6 months after transplantation with normal platelet and white cell count. A complete anemia work-up showed low reticulocyte count; otherwise, inconclusive. Her severe anemia persisted for over 2 weeks despite packed blood cell transfusion, adjustment of immunosuppressant medications, and administration of erythropoietin stimulating agent. PB19 PCR was sent few days after admission and came back positive. MMF was held, and 2 gm/kg of IVIG was given over 4 doses. She was discharged few days after completing the IVIG course with better hemoglobin (90 g/L). The patient was seen after 2 weeks in the clinic with almost normalized hemoglobin (124 g/L). Hence, MMF 500 mg twice daily was restarted. 5 weeks later, the patient presented again to the emergency department with fatigability and shortness of breath and a hemoglobin level of 52 g/L. Another course of IVIG treatment was initiated. She received a total of 2 gm/kg over 4 doses, and MMF was held again. PB19 PCR came back positive yet again. After treatment, she improved and was discharged home. The hemoglobin level normalized after few weeks. Hence, MMF 500 mg BID was restarted. For the third time, the patient represented with severe anemia requiring blood transfusion. She was given IVIG 2 gm/kg again and discharge with a plan to discontinue MMF permanently. Her hemoglobin remained stable during the subsequent 2 years of follow-up with no further relapse.
5.3. Case 3
A 24-year-old female had a combined diseased donor kidney and liver transplant. The induction agent used at the time of transplantation was ATG 4 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
One month after discharge, the patient presented to the clinic with a hemoglobin drop reaching 61 g/L. The anemia was normocytic and normochromic with low reticulocyte. A complete anemia workup was inconclusive. The patient was already on an erythropoietin stimulating agent. PB19 PCR test was sent and came back positive. Patient was also found to have BK viremia with 11000 copies detected via PCR. MMF was discontinued, and she was followed in transplant clinic weekly. Her hemoglobin improved and reached 123 g/L after 4 weeks and she did not require IVIG. BK viremia resolved after 2 months as well. Her hemoglobin remains stable during the subsequent 2-year follow-up period. The MMF was never resumed.
6. Discussion
Kidney transplant recipients are highly susceptible to infections such as PB19 [15]. This is due to the use of potent immunosuppressive agents such as ATG to prevent early acute rejection and because of the effect of sustained long-term immunosuppression to prevent graft loss. In this case series, we are presenting 3 cases presented with symptomatic, normocytic, and normochromic anemia with normal platelet and white cell count. They have positive PB19 PCR. Although posttransplant anemia could be related to medication such as ATG and MMF, this is unlikely in our cases because these medications mainly cause leucopenia and thrombocytopenia as well, in addition to positive PB19 PCR in our cases that suggest pure red cell aplasia due to PB19 infection.
PB19 infection in transplanted patients often leads to pure red cell aplasia by attacking erythroid progenitor cells in the bone marrow [16]. Induction with ATG was found to have a higher risk for PB19 infection compared to the other induction agents [17]. Maintenance regimen also plays a role in the risk for PB19 infection as one study showed substitution of tacrolimus with cyclosporine was followed by resolution of anemia and viral clearance [11]. The presence of viral coinfection with PB19 such as CMV and human herpesvirus 6 has also been reported. In our case series, the noted patients' risk factors for PB19 infection and relapse included induction with ATG and having negative IgG on PB19 serology testing suggesting a primary infection, and not reactivation. Similar to other case reports, one of our patients also has a coinfection with BK virus [18].
PB19 infection is likely underdiagnosed in organ transplant recipients, and a high index of suspicion is necessary to allow for prompt identification of PB19 infection among renal transplant recipients with anemia of unclear etiology.
Our case series further suggests that the treatment of PB19 relies on the reduction of immunosuppression and IVIG administration. There is no clear evidence to support the best practice for adjusting the immunosuppressive medication. Some case reports showed recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [11]. In our cases, we discontinue MMF in all 3 cases by the end. These cases suggest that treatment with IVIG is effective in treating primary infection and relapse, but holding antimetabolite immunosuppressive drugs is essential in treating such cases and preventing further relapses, although we do not know when should we resume it.
7. Conclusion
Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in establishing the diagnosis. IVIG may be an effective treatment in immunocompromised patients with primary and relapsing PB19 infection. Minimizing or holding antimetabolite immunosuppressive drugs plays a vital role in treating and preventing PB19 relapse. Further research and consideration are required to determine an appropriate screening protocol for donors and recipients in the peritransplantation period.
Data Availability
The detailed case data used to support the findings are available from the corresponding author upon request.
Ethical Approval
The study was approved by the King Abdullah International Medical Research Center (KAIMRC) ethical committee with Memo Ref. No. IRBC/01095/21.
Consent
Written informed consent was obtained from the patients for being included in this case report publication.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
A Altheaby, M Alotaibi, N Alajlan, and A Alshareef wrote the proposal and collect the data for 3 cases. M Alruwaymi, Ghaleb Aboalsamh, and M F Shaheen wrote the manuscript. A Altheaby, M Alzunitan, and Z Arabi did all editing and reviewing of the manuscript.
Figure 1 May–Grünwald–Giemsa staining of bone marrow aspirate showing the classical feature of PRCA, namely, a red inclusion in the nucleus of giant pronormoblasts (arrow) [11]. | Recovered | ReactionOutcome | CC BY | 34881070 | 20,206,212 | 2021 |
What was the outcome of reaction 'Polyomavirus viraemia'? | Parvovirus B19 Infection due to over Immunosuppression in Kidney Transplant Recipients: Case Reports and Literature Review.
Parvovirus B19 (PB19) is a single-stranded DNA virus that belongs to the Erythrovirus genus within the Parvoviridae family. Clinical presentations associated with PB19 infection vary greatly, depending on the infected individual's age and hematologic and immunologic status. The limited data available regarding consensus on screening algorithms and indications in donors and recipients prior to kidney transplantation makes diagnosis and management challenging. We presented 3 cases of pure red cell aplasia due to parvovirus B19 after kidney transplant. These patients were diagnosed with severe normocytic, normochromic anemia (hemoglobin below 60 g/L) in the 1st 6 months posttransplant. A complete anemia work-up revealed low reticulocyte count and was otherwise inconclusive. All patients were diagnosed with pure red cell aplasia due to parvovirus B19. Two patients improved after receiving intravenous immunoglobulin 2 gm/kg given over 4 doses. Unfortunately, they relapse after few weeks and required additional doses of intravenous immunoglobulin in conjugation with reduction of their immunosuppressive medication. The third patient improved after holding mycophenolate mofetil (MMF) and did not require intravenous immunoglobulin. Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in confirming the diagnosis. Intravenous immunoglobulin (IVIG) can be an effective treatment in immunocompromised patients with primary or relapsed PB19 infection in conjunction with minimizing immunosuppressive medication. Further research and consideration are required to determine appropriate and targeted screening in donors and recipients in the peritransplantation period.
pmc1. Introduction
Parvovirus (Erythrovirus) B19 (PB19) is a common human infection worldwide. It belongs to the Erythrovirus genus within the Parvoviridae family [1]. PB19 transmission occurs by different routes that include respiratory transmission, vertically from mother to fetus, transfusion of blood or blood-derived products, or organ transplantation [2]. After PB19 infection, immunocompetent individuals are considered immune. However, reinfection has been suspected in some cases [2]. During active infection, the virus binds to globoside (P antigen) receptors that are present in erythroid precursor cells. The virus infects, replicates in, and then, lyses erythroid progenitor cells [2]. This will lead to pure red cell aplasia on bone marrow examination by revealing the presence of giant pronormoblasts which can help the diagnostic process [3].
2. Clinical Presentation
Clinical manifestations depend on host's hematological status and immune responses [1]. There is a wide spectrum of clinical findings in immunocompetent patients with PB19 infection. Most individuals who have serologic evidence of prior infection do not recall ever having any specific symptoms classically associated with PB19. The brief period of red cell aplasia is generally subclinical in otherwise healthy individuals, in children and adults with chronic hemolytic anemia (e.g., sickle cell disease or hereditary spherocytosis); the short-term pure red cell aplasia associated with PB19 infection leads to acute worsening of anemia, termed an “aplastic crisis,” often necessitating blood transfusion. In children, PB19 can manifest in erythema infectiosum, also known as the “fifth” disease, which presents as rash, fever, malaise, and polyarthropathy. In pregnancy, PB19 infection is associated with hydrops fetalis [4].
In solid organ transplant recipients, PB19 infection occurs on average 7 weeks (range, 1 week–8 years) after transplantation. Up to 65% of transplant recipients with PB19 infection present within the first 3 months following transplantation [5]. Anemia is an expected finding of this infection in solid organ transplantation. Fever presents in only 25% while arthralgia occurs in 6% of transplant recipients. Leucopenia and thrombocytopenia are seen in 33% and 18%, respectively, which is similar to noninfected transplant recipient's rates. Notably, skin rash is seen more frequently in hematopoietic stem cell transplant as opposed to solid organ transplant recipients (33% vs. 6%) [5]. Tissue-invasive disease was reported in 11% of transplant recipients, manifesting as hepatitis, myocarditis, pneumonitis, collapsing glomerulopathy, encephalitis, or vasculitis [6–9].
While not common, relapsing PB19-related anemia has been observed in 33% of patients treated with IVIG for primary PB19 infection. The risk of relapse is higher in patients with primary PB19 infection and patients who received antithymocyte globulin (ATG) for induction therapy [10].
3. Diagnosis
Diagnosis is based on the detection of PB19 IgG or IgM antibodies or PB19 DNA in blood or tissue samples by polymerase chain reaction (PCR). Bone marrow study may show giant pronormoblasts with prominent nuclear inclusions, which is characteristic of PB19 infection (Figure 1).
4. Management in Transplant Recipients
Management of presumed or confirmed PB19 infection in transplant recipients includes reduction of immunosuppressive medication. Some case reports have shown recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [12]. While intravenous immunoglobulin (IVIG) has also been used to treat PB19 infection in many transplant recipients, with successful resolution of viremia [5, 13, 14], some other patients experienced long-lasting resolution of the infection without receiving IVIG [5]. Although the optimal dose of IVIG and the frequency of administration are not well studied, a dose of 400 mg/kg/day for 5 days has been recommended in some studies [5].
5. Case Presentation
5.1. Case 1
A 43-year-old man had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to IgA nephropathy. The induction agent used at the time of transplantation was ATG 4.5 mg/kg. Afterwards, he received immunosuppressive maintenance therapy that consisted of mycophenolate mofetil (MMF) 1000 mg twice daily, tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
After the transplant, hemoglobin remained stable in the range of 100-120 g/L until 4-month posttransplantation when the patient started to complain of dizziness and shortness of breath on exertion. Blood work at that time showed hemoglobin level of 58 mg/L that was normocytic and normochromic with normal morphology on the blood smear. The patient's reticulocyte count was inappropriately low at 3 × 109/L (normal range 10 − 86 × 109/L). Vitamin B12 and iron indices were normal, and the hemolytic screen was negative. PCR for Cytomegalovirus (CMV), BK virus, and Epstein-Barr virus (EBV) was negative. Serology for PB19 showed a negative IgG and an indeterminate IgM antibody level. The patient was transfused 2 units of red blood cells and discharged home on erythropoietin stimulating agent. MMF dose also reduced to 500 mg twice daily upon discharge.
Unfortunately, the patient was readmitted 2 weeks later with the same complaints and a hemoglobin level of 56 g/L. The reticulocyte count was persistently low at 5 × 109/L. PB19 serology was repeated and showed negative IgG and an indeterminate IgM. The patient received transfusion of 2 units of RBCs and PB19 PCR also positive this time. Patient started on IVIG (0.5 g/kg) for a total of 4 doses. MMF discontinued on this admission and patient discharge after completing IVIG course on prednisolone and tacrolimus only. On discharge, the patient's symptoms had improved, and hemoglobin was 87 g/L. Patients followed monthly in posttransplant clinic, and hemoglobin normalized after 1 month. MMF resumed at 500 mg bid after 4 months, and hemoglobin remained above 125 g/L during 3 years follow-up with no further relapse.
5.2. Case 2
A 26-year-old female had a deceased-donor renal transplantation for the management of end-stage renal disease secondary to Alport syndrome. The induction agent used at the time of transplantation was ATG 4.2 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
The patient developed severe symptomatic, normocytic, and normochromic anemia (hemoglobin 55 g/L) 6 months after transplantation with normal platelet and white cell count. A complete anemia work-up showed low reticulocyte count; otherwise, inconclusive. Her severe anemia persisted for over 2 weeks despite packed blood cell transfusion, adjustment of immunosuppressant medications, and administration of erythropoietin stimulating agent. PB19 PCR was sent few days after admission and came back positive. MMF was held, and 2 gm/kg of IVIG was given over 4 doses. She was discharged few days after completing the IVIG course with better hemoglobin (90 g/L). The patient was seen after 2 weeks in the clinic with almost normalized hemoglobin (124 g/L). Hence, MMF 500 mg twice daily was restarted. 5 weeks later, the patient presented again to the emergency department with fatigability and shortness of breath and a hemoglobin level of 52 g/L. Another course of IVIG treatment was initiated. She received a total of 2 gm/kg over 4 doses, and MMF was held again. PB19 PCR came back positive yet again. After treatment, she improved and was discharged home. The hemoglobin level normalized after few weeks. Hence, MMF 500 mg BID was restarted. For the third time, the patient represented with severe anemia requiring blood transfusion. She was given IVIG 2 gm/kg again and discharge with a plan to discontinue MMF permanently. Her hemoglobin remained stable during the subsequent 2 years of follow-up with no further relapse.
5.3. Case 3
A 24-year-old female had a combined diseased donor kidney and liver transplant. The induction agent used at the time of transplantation was ATG 4 mg/kg. Afterwards, she received immunosuppressive maintenance therapy that consisted of MMF 1000 mg BID, Tacrolimus, and prednisone 5 mg daily. The donor's and recipient's PB19 statuses were unknown.
One month after discharge, the patient presented to the clinic with a hemoglobin drop reaching 61 g/L. The anemia was normocytic and normochromic with low reticulocyte. A complete anemia workup was inconclusive. The patient was already on an erythropoietin stimulating agent. PB19 PCR test was sent and came back positive. Patient was also found to have BK viremia with 11000 copies detected via PCR. MMF was discontinued, and she was followed in transplant clinic weekly. Her hemoglobin improved and reached 123 g/L after 4 weeks and she did not require IVIG. BK viremia resolved after 2 months as well. Her hemoglobin remains stable during the subsequent 2-year follow-up period. The MMF was never resumed.
6. Discussion
Kidney transplant recipients are highly susceptible to infections such as PB19 [15]. This is due to the use of potent immunosuppressive agents such as ATG to prevent early acute rejection and because of the effect of sustained long-term immunosuppression to prevent graft loss. In this case series, we are presenting 3 cases presented with symptomatic, normocytic, and normochromic anemia with normal platelet and white cell count. They have positive PB19 PCR. Although posttransplant anemia could be related to medication such as ATG and MMF, this is unlikely in our cases because these medications mainly cause leucopenia and thrombocytopenia as well, in addition to positive PB19 PCR in our cases that suggest pure red cell aplasia due to PB19 infection.
PB19 infection in transplanted patients often leads to pure red cell aplasia by attacking erythroid progenitor cells in the bone marrow [16]. Induction with ATG was found to have a higher risk for PB19 infection compared to the other induction agents [17]. Maintenance regimen also plays a role in the risk for PB19 infection as one study showed substitution of tacrolimus with cyclosporine was followed by resolution of anemia and viral clearance [11]. The presence of viral coinfection with PB19 such as CMV and human herpesvirus 6 has also been reported. In our case series, the noted patients' risk factors for PB19 infection and relapse included induction with ATG and having negative IgG on PB19 serology testing suggesting a primary infection, and not reactivation. Similar to other case reports, one of our patients also has a coinfection with BK virus [18].
PB19 infection is likely underdiagnosed in organ transplant recipients, and a high index of suspicion is necessary to allow for prompt identification of PB19 infection among renal transplant recipients with anemia of unclear etiology.
Our case series further suggests that the treatment of PB19 relies on the reduction of immunosuppression and IVIG administration. There is no clear evidence to support the best practice for adjusting the immunosuppressive medication. Some case reports showed recovery after holding tacrolimus or substitution of tacrolimus with cyclosporine [11]. In our cases, we discontinue MMF in all 3 cases by the end. These cases suggest that treatment with IVIG is effective in treating primary infection and relapse, but holding antimetabolite immunosuppressive drugs is essential in treating such cases and preventing further relapses, although we do not know when should we resume it.
7. Conclusion
Whereas PB19 infection is typically self-limiting and associated with positive IgM serology in immunocompetent hosts, these cases highlight the importance of considering PB19 infection in the differential diagnosis of persistent anemia in immunocompromised patients and the challenges in establishing the diagnosis. IVIG may be an effective treatment in immunocompromised patients with primary and relapsing PB19 infection. Minimizing or holding antimetabolite immunosuppressive drugs plays a vital role in treating and preventing PB19 relapse. Further research and consideration are required to determine an appropriate screening protocol for donors and recipients in the peritransplantation period.
Data Availability
The detailed case data used to support the findings are available from the corresponding author upon request.
Ethical Approval
The study was approved by the King Abdullah International Medical Research Center (KAIMRC) ethical committee with Memo Ref. No. IRBC/01095/21.
Consent
Written informed consent was obtained from the patients for being included in this case report publication.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
A Altheaby, M Alotaibi, N Alajlan, and A Alshareef wrote the proposal and collect the data for 3 cases. M Alruwaymi, Ghaleb Aboalsamh, and M F Shaheen wrote the manuscript. A Altheaby, M Alzunitan, and Z Arabi did all editing and reviewing of the manuscript.
Figure 1 May–Grünwald–Giemsa staining of bone marrow aspirate showing the classical feature of PRCA, namely, a red inclusion in the nucleus of giant pronormoblasts (arrow) [11]. | Recovered | ReactionOutcome | CC BY | 34881070 | 20,206,212 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'. | USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still's Disease in Elderly Patients.
BACKGROUND
Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS).
OBJECTIVE
To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome.
METHODS
A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML.
RESULTS
Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS.
CONCLUSIONS
Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.
pmc1. Introduction
Recently, the concept of autoinflammatory disorders keep evolving and an increasing number of new monogenic diseases are identified but numerous autoinflammatory diseases are still to be characterized. Systemic autoinflammatory disorders (SAID) are unprovoked episodic or chronic sterile inflammation which are secondary to innate immune system dysregulation [1]. If well-characterized monogenic diseases such as familial Mediterranean fever are part of it, more than 50% patients presenting with clinical features resembling SAIDs still do not carry any of the know pathogenic mutations in autoinflammatory disease genes [2]. Some patients with SAID fit the criteria for polygenic forms of autoinflammatory diseases, such as adult-onset Still’s disease (AOSD); however, some of them do not. They are defined as undifferentiated systemic autoinflammatory disorders (USAID) [1,3].
Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are part of a heterogeneous group of clonal hematopoietic stem cell diseases characterized by ineffective hematopoiesis, peripheral cytopenia with an increased risk of progression, to acute myeloid leukemia (AML) [4]. About 10 to 20% of MDS/CMML could be associated with various extra hematological features, e.g., neutrophilic dermatoses, systemic vasculitis, inflammatory arthritis, pseudo-Behçet’s disease, and relapsing polychondritis [5,6,7,8]. For years now, the state of autoinflammatory disorders associated with neoplasia reported in the literature were mainly associated with solid cancer but also MDS/CMML, myeloproliferative disorders, and lymphoma, and identified in the literature as “paraneoplastic AOSD” or “malignant associated AOSD” [8,9,10,11,12,13,14,15,16,17].
Recently, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), a newly established X-linked disease associated with a somatic mutation in a gene encoding ubiquitin-like modifier activating enzyme 1 (UBA1) characterized by lipid vacuole inclusions in myeloid precursors of bone marrow examination, has been described [18]. These patients often develop hematologic malignancies, and especially MDS.
In this French nationwide study, our objective was to describe patients with MDS/CMML with unexplained recurrent fever and extra hematological signs, concordant or close to AOSD, and fulfilling the definition of USAID, their management, outcomes, overall survival, and the specific risk of progression to AML. We evaluated the prevalence of the newly described VEXAS syndrome in this group of patients and specifically reported their features.
2. Materials and Methods
2.1. Study Design
Data for patients with MDS or CMML and unexplained recurrent fever associated or not to extra hematological signs, concordant with USAID diagnosed between 2010 and June 2020 were retrospectively collected. All patients provided informed consent, and the study followed the Helsinki declaration and received the approval from the Institutional Review Board of Cochin Hospital (CLEP Decision N°: AAA-2021-08040). In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion. Three hundred and ninety patients were included in the MINHEMON registry across France for extra-hematological features associated to MDS/CMML. From this cohort, we selected patients which presented at least fever of unknown origin and elevated phase reactant. Physicians were also asked by Société Nationale Française de Médecine Interne” (SNFMI), “Club Rhumatisme et Inflammation” group (CRI), “Club Médecine INterne, HEMatologie et ONcologie” (MINHEMON) and the “Centre de référence des maladies auto-inflammatoires et des amyloses d’origine inflammatoire” CEREMAIA to report cases of patients with these features associated with MDS or CMML. Inclusion criteria were as follows: (1) MDS or CMML (WHO criteria); (2) AOSD with complete criteria (Yamaguchi and/or Fautrel criteria), or suspicion of AOSD (at least 3 from 5 criteria including fever) consistent with USAID; and (3) an established diagnosis of AOSD and MDS/CMML within the period of 5 years to avoid any fortuitous association. Exclusion criteria was defined as a diagnosis compatible with another autoimmune, infectious, drug-induced or systemic disease at the time of the inclusion. The diagnosis of suspected AOSD or USAID was made based on a consensus by two specialists (MD, AM) and a senior physician from the reference center of autoinflammatory diseases (SG). We compared our patients with a control group of MDS without extra hematological symptoms. Finally, we decided to screen the included patients for the newly described VEXAS to identify if it could be a new phenotype of this disease.
2.2. MDS, CMML
MDS and CMML were diagnosed based on peripheral blood and bone marrow examinations and classified according to the WHO 2016 criteria [19]. Patients were graded using the Revised International Prognostic Scoring System (IPSS-R) [20] for MDS: very low, low, intermediate, high, and very high risk groups; and the new CMML-specific Prognostic Scoring System (CPSS) for CMML: low, intermediate, and high. Karyotypes, the percentage of medullar blasts, and somatic mutations were assessed at the time of MDS diagnosis.
2.3. Genetic Analysis for VEXAS
Somatic UBA1 mutation was explored by incorporating the targeted gene in a homemade 75-gene panel for the next generation sequencing (NGS) of circulating mononucleated cells with a 2% threshold of detection already used in previous work [21]. Only patients alive or dead with available DNA were tested for UBA1. Tested samples were collected in a single center except for one tested in his reference center. UBA1 exon 3 sequences were determined by specific PCR followed by Sanger sequencing reaction using BigDye ™ Terminator (Applied Biosystems, Waltham, MA, USA) according to the manufacturer’s instructions and using the following primers: (forward) 5′-GTGGGTGGGAAAGTCTTTTGT-3′ and (reverse) 5′-TTACAGCTGCCGGGAGTAAAG-3′. A 3500xL-Dx Genetic Analyzer sequencing system was used, and sequences were analyzed with SeqScape software (Applied Biosystems). As MDS patients from the control group did not show any extra hematological features, they were not screened for UBA1 mutation. UBA1 mutated patients were identified and included in French VEXAS group cohort whom data could be used for other studies. The patients used in different studies are represented with an asterisk* in corresponding table.
2.4. USAID
Patient’s clinical files were screened for other autoinflammatory diagnostics. Symptoms of AOSD were specifically recorded and highlighted: fever, skin rash, arthritis or arthralgia, myalgia, pharyngitis or sore throat, nodes, or splenomegaly as well as these severe complications pericarditis, pleuritis, myocarditis, reactive hemophagocytic syndrome (RHS), disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and interstitial lung disease (ILD).
Data from the laboratory test included complete blood count, liver enzymes, C-reactive protein (CRP), ferritin, and glycosylated ferritin levels.
USAID complete clinical and biological response was defined as a total disappearance of all clinical features present at baseline in exclusion of those possible reliable to MDS and/or CMML and a complete normalization of acute-phase reactants. Partial response was defined as an improvement of at least one the clinical sign without an increase of any other features and at least 50% improvement of acute-phase reactants. Patients treated with corticosteroids as first line were differentiated into two groups: high dosage (0.8 to 1 mg/kg/day of prednisone-equivalent) and low dosage. USAID diagnosis was considered concomitant with MDS/CMML or AML when the diagnosis of both diseases was made within ±3 months before or after MDS/CMML were diagnosed. The overall survival, the cause of death and the progression toward AML, were recorded, as well as the date of the last visit.
2.5. Control Group
The control group consisted of 104 patients from the “Groupe Francophone des Myelodysplasies” registry of MDS/CMML which were seen at least once by the internal medicine specialists (AM, OF). These patients did not exhibit any systemic inflammatory or autoimmune features and were selected without matching.
2.6. Ethics
All patients provided informed consent, and the study followed the Helsinki declaration.
2.7. Statistical Analysis
Descriptive data included medians and interquartile ranges (IQR) for continuous variables and frequencies (expressed in percentages) for categorical variables. To account for missing data, results were expressed as observed data (missing data were not replaced). The Chi-square or Fischer’s exact tests were used to compare categorical variables, and the Student’s t-test or Mann–Whitney U test were applied for the comparison of continuous variables. The significance of findings was determined by a p-value of 0.05 or less. Statistical analyses were performed using 2009 GraphPad software, San Diego, CA, USA v6.1.
3. Results
3.1. Characteristics of Patients
All 26 patients with USAID presented with recurrent unexplained fever and elevated acute phase reactants (Figure 1). The median age of appearance of USAID’s symptoms was 70.5 years (IQR: 64.3–78.9) with 76% being male (Table 1). Besides unexplained recurrent fever, clinical features of USAID included arthritis (n = 16, 62%) and skin rash (n = 11, 42%). Severe complications were noted at the time of diagnosis or during the follow-up period in nine patients (35%). These included RHS (n = 5), myopericarditis (n = 3), interstitial lung disease (n = 3), and ARDS (n = 1) (Table 1). Five patients among the initially identified USAID, presented symptoms concordant with a diagnosis of AOSD according to Yamaguchi (n = 5) and Fautrel (n = 4) criteria [22,23]. Nine patients with USAID, reported atypical signs for AOSD including other skin lesions (n = 7, 78%) such as ulcers, nodules, angioedema, erythema nodosum, urticaria, eczematous lesions; non-infectious ileitis (n = 2, 25%), recurrent superficial venous thrombosis (n = 1, 11%), and periorbital headache (n = 1, 11%).
MDS/CMML characteristics (WHO classification, cytogenetics, and prognostic scores) are shown in Table 2. The most frequent subtype was MDS with excess blasts (30.8% of the patients) (MDS EB-1: 11.5%, MDS EB-2: 19.2%), with a median R-IPSS of 3.7 (IQR: 2–5). NGS somatic mutations screening was available for 17 patients and showed TET2 (n = 5), ASXL1 (n = 4), IDH1 (n = 3), and KRAS (n = 3) mutations (Supplementary Table S1). The diagnosis of USAID co-occurred with preceded and appeared after respectively the diagnosis of MDS/CMML in eight (32%), twelve patients (48%), and five patients (24%). The median time between USAID and MDS/CMML diagnosis was one year (IQR: 0.2–2). Specific hematological treatments were initiated in seventeen cases (65%) within half a year (IQR: 0.2–1.2) after the diagnosis of MDS. First-line treatment mostly consisted of azacytidine (Supplementary Table S2).
Among the 26 patients included, 18 had samples available to be tested for UBA1 mutation was tested in 18 patients and revealed six 33% positive cases, five out six were males (Figure 1 and Table 3). None of these patients progressed to AML during the 2.2 median years of follow up (ranges 1.2 to 5.6 years). Among these six individuals with VEXAS syndrome, none had a confirmed AOSD, including one with incomplete AOSD criteria sets and five remainders presenting additional unusual clinical features for AOSD. None had polychondritis, one patient hand interstitial pneumonia, one alveolitis, and five had cutaneous features distinct from a rash.
Compared to MDS/CMML controls without any inflammatory features (n = 104), USAID-associated MDS/CMML patients were younger (71.4 (IQR: 36–85) vs. 78 years (IQR: 42–92); p = 0.0005), without any other statistically significant differences for demography, MDS/CMML subtype, survival. Even if the rates of deaths were higher in the study group (46% vs. 25%; p = 0.02), the overall survival and the time to progression to AML were not significantly different between the groups (Figure 2).
3.2. Treatment and Outcomes
Twenty-two patients (85%) received specific treatment for USAID. Corticosteroids were used as a first-line treatment in 19 cases (86%) alone (n = 17) or combined with anakinra or infliximab in the other 2 cases. A complete clinical and biological response to first-line treatment was observed in 14 cases (64%) but 5 cases of secondary steroid dependency were described. Thirteen patients (59%) required a second-line treatment because of a resistance to steroids, primary inefficiency, or relapse, with a response in eight (73%) patients. Targeted biological therapy alone or in association with corticosteroids enabled either a partial or complete response in 9 out of 11 patients (anakinra n = 8/9, tocilizumab n = 0/1, and infliximab n = 1/1). Azacytidine used for MDS or steroid dependent autoinflammatory disease (n = 12) resulted in a complete or partial response of systemic features in 10 (83%) cases. Seven patients (26%) progressed to AML and 12 died (46%), all except one in the VEXAS negative group during the follow-up (Supplementary Table S2 and Figure S1).
Among the six patients with VEXAS, four responded temporarily and/or partially to corticosteroids: relapses and steroid dependency were observed in all cases. Anakinra was used in five cases with a complete or partial response in four cases. Tocilizumab was ineffective in one remaining case. When available, azacytidine led to a response on systemic features in all 3 cases.
4. Discussion
Patients with MDS/CMML can develop USAID with various extra hematological features including pattern suggestive of AOSD. This is the first multidisciplinary series (involving both rheumatologists, hematologists, and clinical immunologists) reporting on USAID associated with MDS/CMML features and the prevalence of VEXAS in such cohort(s). The results of the present study have several important implications. In the case of MDS/CMML with recurrent and unexplained fever, our cohort, although limited, shows that VEXAS syndrome represents 33% (6/18) of cases, these inflammatory situations remaining rare. Moreover, over a median follow-up of 26 month, none of the 6 cases of MDS/CMML VEXAS + progressed to AML, versus 23% of MDS/CMML with USAID and 40% of classic MDS/CMML without inflammatory manifestations. At last, although the numbers are small therefore caution must remain prevalent, there could be a potential interest of biological therapies or even azacytidine when UBA1 is mutated.
Patients with MDS and unexplained recurrent fever should be first tested for the UBA1 mutation. The recent work by Beck et al. which identified VEXAS, implying that somatic mutations may be a more frequent cause of human disease than previously recognized [18,24]. A third of our patients screened for UBA1 were positive for this mutation (including one woman). As a cohort of comparison, in relapsing chondritis, a frequently associated clinical picture usually described with VEXAS, only 7.6% had UBA1 mutations [25]. USAID appeared as a new pattern of VEXAS. Interestingly, 50% of our VEXAS patients experienced RHS. In the future, the order of UBA1 screening could be debated: integrated into the first-line genetic exploration of MDS as well as the MDS/SMP NGS panel or rather screened in the case of MDS/CMML with systemic features in particular USAID.
In contrast to other dysimmune manifestations with a near equal frequency distribution before, simultaneously, and after the diagnosis of MDS/CMML (USAID and systemic features of VEXAS tend to precede the diagnosis of hematological diseases) [9]; hence, the importance of an early identification of warning signs to carefully consider an underlying neoplasia, in particular hematological malignancy. Nearly 20% of the patients matched with the criteria concordant with AOSD, but some atypia should raise the physicians’ attention in patients with newly-diagnosed AOSD, with some features such as late-onset disease [26], male sex [27] as well as cytopenia in particular the absence of leukocytosis (a hallmark feature of AOSD), and macrocytosis and monocytosis [9,11]. In a recent Dutch case series of VEXAS, among patients with unclassified autoinflammation, two among the twelve retrospectively identified were initially suspected with AOSD [28]. Thus, elderly patients with late AOSD diagnosis or suspicion as described in some series [29,30] could also benefit from UBA1 mutation screening.
As described previously for systemic inflammatory and autoimmune disorders associated with MDS/CMML, MDS EB, and MDS MLD were the most frequently associated subtypes in USAID patients not UBA1 mutated [6,31]. No association with a specific karyotype was identified but interestingly TET2 and IDH mutation already associated with systemic inflammatory and auto immune disease and T cell dysregulation in a recent work [32] were also frequently found in our cohort. Two out of the six VEXAS patients presented DNMT3A also described in other VEXAS patients [18,28,33,34], but significance is yet unclear. None of the patients with VEXAS had CMML, which is consistent with the recent report published by Zhao et al. [35]. The prognosis of MDS-associated autoimmune disorders remains unclear, as depending on the types of autoimmune disease in each cohort, the impact on survival could be different [7] but we must notice that in our group, despite a high rate of transformation (more than 25%), the twelve death: only one was UBA1 mutated and none of the VEXAS patients transformed into AML.
The treatment of symptoms of patients with malignant associated features concordant or close to AOSD is challenging. Corticosteroids response was similar to AOSD’s but with a high percentage of steroid dependency or secondary failure [27]. Methotrexate, usually used for its steroid-sparing effect, was rarely applied, presumably due to the risk of cytopenia, explaining the frequent use of biologic agents. The preferential utilization of interleukin-1R antagonists rather than TNF-a antagonists usually used in articular rheumatism is justified by the dominance of the systemic character of the disease with frequent spikes in fever and seemed efficient. Most treatments were only transiently effective, but hematological treatment allowed control of the USAID symptoms for 11 patients in our cohort. As in autoimmune and inflammatory disorders, azacytidine, appears to have a beneficial effect on these systemic manifestations [36,37]. Similarly, in a recent retrospective, Bourbon et al.’s study of the hypomethylating agent and signaling inhibitors seemed to achieve interesting results in VEXAS syndrome patients [38]. The occurrence of USAID or AOSD compatible features over the course of myelodysplastic diseases may prompt a hematological treatment, especially in its refractory form, despite the absence of a direct hematological indication. Thus, azacytidine could be a therapeutical hypothesis for USAID associated with MDS as well as it could be for UBA1 mutated patients.
Our study has several important limitations. First, the retrospective design used here carries an inherited risk of bias and missing data. Second, despite the scarcity of the described clinical syndrome, a small sample size limits the generalizability of the findings reported. Herein we chose to select only patient with occurrence of USAID/AOSD suspicion and MDS/CMML within the period of 5 years to avoid any fortuitous association. Further studies should aim at improving study designs with a prospective nature, larger sample size, and detailed comprehensive information collection.
5. Conclusions
Systemic form of VEXAS syndrome can mimic AOSD, especially in the elderly. USAID symptoms including a pattern suggestive of AOSD associated with MDS/CMML was identified in 33% cases with VEXAS syndrome, thereby further expanding the spectrum of this new syndrome. UBA1 should be sequenced in this population, especially in case of macrocytic associated anemia and chronically elevated CRP among old males, but not exclusively. Although the optimal management of UBA1/MDS overlap patients remains to be determined in larger scale cohorts, biological therapies and/or hypomethylating agents seem promising in this situation.
Key messages:
Patients with MDS/CMML can develop a recurrent fever with various extra hematological features suggestive of USAID;
Pseudo-Still disease or USAID associated with a myelodysplastic syndrome are a new phenotype of VEXAS syndrome;
UBA1 mutation should be screened in case of such association.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/jcm10235586/s1, Figure S1: Different lines of USAID treatments and treatment responses. Twenty-two patient (85%) received specific treatment for USAID and 14 (64%) experienced complete response. Fifty-nine percent of the patient needed a second line treatment and 54% a third line, Table S1: Main features of MDS/CMML patients with USAID, Table S2: USAID including pattern suggestive of AOSD natural history and therapeutical management.
Click here for additional data file.
Author Contributions
Conceptualization, M.D. (Marion Delplanque), S.G.-L. and A.M.; Supervision, S.G.-L. and A.M.; Writing—original draft, M.D. (Marion Delplanque); Writing—review & editing, M.D. (Marion Delplanque), A.A., P.H., P.F., J.G., F.M., D.R.-W., N.B., L.D., A.O., M.G., M.M., J.R. (Jerome Razanamahery), G.M., M.D. (Matthieu Décamp), S.M., T.Q., J.R. (Julien Rossignol), L.S., M.S., L.T., A.S., Y.H., S.G.-L. and A.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Cochin Hospital Institutional Review Board (CLEP Decision N°: AAA-2021-08040).
Informed Consent Statement
In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion.
Data Availability Statement
Data are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
A Arthritis/arthralgia
AML Acute myeloid leukemia
ANA Antinuclear antibody
AOSD Adult-onset Still’s disease
ARDS Acute respiratory distress syndrome
C Cytolysis
CBC Complete blood count
CC Corticosteroids
CMML Chronic myelomonocytic leukemia
CPSS CMML-specific prognostic scoring system
CR Complete remission
CRP C-reactive protein
DIC Disseminated intravascular coagulation
F Female
F Fever
Fr High ferritin
G Low glycosylated ferritin
IL Interleukin
ILD interstitial lung disease
L Lymph nodes and splenomegaly
M Male
M/F Male-to-female ratio
MAS Macrophage activation syndrome
MDS Myelodysplastic syndrome
MDS MLD MDS with multilineage dysplasia
MDS SLD MDS with single lineage dysplasia
MDS-EB1 MDS with excess of blasts <5%
MDS-EB2 MDS with excess of blasts >5%
MDS-RS MDS with ring sideroblasts
MM Myelodysplastic malignancy
MTX Methotrexate
PNN Polymorphonuclear neutrophils >80%
PET scan Positron emission tomography scan
PR Partial remission
RF Rheumatoid factor
RHS Reactive hemophagocytic syndrome
R-IPPS Revised International Prognostic Scoring System
SAID Systemic autoinflammatory disorder
S Skin rash
T Sore throat
TNF Tumor necrosis factor
UBA1 Ubiquitin-like modifier activating enzyme 1
USAID Undifferentiated systemic autoinflammatory disorder
VEXAS Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome
W Leukocytosis
Yrs Years
Figure 1 Flow-chart depicting patient selection. From the 46 patients screened, 26 were included. Six UBA1 mutated patients identified from the included patients.
Figure 2 Kaplan–Meier curves of overall survival (a), progression to AML (b) in MDS patients with and without USAID. Data were censored at time of last visit or death. The response MDS control group is in blue and the one with autoinflammatory features is in red.
jcm-10-05586-t001_Table 1 Table 1 Baseline characteristics of USAID including pattern suggestive of AOSD.
Patients (n = 26) No VEXAS (n = 18) VEXAS (n = 6)
Epidemiology
Male-to-female ratio 3.16 2.8 4
Age at 1st signs (years) (range) 70.5 (64.3–78.9) 71 (65.5–79.3) 64.3 (63.6–68.2)
Time between USAID and MDS (years) (range) 1.0 (0.2–2) 0.9 (1.8–0.2) 1.2 (1.1–3)
Medical history (%)
Personal or familial history of autoimmunity 2 (9) 1 (6) 1 (25)
Symptoms (%)
Fever 26 (100) 18(100) 6 (100)
Skin rash 11 (42) 6 (33) 5 (83)
Arthritis/arthralgia 16 (62) 14 (78) 2 (33)
Pharyngitis/sore throat 5 (19) 1 (22) 1 (17)
Myalgia 5 (19) 3 (17) 2 (33)
Lymph nodes or splenomegaly 12 (46) 8 (44) 4 (67)
Blood test results (%)
Leukocytosis > 10,000/mm3 10 (38) 9 (50) 1 (17)
Granulocytes ≥ 80% 7 (26) 6 (67) 1 (17)
CRP >30 mg/L 26 (100) 18 (100) 6 (100)
Elevated liver enzymes 9 (35) 7 (39) 2 (67)
High ferritin 19/20 (95) 15 (94) 4 (100)
>2000 µg/L 14/20 (70) 13 (81) 1 (25)
Glycosylated ferritin < 20% 4/11 (36) 3 (30) 1 (50)
Severe complications
Pericarditis 3 (12) 3 (18) 0 (0)
Myocarditis 0 (0) 0 (0) 0 (0)
DIC 0 (0) 0 (0) 0 (0)
RHS 5 (19) 2 (11) 3 (50)
ARDS 1 (4) 1 (4) 0 (0)
ILD, alveolitis 3 (12) 1 (4) 2 (67)
Pleurisy 6 (23) 6 (33) 0 (0)
AOSD, adult-onset Still’s disease; ARDS, acute respiratory distress syndrome; CRP, C-reactive protein; DIC, disseminated intravascular syndrome; ILD, interstitial lung disease; MDS, myelodysplastic syndrome; RHS, reactive hemophagocytic syndrome.
jcm-10-05586-t002_Table 2 Table 2 Main features of MDS/CMML patients with USAID.
MDS-Related USAID
n = 26 (%) MDS/CMML Controls
n = 104 (%)
Mean age at diagnosis (range) 71.4 (36–85) 78 (42–92) *
Male 19 (76) 79 (76)
Myelodysplastic syndrome (MDS) 23 (89) 83 (80)
MDS with single lineage dysplasia 3 (12) 14 (13)
MDS with ring sideroblasts (MDS-RS) 2 (8) 6 (6)
MDS with multilineage dysplasia 5 (19) 33 (32)
MDS with excess blasts (EB) 8 (31) 14 (13)
MDS with isolated del(5q) 0 4 (4)
MDS, unclassifiable/missing data 5 (19) 7 (7)
Chronic myelomonocytic leukemia (CMML) 3 (12) 21 (20)
Acute myeloid leukemia (AML) (progressed to) 7 (27) 11 (10)
IPPS-R (IQR) 3.7 (2–5) 2.5 (0–8)
Deaths 12 (46) 26 (25) *
Follow-up (range) 16.8 (0–104) 21.5 (0–86)
* p value < 0.05.
jcm-10-05586-t003_Table 3 Table 3 Main features of the patients with UBA1 mutations (VEXAS syndrome).
Patient Sex Type MDS Age at Diagnosis of MDS Characteristics of MDS Age at USAID Onset Signs of USAID Other Symptoms Evolution
Patient #1 * M MDS UL 59.8 IPPS = NS 58.8 Fever, rash, cytolysis, high ferritin, RHS Recurrent superficial veinous thrombosis, cutaneous atypia Azacytidine for MDS just begun
NGS: DNMT3A, BRCA2, and ZRSR2 mutated
Bone marrow: vacuoles in myeloid precursor cells No response to CTC high dose rapidly completed with cyclosporine permitting, PR
Del 6q Blasts: NS Alive under azacytidine, CTC 20 mg and cyclosporine
Patient #2 * M MDS EB1 64.5 IPPS = 4 63.3 Fever, arthralgia, leukocytosis, lymphadenopathy, splenomegaly, granulocytes, cytolysis CR under azacytidine for MDS
NGS: Normal Periorbital headache, skin nodules, edema, diarrhea, abdominal pain Multiple lines of treatments: response and relapses to high-dose CTC and anakinra; no response to infliximab, tocilizumab, IV Ig, cyclosporine
Blasts: 7% Alive and disappearance of systemic features under azacytidine and CTC 20 mg/day
Patient #3 * M Unclassifiable MDS 73.5 IPPS-R: 2 73.5 Fever, rash, lymphadenopathy, splenomegaly, high ferritin, RHS Recurrent face edema, urticaria, skin nodules and eczematous skin lesions PR with azacytidine for MDS
NGS: DNMT3A mutated 31.7% No response to high-dose CTC and anakinra
Blasts: 0% Alive, PR and systemic symptoms with azacytidine
Patient #4 F Unclassifiable MDS 64.3 IPPS-R: NS NS Fever, rash, RHS Unknown response with hydroxyurea
Del X Blasts: NS Interstitial pneumonia, diarrhea CR with high-dose CTC, steroid dependence; CR with anakinra and CTC
Alive at last visit
Patient #5 * M MDS MLD 69.4 IPPS-R: 2
NGS: TET2 mutated 3% 65.8 Fever, rash, arthritis, sore throat, lymphadenopathy, splenomegaly, high ferritin, myalgia Pustular eruption and other cutaneous atypia CR with azacytidine; failure with methotrexate; leflunomide stopped early due to cytopenia; CR (with few relapses) with CTC and anakinra
Patient #6 M Unclassifiable MDS NS IPPS-R: NS
NGS: normal 69 Fever, rash, high ferritin, myalgia Oedema, angioedema chronic urticaria, alveolitis No hematological treatment CR under high dose CTC but CTC dependency, CR under anakinra and CTC stopped for neutropenia
Death at 73 years from sepsis and cardiac failure and anakinra
Median (yrs) (IQ 25;75) n = (%) M/F = 5:1 Follow up 2.2 (1.5; 3.3) 64.5 (64.3; 69.4) Fever (n = 6, 100%), skin rash (n = 5, 83%), arthralgia arthritis (n = 2, 33%), lymph nodes/splenomegaly n = 3 (50), sore throat (n = 1, 17%), RHS n = 3 (50), leukocytosis (n = 1, 17%), granulocytosis (n = 1, 17%), cytolysis (n = 2, 33%), high ferritin (n = 4, 67%)
CR, complete remission; CTC, corticosteroids; Ig, immunoglobulin; IPPS-R, Revised International Prognostic Scoring System; IV, intravenous; MDS, myelodysplastic syndrome; MDS EB1, MDS with excess of blasts < 5%; MDS: myelodysplastic syndrome; NGS, next-generation sequencing; NS, not significant; PR, partial response; RHS, reactive hemophagocytic syndrome; MDS SLD, MDS with single lineage dysplasia; MDS UL. Patients marked with an * were identified and included in French VEXAS group cohort and could have been used in other published studies.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ANAKINRA | DrugsGivenReaction | CC BY | 34884286 | 20,184,789 | 2021-11-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still's Disease in Elderly Patients.
BACKGROUND
Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS).
OBJECTIVE
To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome.
METHODS
A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML.
RESULTS
Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS.
CONCLUSIONS
Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.
pmc1. Introduction
Recently, the concept of autoinflammatory disorders keep evolving and an increasing number of new monogenic diseases are identified but numerous autoinflammatory diseases are still to be characterized. Systemic autoinflammatory disorders (SAID) are unprovoked episodic or chronic sterile inflammation which are secondary to innate immune system dysregulation [1]. If well-characterized monogenic diseases such as familial Mediterranean fever are part of it, more than 50% patients presenting with clinical features resembling SAIDs still do not carry any of the know pathogenic mutations in autoinflammatory disease genes [2]. Some patients with SAID fit the criteria for polygenic forms of autoinflammatory diseases, such as adult-onset Still’s disease (AOSD); however, some of them do not. They are defined as undifferentiated systemic autoinflammatory disorders (USAID) [1,3].
Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are part of a heterogeneous group of clonal hematopoietic stem cell diseases characterized by ineffective hematopoiesis, peripheral cytopenia with an increased risk of progression, to acute myeloid leukemia (AML) [4]. About 10 to 20% of MDS/CMML could be associated with various extra hematological features, e.g., neutrophilic dermatoses, systemic vasculitis, inflammatory arthritis, pseudo-Behçet’s disease, and relapsing polychondritis [5,6,7,8]. For years now, the state of autoinflammatory disorders associated with neoplasia reported in the literature were mainly associated with solid cancer but also MDS/CMML, myeloproliferative disorders, and lymphoma, and identified in the literature as “paraneoplastic AOSD” or “malignant associated AOSD” [8,9,10,11,12,13,14,15,16,17].
Recently, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), a newly established X-linked disease associated with a somatic mutation in a gene encoding ubiquitin-like modifier activating enzyme 1 (UBA1) characterized by lipid vacuole inclusions in myeloid precursors of bone marrow examination, has been described [18]. These patients often develop hematologic malignancies, and especially MDS.
In this French nationwide study, our objective was to describe patients with MDS/CMML with unexplained recurrent fever and extra hematological signs, concordant or close to AOSD, and fulfilling the definition of USAID, their management, outcomes, overall survival, and the specific risk of progression to AML. We evaluated the prevalence of the newly described VEXAS syndrome in this group of patients and specifically reported their features.
2. Materials and Methods
2.1. Study Design
Data for patients with MDS or CMML and unexplained recurrent fever associated or not to extra hematological signs, concordant with USAID diagnosed between 2010 and June 2020 were retrospectively collected. All patients provided informed consent, and the study followed the Helsinki declaration and received the approval from the Institutional Review Board of Cochin Hospital (CLEP Decision N°: AAA-2021-08040). In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion. Three hundred and ninety patients were included in the MINHEMON registry across France for extra-hematological features associated to MDS/CMML. From this cohort, we selected patients which presented at least fever of unknown origin and elevated phase reactant. Physicians were also asked by Société Nationale Française de Médecine Interne” (SNFMI), “Club Rhumatisme et Inflammation” group (CRI), “Club Médecine INterne, HEMatologie et ONcologie” (MINHEMON) and the “Centre de référence des maladies auto-inflammatoires et des amyloses d’origine inflammatoire” CEREMAIA to report cases of patients with these features associated with MDS or CMML. Inclusion criteria were as follows: (1) MDS or CMML (WHO criteria); (2) AOSD with complete criteria (Yamaguchi and/or Fautrel criteria), or suspicion of AOSD (at least 3 from 5 criteria including fever) consistent with USAID; and (3) an established diagnosis of AOSD and MDS/CMML within the period of 5 years to avoid any fortuitous association. Exclusion criteria was defined as a diagnosis compatible with another autoimmune, infectious, drug-induced or systemic disease at the time of the inclusion. The diagnosis of suspected AOSD or USAID was made based on a consensus by two specialists (MD, AM) and a senior physician from the reference center of autoinflammatory diseases (SG). We compared our patients with a control group of MDS without extra hematological symptoms. Finally, we decided to screen the included patients for the newly described VEXAS to identify if it could be a new phenotype of this disease.
2.2. MDS, CMML
MDS and CMML were diagnosed based on peripheral blood and bone marrow examinations and classified according to the WHO 2016 criteria [19]. Patients were graded using the Revised International Prognostic Scoring System (IPSS-R) [20] for MDS: very low, low, intermediate, high, and very high risk groups; and the new CMML-specific Prognostic Scoring System (CPSS) for CMML: low, intermediate, and high. Karyotypes, the percentage of medullar blasts, and somatic mutations were assessed at the time of MDS diagnosis.
2.3. Genetic Analysis for VEXAS
Somatic UBA1 mutation was explored by incorporating the targeted gene in a homemade 75-gene panel for the next generation sequencing (NGS) of circulating mononucleated cells with a 2% threshold of detection already used in previous work [21]. Only patients alive or dead with available DNA were tested for UBA1. Tested samples were collected in a single center except for one tested in his reference center. UBA1 exon 3 sequences were determined by specific PCR followed by Sanger sequencing reaction using BigDye ™ Terminator (Applied Biosystems, Waltham, MA, USA) according to the manufacturer’s instructions and using the following primers: (forward) 5′-GTGGGTGGGAAAGTCTTTTGT-3′ and (reverse) 5′-TTACAGCTGCCGGGAGTAAAG-3′. A 3500xL-Dx Genetic Analyzer sequencing system was used, and sequences were analyzed with SeqScape software (Applied Biosystems). As MDS patients from the control group did not show any extra hematological features, they were not screened for UBA1 mutation. UBA1 mutated patients were identified and included in French VEXAS group cohort whom data could be used for other studies. The patients used in different studies are represented with an asterisk* in corresponding table.
2.4. USAID
Patient’s clinical files were screened for other autoinflammatory diagnostics. Symptoms of AOSD were specifically recorded and highlighted: fever, skin rash, arthritis or arthralgia, myalgia, pharyngitis or sore throat, nodes, or splenomegaly as well as these severe complications pericarditis, pleuritis, myocarditis, reactive hemophagocytic syndrome (RHS), disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and interstitial lung disease (ILD).
Data from the laboratory test included complete blood count, liver enzymes, C-reactive protein (CRP), ferritin, and glycosylated ferritin levels.
USAID complete clinical and biological response was defined as a total disappearance of all clinical features present at baseline in exclusion of those possible reliable to MDS and/or CMML and a complete normalization of acute-phase reactants. Partial response was defined as an improvement of at least one the clinical sign without an increase of any other features and at least 50% improvement of acute-phase reactants. Patients treated with corticosteroids as first line were differentiated into two groups: high dosage (0.8 to 1 mg/kg/day of prednisone-equivalent) and low dosage. USAID diagnosis was considered concomitant with MDS/CMML or AML when the diagnosis of both diseases was made within ±3 months before or after MDS/CMML were diagnosed. The overall survival, the cause of death and the progression toward AML, were recorded, as well as the date of the last visit.
2.5. Control Group
The control group consisted of 104 patients from the “Groupe Francophone des Myelodysplasies” registry of MDS/CMML which were seen at least once by the internal medicine specialists (AM, OF). These patients did not exhibit any systemic inflammatory or autoimmune features and were selected without matching.
2.6. Ethics
All patients provided informed consent, and the study followed the Helsinki declaration.
2.7. Statistical Analysis
Descriptive data included medians and interquartile ranges (IQR) for continuous variables and frequencies (expressed in percentages) for categorical variables. To account for missing data, results were expressed as observed data (missing data were not replaced). The Chi-square or Fischer’s exact tests were used to compare categorical variables, and the Student’s t-test or Mann–Whitney U test were applied for the comparison of continuous variables. The significance of findings was determined by a p-value of 0.05 or less. Statistical analyses were performed using 2009 GraphPad software, San Diego, CA, USA v6.1.
3. Results
3.1. Characteristics of Patients
All 26 patients with USAID presented with recurrent unexplained fever and elevated acute phase reactants (Figure 1). The median age of appearance of USAID’s symptoms was 70.5 years (IQR: 64.3–78.9) with 76% being male (Table 1). Besides unexplained recurrent fever, clinical features of USAID included arthritis (n = 16, 62%) and skin rash (n = 11, 42%). Severe complications were noted at the time of diagnosis or during the follow-up period in nine patients (35%). These included RHS (n = 5), myopericarditis (n = 3), interstitial lung disease (n = 3), and ARDS (n = 1) (Table 1). Five patients among the initially identified USAID, presented symptoms concordant with a diagnosis of AOSD according to Yamaguchi (n = 5) and Fautrel (n = 4) criteria [22,23]. Nine patients with USAID, reported atypical signs for AOSD including other skin lesions (n = 7, 78%) such as ulcers, nodules, angioedema, erythema nodosum, urticaria, eczematous lesions; non-infectious ileitis (n = 2, 25%), recurrent superficial venous thrombosis (n = 1, 11%), and periorbital headache (n = 1, 11%).
MDS/CMML characteristics (WHO classification, cytogenetics, and prognostic scores) are shown in Table 2. The most frequent subtype was MDS with excess blasts (30.8% of the patients) (MDS EB-1: 11.5%, MDS EB-2: 19.2%), with a median R-IPSS of 3.7 (IQR: 2–5). NGS somatic mutations screening was available for 17 patients and showed TET2 (n = 5), ASXL1 (n = 4), IDH1 (n = 3), and KRAS (n = 3) mutations (Supplementary Table S1). The diagnosis of USAID co-occurred with preceded and appeared after respectively the diagnosis of MDS/CMML in eight (32%), twelve patients (48%), and five patients (24%). The median time between USAID and MDS/CMML diagnosis was one year (IQR: 0.2–2). Specific hematological treatments were initiated in seventeen cases (65%) within half a year (IQR: 0.2–1.2) after the diagnosis of MDS. First-line treatment mostly consisted of azacytidine (Supplementary Table S2).
Among the 26 patients included, 18 had samples available to be tested for UBA1 mutation was tested in 18 patients and revealed six 33% positive cases, five out six were males (Figure 1 and Table 3). None of these patients progressed to AML during the 2.2 median years of follow up (ranges 1.2 to 5.6 years). Among these six individuals with VEXAS syndrome, none had a confirmed AOSD, including one with incomplete AOSD criteria sets and five remainders presenting additional unusual clinical features for AOSD. None had polychondritis, one patient hand interstitial pneumonia, one alveolitis, and five had cutaneous features distinct from a rash.
Compared to MDS/CMML controls without any inflammatory features (n = 104), USAID-associated MDS/CMML patients were younger (71.4 (IQR: 36–85) vs. 78 years (IQR: 42–92); p = 0.0005), without any other statistically significant differences for demography, MDS/CMML subtype, survival. Even if the rates of deaths were higher in the study group (46% vs. 25%; p = 0.02), the overall survival and the time to progression to AML were not significantly different between the groups (Figure 2).
3.2. Treatment and Outcomes
Twenty-two patients (85%) received specific treatment for USAID. Corticosteroids were used as a first-line treatment in 19 cases (86%) alone (n = 17) or combined with anakinra or infliximab in the other 2 cases. A complete clinical and biological response to first-line treatment was observed in 14 cases (64%) but 5 cases of secondary steroid dependency were described. Thirteen patients (59%) required a second-line treatment because of a resistance to steroids, primary inefficiency, or relapse, with a response in eight (73%) patients. Targeted biological therapy alone or in association with corticosteroids enabled either a partial or complete response in 9 out of 11 patients (anakinra n = 8/9, tocilizumab n = 0/1, and infliximab n = 1/1). Azacytidine used for MDS or steroid dependent autoinflammatory disease (n = 12) resulted in a complete or partial response of systemic features in 10 (83%) cases. Seven patients (26%) progressed to AML and 12 died (46%), all except one in the VEXAS negative group during the follow-up (Supplementary Table S2 and Figure S1).
Among the six patients with VEXAS, four responded temporarily and/or partially to corticosteroids: relapses and steroid dependency were observed in all cases. Anakinra was used in five cases with a complete or partial response in four cases. Tocilizumab was ineffective in one remaining case. When available, azacytidine led to a response on systemic features in all 3 cases.
4. Discussion
Patients with MDS/CMML can develop USAID with various extra hematological features including pattern suggestive of AOSD. This is the first multidisciplinary series (involving both rheumatologists, hematologists, and clinical immunologists) reporting on USAID associated with MDS/CMML features and the prevalence of VEXAS in such cohort(s). The results of the present study have several important implications. In the case of MDS/CMML with recurrent and unexplained fever, our cohort, although limited, shows that VEXAS syndrome represents 33% (6/18) of cases, these inflammatory situations remaining rare. Moreover, over a median follow-up of 26 month, none of the 6 cases of MDS/CMML VEXAS + progressed to AML, versus 23% of MDS/CMML with USAID and 40% of classic MDS/CMML without inflammatory manifestations. At last, although the numbers are small therefore caution must remain prevalent, there could be a potential interest of biological therapies or even azacytidine when UBA1 is mutated.
Patients with MDS and unexplained recurrent fever should be first tested for the UBA1 mutation. The recent work by Beck et al. which identified VEXAS, implying that somatic mutations may be a more frequent cause of human disease than previously recognized [18,24]. A third of our patients screened for UBA1 were positive for this mutation (including one woman). As a cohort of comparison, in relapsing chondritis, a frequently associated clinical picture usually described with VEXAS, only 7.6% had UBA1 mutations [25]. USAID appeared as a new pattern of VEXAS. Interestingly, 50% of our VEXAS patients experienced RHS. In the future, the order of UBA1 screening could be debated: integrated into the first-line genetic exploration of MDS as well as the MDS/SMP NGS panel or rather screened in the case of MDS/CMML with systemic features in particular USAID.
In contrast to other dysimmune manifestations with a near equal frequency distribution before, simultaneously, and after the diagnosis of MDS/CMML (USAID and systemic features of VEXAS tend to precede the diagnosis of hematological diseases) [9]; hence, the importance of an early identification of warning signs to carefully consider an underlying neoplasia, in particular hematological malignancy. Nearly 20% of the patients matched with the criteria concordant with AOSD, but some atypia should raise the physicians’ attention in patients with newly-diagnosed AOSD, with some features such as late-onset disease [26], male sex [27] as well as cytopenia in particular the absence of leukocytosis (a hallmark feature of AOSD), and macrocytosis and monocytosis [9,11]. In a recent Dutch case series of VEXAS, among patients with unclassified autoinflammation, two among the twelve retrospectively identified were initially suspected with AOSD [28]. Thus, elderly patients with late AOSD diagnosis or suspicion as described in some series [29,30] could also benefit from UBA1 mutation screening.
As described previously for systemic inflammatory and autoimmune disorders associated with MDS/CMML, MDS EB, and MDS MLD were the most frequently associated subtypes in USAID patients not UBA1 mutated [6,31]. No association with a specific karyotype was identified but interestingly TET2 and IDH mutation already associated with systemic inflammatory and auto immune disease and T cell dysregulation in a recent work [32] were also frequently found in our cohort. Two out of the six VEXAS patients presented DNMT3A also described in other VEXAS patients [18,28,33,34], but significance is yet unclear. None of the patients with VEXAS had CMML, which is consistent with the recent report published by Zhao et al. [35]. The prognosis of MDS-associated autoimmune disorders remains unclear, as depending on the types of autoimmune disease in each cohort, the impact on survival could be different [7] but we must notice that in our group, despite a high rate of transformation (more than 25%), the twelve death: only one was UBA1 mutated and none of the VEXAS patients transformed into AML.
The treatment of symptoms of patients with malignant associated features concordant or close to AOSD is challenging. Corticosteroids response was similar to AOSD’s but with a high percentage of steroid dependency or secondary failure [27]. Methotrexate, usually used for its steroid-sparing effect, was rarely applied, presumably due to the risk of cytopenia, explaining the frequent use of biologic agents. The preferential utilization of interleukin-1R antagonists rather than TNF-a antagonists usually used in articular rheumatism is justified by the dominance of the systemic character of the disease with frequent spikes in fever and seemed efficient. Most treatments were only transiently effective, but hematological treatment allowed control of the USAID symptoms for 11 patients in our cohort. As in autoimmune and inflammatory disorders, azacytidine, appears to have a beneficial effect on these systemic manifestations [36,37]. Similarly, in a recent retrospective, Bourbon et al.’s study of the hypomethylating agent and signaling inhibitors seemed to achieve interesting results in VEXAS syndrome patients [38]. The occurrence of USAID or AOSD compatible features over the course of myelodysplastic diseases may prompt a hematological treatment, especially in its refractory form, despite the absence of a direct hematological indication. Thus, azacytidine could be a therapeutical hypothesis for USAID associated with MDS as well as it could be for UBA1 mutated patients.
Our study has several important limitations. First, the retrospective design used here carries an inherited risk of bias and missing data. Second, despite the scarcity of the described clinical syndrome, a small sample size limits the generalizability of the findings reported. Herein we chose to select only patient with occurrence of USAID/AOSD suspicion and MDS/CMML within the period of 5 years to avoid any fortuitous association. Further studies should aim at improving study designs with a prospective nature, larger sample size, and detailed comprehensive information collection.
5. Conclusions
Systemic form of VEXAS syndrome can mimic AOSD, especially in the elderly. USAID symptoms including a pattern suggestive of AOSD associated with MDS/CMML was identified in 33% cases with VEXAS syndrome, thereby further expanding the spectrum of this new syndrome. UBA1 should be sequenced in this population, especially in case of macrocytic associated anemia and chronically elevated CRP among old males, but not exclusively. Although the optimal management of UBA1/MDS overlap patients remains to be determined in larger scale cohorts, biological therapies and/or hypomethylating agents seem promising in this situation.
Key messages:
Patients with MDS/CMML can develop a recurrent fever with various extra hematological features suggestive of USAID;
Pseudo-Still disease or USAID associated with a myelodysplastic syndrome are a new phenotype of VEXAS syndrome;
UBA1 mutation should be screened in case of such association.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/jcm10235586/s1, Figure S1: Different lines of USAID treatments and treatment responses. Twenty-two patient (85%) received specific treatment for USAID and 14 (64%) experienced complete response. Fifty-nine percent of the patient needed a second line treatment and 54% a third line, Table S1: Main features of MDS/CMML patients with USAID, Table S2: USAID including pattern suggestive of AOSD natural history and therapeutical management.
Click here for additional data file.
Author Contributions
Conceptualization, M.D. (Marion Delplanque), S.G.-L. and A.M.; Supervision, S.G.-L. and A.M.; Writing—original draft, M.D. (Marion Delplanque); Writing—review & editing, M.D. (Marion Delplanque), A.A., P.H., P.F., J.G., F.M., D.R.-W., N.B., L.D., A.O., M.G., M.M., J.R. (Jerome Razanamahery), G.M., M.D. (Matthieu Décamp), S.M., T.Q., J.R. (Julien Rossignol), L.S., M.S., L.T., A.S., Y.H., S.G.-L. and A.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Cochin Hospital Institutional Review Board (CLEP Decision N°: AAA-2021-08040).
Informed Consent Statement
In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion.
Data Availability Statement
Data are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
A Arthritis/arthralgia
AML Acute myeloid leukemia
ANA Antinuclear antibody
AOSD Adult-onset Still’s disease
ARDS Acute respiratory distress syndrome
C Cytolysis
CBC Complete blood count
CC Corticosteroids
CMML Chronic myelomonocytic leukemia
CPSS CMML-specific prognostic scoring system
CR Complete remission
CRP C-reactive protein
DIC Disseminated intravascular coagulation
F Female
F Fever
Fr High ferritin
G Low glycosylated ferritin
IL Interleukin
ILD interstitial lung disease
L Lymph nodes and splenomegaly
M Male
M/F Male-to-female ratio
MAS Macrophage activation syndrome
MDS Myelodysplastic syndrome
MDS MLD MDS with multilineage dysplasia
MDS SLD MDS with single lineage dysplasia
MDS-EB1 MDS with excess of blasts <5%
MDS-EB2 MDS with excess of blasts >5%
MDS-RS MDS with ring sideroblasts
MM Myelodysplastic malignancy
MTX Methotrexate
PNN Polymorphonuclear neutrophils >80%
PET scan Positron emission tomography scan
PR Partial remission
RF Rheumatoid factor
RHS Reactive hemophagocytic syndrome
R-IPPS Revised International Prognostic Scoring System
SAID Systemic autoinflammatory disorder
S Skin rash
T Sore throat
TNF Tumor necrosis factor
UBA1 Ubiquitin-like modifier activating enzyme 1
USAID Undifferentiated systemic autoinflammatory disorder
VEXAS Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome
W Leukocytosis
Yrs Years
Figure 1 Flow-chart depicting patient selection. From the 46 patients screened, 26 were included. Six UBA1 mutated patients identified from the included patients.
Figure 2 Kaplan–Meier curves of overall survival (a), progression to AML (b) in MDS patients with and without USAID. Data were censored at time of last visit or death. The response MDS control group is in blue and the one with autoinflammatory features is in red.
jcm-10-05586-t001_Table 1 Table 1 Baseline characteristics of USAID including pattern suggestive of AOSD.
Patients (n = 26) No VEXAS (n = 18) VEXAS (n = 6)
Epidemiology
Male-to-female ratio 3.16 2.8 4
Age at 1st signs (years) (range) 70.5 (64.3–78.9) 71 (65.5–79.3) 64.3 (63.6–68.2)
Time between USAID and MDS (years) (range) 1.0 (0.2–2) 0.9 (1.8–0.2) 1.2 (1.1–3)
Medical history (%)
Personal or familial history of autoimmunity 2 (9) 1 (6) 1 (25)
Symptoms (%)
Fever 26 (100) 18(100) 6 (100)
Skin rash 11 (42) 6 (33) 5 (83)
Arthritis/arthralgia 16 (62) 14 (78) 2 (33)
Pharyngitis/sore throat 5 (19) 1 (22) 1 (17)
Myalgia 5 (19) 3 (17) 2 (33)
Lymph nodes or splenomegaly 12 (46) 8 (44) 4 (67)
Blood test results (%)
Leukocytosis > 10,000/mm3 10 (38) 9 (50) 1 (17)
Granulocytes ≥ 80% 7 (26) 6 (67) 1 (17)
CRP >30 mg/L 26 (100) 18 (100) 6 (100)
Elevated liver enzymes 9 (35) 7 (39) 2 (67)
High ferritin 19/20 (95) 15 (94) 4 (100)
>2000 µg/L 14/20 (70) 13 (81) 1 (25)
Glycosylated ferritin < 20% 4/11 (36) 3 (30) 1 (50)
Severe complications
Pericarditis 3 (12) 3 (18) 0 (0)
Myocarditis 0 (0) 0 (0) 0 (0)
DIC 0 (0) 0 (0) 0 (0)
RHS 5 (19) 2 (11) 3 (50)
ARDS 1 (4) 1 (4) 0 (0)
ILD, alveolitis 3 (12) 1 (4) 2 (67)
Pleurisy 6 (23) 6 (33) 0 (0)
AOSD, adult-onset Still’s disease; ARDS, acute respiratory distress syndrome; CRP, C-reactive protein; DIC, disseminated intravascular syndrome; ILD, interstitial lung disease; MDS, myelodysplastic syndrome; RHS, reactive hemophagocytic syndrome.
jcm-10-05586-t002_Table 2 Table 2 Main features of MDS/CMML patients with USAID.
MDS-Related USAID
n = 26 (%) MDS/CMML Controls
n = 104 (%)
Mean age at diagnosis (range) 71.4 (36–85) 78 (42–92) *
Male 19 (76) 79 (76)
Myelodysplastic syndrome (MDS) 23 (89) 83 (80)
MDS with single lineage dysplasia 3 (12) 14 (13)
MDS with ring sideroblasts (MDS-RS) 2 (8) 6 (6)
MDS with multilineage dysplasia 5 (19) 33 (32)
MDS with excess blasts (EB) 8 (31) 14 (13)
MDS with isolated del(5q) 0 4 (4)
MDS, unclassifiable/missing data 5 (19) 7 (7)
Chronic myelomonocytic leukemia (CMML) 3 (12) 21 (20)
Acute myeloid leukemia (AML) (progressed to) 7 (27) 11 (10)
IPPS-R (IQR) 3.7 (2–5) 2.5 (0–8)
Deaths 12 (46) 26 (25) *
Follow-up (range) 16.8 (0–104) 21.5 (0–86)
* p value < 0.05.
jcm-10-05586-t003_Table 3 Table 3 Main features of the patients with UBA1 mutations (VEXAS syndrome).
Patient Sex Type MDS Age at Diagnosis of MDS Characteristics of MDS Age at USAID Onset Signs of USAID Other Symptoms Evolution
Patient #1 * M MDS UL 59.8 IPPS = NS 58.8 Fever, rash, cytolysis, high ferritin, RHS Recurrent superficial veinous thrombosis, cutaneous atypia Azacytidine for MDS just begun
NGS: DNMT3A, BRCA2, and ZRSR2 mutated
Bone marrow: vacuoles in myeloid precursor cells No response to CTC high dose rapidly completed with cyclosporine permitting, PR
Del 6q Blasts: NS Alive under azacytidine, CTC 20 mg and cyclosporine
Patient #2 * M MDS EB1 64.5 IPPS = 4 63.3 Fever, arthralgia, leukocytosis, lymphadenopathy, splenomegaly, granulocytes, cytolysis CR under azacytidine for MDS
NGS: Normal Periorbital headache, skin nodules, edema, diarrhea, abdominal pain Multiple lines of treatments: response and relapses to high-dose CTC and anakinra; no response to infliximab, tocilizumab, IV Ig, cyclosporine
Blasts: 7% Alive and disappearance of systemic features under azacytidine and CTC 20 mg/day
Patient #3 * M Unclassifiable MDS 73.5 IPPS-R: 2 73.5 Fever, rash, lymphadenopathy, splenomegaly, high ferritin, RHS Recurrent face edema, urticaria, skin nodules and eczematous skin lesions PR with azacytidine for MDS
NGS: DNMT3A mutated 31.7% No response to high-dose CTC and anakinra
Blasts: 0% Alive, PR and systemic symptoms with azacytidine
Patient #4 F Unclassifiable MDS 64.3 IPPS-R: NS NS Fever, rash, RHS Unknown response with hydroxyurea
Del X Blasts: NS Interstitial pneumonia, diarrhea CR with high-dose CTC, steroid dependence; CR with anakinra and CTC
Alive at last visit
Patient #5 * M MDS MLD 69.4 IPPS-R: 2
NGS: TET2 mutated 3% 65.8 Fever, rash, arthritis, sore throat, lymphadenopathy, splenomegaly, high ferritin, myalgia Pustular eruption and other cutaneous atypia CR with azacytidine; failure with methotrexate; leflunomide stopped early due to cytopenia; CR (with few relapses) with CTC and anakinra
Patient #6 M Unclassifiable MDS NS IPPS-R: NS
NGS: normal 69 Fever, rash, high ferritin, myalgia Oedema, angioedema chronic urticaria, alveolitis No hematological treatment CR under high dose CTC but CTC dependency, CR under anakinra and CTC stopped for neutropenia
Death at 73 years from sepsis and cardiac failure and anakinra
Median (yrs) (IQ 25;75) n = (%) M/F = 5:1 Follow up 2.2 (1.5; 3.3) 64.5 (64.3; 69.4) Fever (n = 6, 100%), skin rash (n = 5, 83%), arthralgia arthritis (n = 2, 33%), lymph nodes/splenomegaly n = 3 (50), sore throat (n = 1, 17%), RHS n = 3 (50), leukocytosis (n = 1, 17%), granulocytosis (n = 1, 17%), cytolysis (n = 2, 33%), high ferritin (n = 4, 67%)
CR, complete remission; CTC, corticosteroids; Ig, immunoglobulin; IPPS-R, Revised International Prognostic Scoring System; IV, intravenous; MDS, myelodysplastic syndrome; MDS EB1, MDS with excess of blasts < 5%; MDS: myelodysplastic syndrome; NGS, next-generation sequencing; NS, not significant; PR, partial response; RHS, reactive hemophagocytic syndrome; MDS SLD, MDS with single lineage dysplasia; MDS UL. Patients marked with an * were identified and included in French VEXAS group cohort and could have been used in other published studies.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ANAKINRA | DrugsGivenReaction | CC BY | 34884286 | 20,184,789 | 2021-11-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still's Disease in Elderly Patients.
BACKGROUND
Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS).
OBJECTIVE
To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome.
METHODS
A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML.
RESULTS
Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS.
CONCLUSIONS
Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.
pmc1. Introduction
Recently, the concept of autoinflammatory disorders keep evolving and an increasing number of new monogenic diseases are identified but numerous autoinflammatory diseases are still to be characterized. Systemic autoinflammatory disorders (SAID) are unprovoked episodic or chronic sterile inflammation which are secondary to innate immune system dysregulation [1]. If well-characterized monogenic diseases such as familial Mediterranean fever are part of it, more than 50% patients presenting with clinical features resembling SAIDs still do not carry any of the know pathogenic mutations in autoinflammatory disease genes [2]. Some patients with SAID fit the criteria for polygenic forms of autoinflammatory diseases, such as adult-onset Still’s disease (AOSD); however, some of them do not. They are defined as undifferentiated systemic autoinflammatory disorders (USAID) [1,3].
Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are part of a heterogeneous group of clonal hematopoietic stem cell diseases characterized by ineffective hematopoiesis, peripheral cytopenia with an increased risk of progression, to acute myeloid leukemia (AML) [4]. About 10 to 20% of MDS/CMML could be associated with various extra hematological features, e.g., neutrophilic dermatoses, systemic vasculitis, inflammatory arthritis, pseudo-Behçet’s disease, and relapsing polychondritis [5,6,7,8]. For years now, the state of autoinflammatory disorders associated with neoplasia reported in the literature were mainly associated with solid cancer but also MDS/CMML, myeloproliferative disorders, and lymphoma, and identified in the literature as “paraneoplastic AOSD” or “malignant associated AOSD” [8,9,10,11,12,13,14,15,16,17].
Recently, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), a newly established X-linked disease associated with a somatic mutation in a gene encoding ubiquitin-like modifier activating enzyme 1 (UBA1) characterized by lipid vacuole inclusions in myeloid precursors of bone marrow examination, has been described [18]. These patients often develop hematologic malignancies, and especially MDS.
In this French nationwide study, our objective was to describe patients with MDS/CMML with unexplained recurrent fever and extra hematological signs, concordant or close to AOSD, and fulfilling the definition of USAID, their management, outcomes, overall survival, and the specific risk of progression to AML. We evaluated the prevalence of the newly described VEXAS syndrome in this group of patients and specifically reported their features.
2. Materials and Methods
2.1. Study Design
Data for patients with MDS or CMML and unexplained recurrent fever associated or not to extra hematological signs, concordant with USAID diagnosed between 2010 and June 2020 were retrospectively collected. All patients provided informed consent, and the study followed the Helsinki declaration and received the approval from the Institutional Review Board of Cochin Hospital (CLEP Decision N°: AAA-2021-08040). In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion. Three hundred and ninety patients were included in the MINHEMON registry across France for extra-hematological features associated to MDS/CMML. From this cohort, we selected patients which presented at least fever of unknown origin and elevated phase reactant. Physicians were also asked by Société Nationale Française de Médecine Interne” (SNFMI), “Club Rhumatisme et Inflammation” group (CRI), “Club Médecine INterne, HEMatologie et ONcologie” (MINHEMON) and the “Centre de référence des maladies auto-inflammatoires et des amyloses d’origine inflammatoire” CEREMAIA to report cases of patients with these features associated with MDS or CMML. Inclusion criteria were as follows: (1) MDS or CMML (WHO criteria); (2) AOSD with complete criteria (Yamaguchi and/or Fautrel criteria), or suspicion of AOSD (at least 3 from 5 criteria including fever) consistent with USAID; and (3) an established diagnosis of AOSD and MDS/CMML within the period of 5 years to avoid any fortuitous association. Exclusion criteria was defined as a diagnosis compatible with another autoimmune, infectious, drug-induced or systemic disease at the time of the inclusion. The diagnosis of suspected AOSD or USAID was made based on a consensus by two specialists (MD, AM) and a senior physician from the reference center of autoinflammatory diseases (SG). We compared our patients with a control group of MDS without extra hematological symptoms. Finally, we decided to screen the included patients for the newly described VEXAS to identify if it could be a new phenotype of this disease.
2.2. MDS, CMML
MDS and CMML were diagnosed based on peripheral blood and bone marrow examinations and classified according to the WHO 2016 criteria [19]. Patients were graded using the Revised International Prognostic Scoring System (IPSS-R) [20] for MDS: very low, low, intermediate, high, and very high risk groups; and the new CMML-specific Prognostic Scoring System (CPSS) for CMML: low, intermediate, and high. Karyotypes, the percentage of medullar blasts, and somatic mutations were assessed at the time of MDS diagnosis.
2.3. Genetic Analysis for VEXAS
Somatic UBA1 mutation was explored by incorporating the targeted gene in a homemade 75-gene panel for the next generation sequencing (NGS) of circulating mononucleated cells with a 2% threshold of detection already used in previous work [21]. Only patients alive or dead with available DNA were tested for UBA1. Tested samples were collected in a single center except for one tested in his reference center. UBA1 exon 3 sequences were determined by specific PCR followed by Sanger sequencing reaction using BigDye ™ Terminator (Applied Biosystems, Waltham, MA, USA) according to the manufacturer’s instructions and using the following primers: (forward) 5′-GTGGGTGGGAAAGTCTTTTGT-3′ and (reverse) 5′-TTACAGCTGCCGGGAGTAAAG-3′. A 3500xL-Dx Genetic Analyzer sequencing system was used, and sequences were analyzed with SeqScape software (Applied Biosystems). As MDS patients from the control group did not show any extra hematological features, they were not screened for UBA1 mutation. UBA1 mutated patients were identified and included in French VEXAS group cohort whom data could be used for other studies. The patients used in different studies are represented with an asterisk* in corresponding table.
2.4. USAID
Patient’s clinical files were screened for other autoinflammatory diagnostics. Symptoms of AOSD were specifically recorded and highlighted: fever, skin rash, arthritis or arthralgia, myalgia, pharyngitis or sore throat, nodes, or splenomegaly as well as these severe complications pericarditis, pleuritis, myocarditis, reactive hemophagocytic syndrome (RHS), disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and interstitial lung disease (ILD).
Data from the laboratory test included complete blood count, liver enzymes, C-reactive protein (CRP), ferritin, and glycosylated ferritin levels.
USAID complete clinical and biological response was defined as a total disappearance of all clinical features present at baseline in exclusion of those possible reliable to MDS and/or CMML and a complete normalization of acute-phase reactants. Partial response was defined as an improvement of at least one the clinical sign without an increase of any other features and at least 50% improvement of acute-phase reactants. Patients treated with corticosteroids as first line were differentiated into two groups: high dosage (0.8 to 1 mg/kg/day of prednisone-equivalent) and low dosage. USAID diagnosis was considered concomitant with MDS/CMML or AML when the diagnosis of both diseases was made within ±3 months before or after MDS/CMML were diagnosed. The overall survival, the cause of death and the progression toward AML, were recorded, as well as the date of the last visit.
2.5. Control Group
The control group consisted of 104 patients from the “Groupe Francophone des Myelodysplasies” registry of MDS/CMML which were seen at least once by the internal medicine specialists (AM, OF). These patients did not exhibit any systemic inflammatory or autoimmune features and were selected without matching.
2.6. Ethics
All patients provided informed consent, and the study followed the Helsinki declaration.
2.7. Statistical Analysis
Descriptive data included medians and interquartile ranges (IQR) for continuous variables and frequencies (expressed in percentages) for categorical variables. To account for missing data, results were expressed as observed data (missing data were not replaced). The Chi-square or Fischer’s exact tests were used to compare categorical variables, and the Student’s t-test or Mann–Whitney U test were applied for the comparison of continuous variables. The significance of findings was determined by a p-value of 0.05 or less. Statistical analyses were performed using 2009 GraphPad software, San Diego, CA, USA v6.1.
3. Results
3.1. Characteristics of Patients
All 26 patients with USAID presented with recurrent unexplained fever and elevated acute phase reactants (Figure 1). The median age of appearance of USAID’s symptoms was 70.5 years (IQR: 64.3–78.9) with 76% being male (Table 1). Besides unexplained recurrent fever, clinical features of USAID included arthritis (n = 16, 62%) and skin rash (n = 11, 42%). Severe complications were noted at the time of diagnosis or during the follow-up period in nine patients (35%). These included RHS (n = 5), myopericarditis (n = 3), interstitial lung disease (n = 3), and ARDS (n = 1) (Table 1). Five patients among the initially identified USAID, presented symptoms concordant with a diagnosis of AOSD according to Yamaguchi (n = 5) and Fautrel (n = 4) criteria [22,23]. Nine patients with USAID, reported atypical signs for AOSD including other skin lesions (n = 7, 78%) such as ulcers, nodules, angioedema, erythema nodosum, urticaria, eczematous lesions; non-infectious ileitis (n = 2, 25%), recurrent superficial venous thrombosis (n = 1, 11%), and periorbital headache (n = 1, 11%).
MDS/CMML characteristics (WHO classification, cytogenetics, and prognostic scores) are shown in Table 2. The most frequent subtype was MDS with excess blasts (30.8% of the patients) (MDS EB-1: 11.5%, MDS EB-2: 19.2%), with a median R-IPSS of 3.7 (IQR: 2–5). NGS somatic mutations screening was available for 17 patients and showed TET2 (n = 5), ASXL1 (n = 4), IDH1 (n = 3), and KRAS (n = 3) mutations (Supplementary Table S1). The diagnosis of USAID co-occurred with preceded and appeared after respectively the diagnosis of MDS/CMML in eight (32%), twelve patients (48%), and five patients (24%). The median time between USAID and MDS/CMML diagnosis was one year (IQR: 0.2–2). Specific hematological treatments were initiated in seventeen cases (65%) within half a year (IQR: 0.2–1.2) after the diagnosis of MDS. First-line treatment mostly consisted of azacytidine (Supplementary Table S2).
Among the 26 patients included, 18 had samples available to be tested for UBA1 mutation was tested in 18 patients and revealed six 33% positive cases, five out six were males (Figure 1 and Table 3). None of these patients progressed to AML during the 2.2 median years of follow up (ranges 1.2 to 5.6 years). Among these six individuals with VEXAS syndrome, none had a confirmed AOSD, including one with incomplete AOSD criteria sets and five remainders presenting additional unusual clinical features for AOSD. None had polychondritis, one patient hand interstitial pneumonia, one alveolitis, and five had cutaneous features distinct from a rash.
Compared to MDS/CMML controls without any inflammatory features (n = 104), USAID-associated MDS/CMML patients were younger (71.4 (IQR: 36–85) vs. 78 years (IQR: 42–92); p = 0.0005), without any other statistically significant differences for demography, MDS/CMML subtype, survival. Even if the rates of deaths were higher in the study group (46% vs. 25%; p = 0.02), the overall survival and the time to progression to AML were not significantly different between the groups (Figure 2).
3.2. Treatment and Outcomes
Twenty-two patients (85%) received specific treatment for USAID. Corticosteroids were used as a first-line treatment in 19 cases (86%) alone (n = 17) or combined with anakinra or infliximab in the other 2 cases. A complete clinical and biological response to first-line treatment was observed in 14 cases (64%) but 5 cases of secondary steroid dependency were described. Thirteen patients (59%) required a second-line treatment because of a resistance to steroids, primary inefficiency, or relapse, with a response in eight (73%) patients. Targeted biological therapy alone or in association with corticosteroids enabled either a partial or complete response in 9 out of 11 patients (anakinra n = 8/9, tocilizumab n = 0/1, and infliximab n = 1/1). Azacytidine used for MDS or steroid dependent autoinflammatory disease (n = 12) resulted in a complete or partial response of systemic features in 10 (83%) cases. Seven patients (26%) progressed to AML and 12 died (46%), all except one in the VEXAS negative group during the follow-up (Supplementary Table S2 and Figure S1).
Among the six patients with VEXAS, four responded temporarily and/or partially to corticosteroids: relapses and steroid dependency were observed in all cases. Anakinra was used in five cases with a complete or partial response in four cases. Tocilizumab was ineffective in one remaining case. When available, azacytidine led to a response on systemic features in all 3 cases.
4. Discussion
Patients with MDS/CMML can develop USAID with various extra hematological features including pattern suggestive of AOSD. This is the first multidisciplinary series (involving both rheumatologists, hematologists, and clinical immunologists) reporting on USAID associated with MDS/CMML features and the prevalence of VEXAS in such cohort(s). The results of the present study have several important implications. In the case of MDS/CMML with recurrent and unexplained fever, our cohort, although limited, shows that VEXAS syndrome represents 33% (6/18) of cases, these inflammatory situations remaining rare. Moreover, over a median follow-up of 26 month, none of the 6 cases of MDS/CMML VEXAS + progressed to AML, versus 23% of MDS/CMML with USAID and 40% of classic MDS/CMML without inflammatory manifestations. At last, although the numbers are small therefore caution must remain prevalent, there could be a potential interest of biological therapies or even azacytidine when UBA1 is mutated.
Patients with MDS and unexplained recurrent fever should be first tested for the UBA1 mutation. The recent work by Beck et al. which identified VEXAS, implying that somatic mutations may be a more frequent cause of human disease than previously recognized [18,24]. A third of our patients screened for UBA1 were positive for this mutation (including one woman). As a cohort of comparison, in relapsing chondritis, a frequently associated clinical picture usually described with VEXAS, only 7.6% had UBA1 mutations [25]. USAID appeared as a new pattern of VEXAS. Interestingly, 50% of our VEXAS patients experienced RHS. In the future, the order of UBA1 screening could be debated: integrated into the first-line genetic exploration of MDS as well as the MDS/SMP NGS panel or rather screened in the case of MDS/CMML with systemic features in particular USAID.
In contrast to other dysimmune manifestations with a near equal frequency distribution before, simultaneously, and after the diagnosis of MDS/CMML (USAID and systemic features of VEXAS tend to precede the diagnosis of hematological diseases) [9]; hence, the importance of an early identification of warning signs to carefully consider an underlying neoplasia, in particular hematological malignancy. Nearly 20% of the patients matched with the criteria concordant with AOSD, but some atypia should raise the physicians’ attention in patients with newly-diagnosed AOSD, with some features such as late-onset disease [26], male sex [27] as well as cytopenia in particular the absence of leukocytosis (a hallmark feature of AOSD), and macrocytosis and monocytosis [9,11]. In a recent Dutch case series of VEXAS, among patients with unclassified autoinflammation, two among the twelve retrospectively identified were initially suspected with AOSD [28]. Thus, elderly patients with late AOSD diagnosis or suspicion as described in some series [29,30] could also benefit from UBA1 mutation screening.
As described previously for systemic inflammatory and autoimmune disorders associated with MDS/CMML, MDS EB, and MDS MLD were the most frequently associated subtypes in USAID patients not UBA1 mutated [6,31]. No association with a specific karyotype was identified but interestingly TET2 and IDH mutation already associated with systemic inflammatory and auto immune disease and T cell dysregulation in a recent work [32] were also frequently found in our cohort. Two out of the six VEXAS patients presented DNMT3A also described in other VEXAS patients [18,28,33,34], but significance is yet unclear. None of the patients with VEXAS had CMML, which is consistent with the recent report published by Zhao et al. [35]. The prognosis of MDS-associated autoimmune disorders remains unclear, as depending on the types of autoimmune disease in each cohort, the impact on survival could be different [7] but we must notice that in our group, despite a high rate of transformation (more than 25%), the twelve death: only one was UBA1 mutated and none of the VEXAS patients transformed into AML.
The treatment of symptoms of patients with malignant associated features concordant or close to AOSD is challenging. Corticosteroids response was similar to AOSD’s but with a high percentage of steroid dependency or secondary failure [27]. Methotrexate, usually used for its steroid-sparing effect, was rarely applied, presumably due to the risk of cytopenia, explaining the frequent use of biologic agents. The preferential utilization of interleukin-1R antagonists rather than TNF-a antagonists usually used in articular rheumatism is justified by the dominance of the systemic character of the disease with frequent spikes in fever and seemed efficient. Most treatments were only transiently effective, but hematological treatment allowed control of the USAID symptoms for 11 patients in our cohort. As in autoimmune and inflammatory disorders, azacytidine, appears to have a beneficial effect on these systemic manifestations [36,37]. Similarly, in a recent retrospective, Bourbon et al.’s study of the hypomethylating agent and signaling inhibitors seemed to achieve interesting results in VEXAS syndrome patients [38]. The occurrence of USAID or AOSD compatible features over the course of myelodysplastic diseases may prompt a hematological treatment, especially in its refractory form, despite the absence of a direct hematological indication. Thus, azacytidine could be a therapeutical hypothesis for USAID associated with MDS as well as it could be for UBA1 mutated patients.
Our study has several important limitations. First, the retrospective design used here carries an inherited risk of bias and missing data. Second, despite the scarcity of the described clinical syndrome, a small sample size limits the generalizability of the findings reported. Herein we chose to select only patient with occurrence of USAID/AOSD suspicion and MDS/CMML within the period of 5 years to avoid any fortuitous association. Further studies should aim at improving study designs with a prospective nature, larger sample size, and detailed comprehensive information collection.
5. Conclusions
Systemic form of VEXAS syndrome can mimic AOSD, especially in the elderly. USAID symptoms including a pattern suggestive of AOSD associated with MDS/CMML was identified in 33% cases with VEXAS syndrome, thereby further expanding the spectrum of this new syndrome. UBA1 should be sequenced in this population, especially in case of macrocytic associated anemia and chronically elevated CRP among old males, but not exclusively. Although the optimal management of UBA1/MDS overlap patients remains to be determined in larger scale cohorts, biological therapies and/or hypomethylating agents seem promising in this situation.
Key messages:
Patients with MDS/CMML can develop a recurrent fever with various extra hematological features suggestive of USAID;
Pseudo-Still disease or USAID associated with a myelodysplastic syndrome are a new phenotype of VEXAS syndrome;
UBA1 mutation should be screened in case of such association.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/jcm10235586/s1, Figure S1: Different lines of USAID treatments and treatment responses. Twenty-two patient (85%) received specific treatment for USAID and 14 (64%) experienced complete response. Fifty-nine percent of the patient needed a second line treatment and 54% a third line, Table S1: Main features of MDS/CMML patients with USAID, Table S2: USAID including pattern suggestive of AOSD natural history and therapeutical management.
Click here for additional data file.
Author Contributions
Conceptualization, M.D. (Marion Delplanque), S.G.-L. and A.M.; Supervision, S.G.-L. and A.M.; Writing—original draft, M.D. (Marion Delplanque); Writing—review & editing, M.D. (Marion Delplanque), A.A., P.H., P.F., J.G., F.M., D.R.-W., N.B., L.D., A.O., M.G., M.M., J.R. (Jerome Razanamahery), G.M., M.D. (Matthieu Décamp), S.M., T.Q., J.R. (Julien Rossignol), L.S., M.S., L.T., A.S., Y.H., S.G.-L. and A.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Cochin Hospital Institutional Review Board (CLEP Decision N°: AAA-2021-08040).
Informed Consent Statement
In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion.
Data Availability Statement
Data are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
A Arthritis/arthralgia
AML Acute myeloid leukemia
ANA Antinuclear antibody
AOSD Adult-onset Still’s disease
ARDS Acute respiratory distress syndrome
C Cytolysis
CBC Complete blood count
CC Corticosteroids
CMML Chronic myelomonocytic leukemia
CPSS CMML-specific prognostic scoring system
CR Complete remission
CRP C-reactive protein
DIC Disseminated intravascular coagulation
F Female
F Fever
Fr High ferritin
G Low glycosylated ferritin
IL Interleukin
ILD interstitial lung disease
L Lymph nodes and splenomegaly
M Male
M/F Male-to-female ratio
MAS Macrophage activation syndrome
MDS Myelodysplastic syndrome
MDS MLD MDS with multilineage dysplasia
MDS SLD MDS with single lineage dysplasia
MDS-EB1 MDS with excess of blasts <5%
MDS-EB2 MDS with excess of blasts >5%
MDS-RS MDS with ring sideroblasts
MM Myelodysplastic malignancy
MTX Methotrexate
PNN Polymorphonuclear neutrophils >80%
PET scan Positron emission tomography scan
PR Partial remission
RF Rheumatoid factor
RHS Reactive hemophagocytic syndrome
R-IPPS Revised International Prognostic Scoring System
SAID Systemic autoinflammatory disorder
S Skin rash
T Sore throat
TNF Tumor necrosis factor
UBA1 Ubiquitin-like modifier activating enzyme 1
USAID Undifferentiated systemic autoinflammatory disorder
VEXAS Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome
W Leukocytosis
Yrs Years
Figure 1 Flow-chart depicting patient selection. From the 46 patients screened, 26 were included. Six UBA1 mutated patients identified from the included patients.
Figure 2 Kaplan–Meier curves of overall survival (a), progression to AML (b) in MDS patients with and without USAID. Data were censored at time of last visit or death. The response MDS control group is in blue and the one with autoinflammatory features is in red.
jcm-10-05586-t001_Table 1 Table 1 Baseline characteristics of USAID including pattern suggestive of AOSD.
Patients (n = 26) No VEXAS (n = 18) VEXAS (n = 6)
Epidemiology
Male-to-female ratio 3.16 2.8 4
Age at 1st signs (years) (range) 70.5 (64.3–78.9) 71 (65.5–79.3) 64.3 (63.6–68.2)
Time between USAID and MDS (years) (range) 1.0 (0.2–2) 0.9 (1.8–0.2) 1.2 (1.1–3)
Medical history (%)
Personal or familial history of autoimmunity 2 (9) 1 (6) 1 (25)
Symptoms (%)
Fever 26 (100) 18(100) 6 (100)
Skin rash 11 (42) 6 (33) 5 (83)
Arthritis/arthralgia 16 (62) 14 (78) 2 (33)
Pharyngitis/sore throat 5 (19) 1 (22) 1 (17)
Myalgia 5 (19) 3 (17) 2 (33)
Lymph nodes or splenomegaly 12 (46) 8 (44) 4 (67)
Blood test results (%)
Leukocytosis > 10,000/mm3 10 (38) 9 (50) 1 (17)
Granulocytes ≥ 80% 7 (26) 6 (67) 1 (17)
CRP >30 mg/L 26 (100) 18 (100) 6 (100)
Elevated liver enzymes 9 (35) 7 (39) 2 (67)
High ferritin 19/20 (95) 15 (94) 4 (100)
>2000 µg/L 14/20 (70) 13 (81) 1 (25)
Glycosylated ferritin < 20% 4/11 (36) 3 (30) 1 (50)
Severe complications
Pericarditis 3 (12) 3 (18) 0 (0)
Myocarditis 0 (0) 0 (0) 0 (0)
DIC 0 (0) 0 (0) 0 (0)
RHS 5 (19) 2 (11) 3 (50)
ARDS 1 (4) 1 (4) 0 (0)
ILD, alveolitis 3 (12) 1 (4) 2 (67)
Pleurisy 6 (23) 6 (33) 0 (0)
AOSD, adult-onset Still’s disease; ARDS, acute respiratory distress syndrome; CRP, C-reactive protein; DIC, disseminated intravascular syndrome; ILD, interstitial lung disease; MDS, myelodysplastic syndrome; RHS, reactive hemophagocytic syndrome.
jcm-10-05586-t002_Table 2 Table 2 Main features of MDS/CMML patients with USAID.
MDS-Related USAID
n = 26 (%) MDS/CMML Controls
n = 104 (%)
Mean age at diagnosis (range) 71.4 (36–85) 78 (42–92) *
Male 19 (76) 79 (76)
Myelodysplastic syndrome (MDS) 23 (89) 83 (80)
MDS with single lineage dysplasia 3 (12) 14 (13)
MDS with ring sideroblasts (MDS-RS) 2 (8) 6 (6)
MDS with multilineage dysplasia 5 (19) 33 (32)
MDS with excess blasts (EB) 8 (31) 14 (13)
MDS with isolated del(5q) 0 4 (4)
MDS, unclassifiable/missing data 5 (19) 7 (7)
Chronic myelomonocytic leukemia (CMML) 3 (12) 21 (20)
Acute myeloid leukemia (AML) (progressed to) 7 (27) 11 (10)
IPPS-R (IQR) 3.7 (2–5) 2.5 (0–8)
Deaths 12 (46) 26 (25) *
Follow-up (range) 16.8 (0–104) 21.5 (0–86)
* p value < 0.05.
jcm-10-05586-t003_Table 3 Table 3 Main features of the patients with UBA1 mutations (VEXAS syndrome).
Patient Sex Type MDS Age at Diagnosis of MDS Characteristics of MDS Age at USAID Onset Signs of USAID Other Symptoms Evolution
Patient #1 * M MDS UL 59.8 IPPS = NS 58.8 Fever, rash, cytolysis, high ferritin, RHS Recurrent superficial veinous thrombosis, cutaneous atypia Azacytidine for MDS just begun
NGS: DNMT3A, BRCA2, and ZRSR2 mutated
Bone marrow: vacuoles in myeloid precursor cells No response to CTC high dose rapidly completed with cyclosporine permitting, PR
Del 6q Blasts: NS Alive under azacytidine, CTC 20 mg and cyclosporine
Patient #2 * M MDS EB1 64.5 IPPS = 4 63.3 Fever, arthralgia, leukocytosis, lymphadenopathy, splenomegaly, granulocytes, cytolysis CR under azacytidine for MDS
NGS: Normal Periorbital headache, skin nodules, edema, diarrhea, abdominal pain Multiple lines of treatments: response and relapses to high-dose CTC and anakinra; no response to infliximab, tocilizumab, IV Ig, cyclosporine
Blasts: 7% Alive and disappearance of systemic features under azacytidine and CTC 20 mg/day
Patient #3 * M Unclassifiable MDS 73.5 IPPS-R: 2 73.5 Fever, rash, lymphadenopathy, splenomegaly, high ferritin, RHS Recurrent face edema, urticaria, skin nodules and eczematous skin lesions PR with azacytidine for MDS
NGS: DNMT3A mutated 31.7% No response to high-dose CTC and anakinra
Blasts: 0% Alive, PR and systemic symptoms with azacytidine
Patient #4 F Unclassifiable MDS 64.3 IPPS-R: NS NS Fever, rash, RHS Unknown response with hydroxyurea
Del X Blasts: NS Interstitial pneumonia, diarrhea CR with high-dose CTC, steroid dependence; CR with anakinra and CTC
Alive at last visit
Patient #5 * M MDS MLD 69.4 IPPS-R: 2
NGS: TET2 mutated 3% 65.8 Fever, rash, arthritis, sore throat, lymphadenopathy, splenomegaly, high ferritin, myalgia Pustular eruption and other cutaneous atypia CR with azacytidine; failure with methotrexate; leflunomide stopped early due to cytopenia; CR (with few relapses) with CTC and anakinra
Patient #6 M Unclassifiable MDS NS IPPS-R: NS
NGS: normal 69 Fever, rash, high ferritin, myalgia Oedema, angioedema chronic urticaria, alveolitis No hematological treatment CR under high dose CTC but CTC dependency, CR under anakinra and CTC stopped for neutropenia
Death at 73 years from sepsis and cardiac failure and anakinra
Median (yrs) (IQ 25;75) n = (%) M/F = 5:1 Follow up 2.2 (1.5; 3.3) 64.5 (64.3; 69.4) Fever (n = 6, 100%), skin rash (n = 5, 83%), arthralgia arthritis (n = 2, 33%), lymph nodes/splenomegaly n = 3 (50), sore throat (n = 1, 17%), RHS n = 3 (50), leukocytosis (n = 1, 17%), granulocytosis (n = 1, 17%), cytolysis (n = 2, 33%), high ferritin (n = 4, 67%)
CR, complete remission; CTC, corticosteroids; Ig, immunoglobulin; IPPS-R, Revised International Prognostic Scoring System; IV, intravenous; MDS, myelodysplastic syndrome; MDS EB1, MDS with excess of blasts < 5%; MDS: myelodysplastic syndrome; NGS, next-generation sequencing; NS, not significant; PR, partial response; RHS, reactive hemophagocytic syndrome; MDS SLD, MDS with single lineage dysplasia; MDS UL. Patients marked with an * were identified and included in French VEXAS group cohort and could have been used in other published studies.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ANAKINRA | DrugsGivenReaction | CC BY | 34884286 | 20,184,789 | 2021-11-27 |
What was the outcome of reaction 'Cardiac failure'? | USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still's Disease in Elderly Patients.
BACKGROUND
Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS).
OBJECTIVE
To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome.
METHODS
A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML.
RESULTS
Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS.
CONCLUSIONS
Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.
pmc1. Introduction
Recently, the concept of autoinflammatory disorders keep evolving and an increasing number of new monogenic diseases are identified but numerous autoinflammatory diseases are still to be characterized. Systemic autoinflammatory disorders (SAID) are unprovoked episodic or chronic sterile inflammation which are secondary to innate immune system dysregulation [1]. If well-characterized monogenic diseases such as familial Mediterranean fever are part of it, more than 50% patients presenting with clinical features resembling SAIDs still do not carry any of the know pathogenic mutations in autoinflammatory disease genes [2]. Some patients with SAID fit the criteria for polygenic forms of autoinflammatory diseases, such as adult-onset Still’s disease (AOSD); however, some of them do not. They are defined as undifferentiated systemic autoinflammatory disorders (USAID) [1,3].
Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are part of a heterogeneous group of clonal hematopoietic stem cell diseases characterized by ineffective hematopoiesis, peripheral cytopenia with an increased risk of progression, to acute myeloid leukemia (AML) [4]. About 10 to 20% of MDS/CMML could be associated with various extra hematological features, e.g., neutrophilic dermatoses, systemic vasculitis, inflammatory arthritis, pseudo-Behçet’s disease, and relapsing polychondritis [5,6,7,8]. For years now, the state of autoinflammatory disorders associated with neoplasia reported in the literature were mainly associated with solid cancer but also MDS/CMML, myeloproliferative disorders, and lymphoma, and identified in the literature as “paraneoplastic AOSD” or “malignant associated AOSD” [8,9,10,11,12,13,14,15,16,17].
Recently, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), a newly established X-linked disease associated with a somatic mutation in a gene encoding ubiquitin-like modifier activating enzyme 1 (UBA1) characterized by lipid vacuole inclusions in myeloid precursors of bone marrow examination, has been described [18]. These patients often develop hematologic malignancies, and especially MDS.
In this French nationwide study, our objective was to describe patients with MDS/CMML with unexplained recurrent fever and extra hematological signs, concordant or close to AOSD, and fulfilling the definition of USAID, their management, outcomes, overall survival, and the specific risk of progression to AML. We evaluated the prevalence of the newly described VEXAS syndrome in this group of patients and specifically reported their features.
2. Materials and Methods
2.1. Study Design
Data for patients with MDS or CMML and unexplained recurrent fever associated or not to extra hematological signs, concordant with USAID diagnosed between 2010 and June 2020 were retrospectively collected. All patients provided informed consent, and the study followed the Helsinki declaration and received the approval from the Institutional Review Board of Cochin Hospital (CLEP Decision N°: AAA-2021-08040). In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion. Three hundred and ninety patients were included in the MINHEMON registry across France for extra-hematological features associated to MDS/CMML. From this cohort, we selected patients which presented at least fever of unknown origin and elevated phase reactant. Physicians were also asked by Société Nationale Française de Médecine Interne” (SNFMI), “Club Rhumatisme et Inflammation” group (CRI), “Club Médecine INterne, HEMatologie et ONcologie” (MINHEMON) and the “Centre de référence des maladies auto-inflammatoires et des amyloses d’origine inflammatoire” CEREMAIA to report cases of patients with these features associated with MDS or CMML. Inclusion criteria were as follows: (1) MDS or CMML (WHO criteria); (2) AOSD with complete criteria (Yamaguchi and/or Fautrel criteria), or suspicion of AOSD (at least 3 from 5 criteria including fever) consistent with USAID; and (3) an established diagnosis of AOSD and MDS/CMML within the period of 5 years to avoid any fortuitous association. Exclusion criteria was defined as a diagnosis compatible with another autoimmune, infectious, drug-induced or systemic disease at the time of the inclusion. The diagnosis of suspected AOSD or USAID was made based on a consensus by two specialists (MD, AM) and a senior physician from the reference center of autoinflammatory diseases (SG). We compared our patients with a control group of MDS without extra hematological symptoms. Finally, we decided to screen the included patients for the newly described VEXAS to identify if it could be a new phenotype of this disease.
2.2. MDS, CMML
MDS and CMML were diagnosed based on peripheral blood and bone marrow examinations and classified according to the WHO 2016 criteria [19]. Patients were graded using the Revised International Prognostic Scoring System (IPSS-R) [20] for MDS: very low, low, intermediate, high, and very high risk groups; and the new CMML-specific Prognostic Scoring System (CPSS) for CMML: low, intermediate, and high. Karyotypes, the percentage of medullar blasts, and somatic mutations were assessed at the time of MDS diagnosis.
2.3. Genetic Analysis for VEXAS
Somatic UBA1 mutation was explored by incorporating the targeted gene in a homemade 75-gene panel for the next generation sequencing (NGS) of circulating mononucleated cells with a 2% threshold of detection already used in previous work [21]. Only patients alive or dead with available DNA were tested for UBA1. Tested samples were collected in a single center except for one tested in his reference center. UBA1 exon 3 sequences were determined by specific PCR followed by Sanger sequencing reaction using BigDye ™ Terminator (Applied Biosystems, Waltham, MA, USA) according to the manufacturer’s instructions and using the following primers: (forward) 5′-GTGGGTGGGAAAGTCTTTTGT-3′ and (reverse) 5′-TTACAGCTGCCGGGAGTAAAG-3′. A 3500xL-Dx Genetic Analyzer sequencing system was used, and sequences were analyzed with SeqScape software (Applied Biosystems). As MDS patients from the control group did not show any extra hematological features, they were not screened for UBA1 mutation. UBA1 mutated patients were identified and included in French VEXAS group cohort whom data could be used for other studies. The patients used in different studies are represented with an asterisk* in corresponding table.
2.4. USAID
Patient’s clinical files were screened for other autoinflammatory diagnostics. Symptoms of AOSD were specifically recorded and highlighted: fever, skin rash, arthritis or arthralgia, myalgia, pharyngitis or sore throat, nodes, or splenomegaly as well as these severe complications pericarditis, pleuritis, myocarditis, reactive hemophagocytic syndrome (RHS), disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and interstitial lung disease (ILD).
Data from the laboratory test included complete blood count, liver enzymes, C-reactive protein (CRP), ferritin, and glycosylated ferritin levels.
USAID complete clinical and biological response was defined as a total disappearance of all clinical features present at baseline in exclusion of those possible reliable to MDS and/or CMML and a complete normalization of acute-phase reactants. Partial response was defined as an improvement of at least one the clinical sign without an increase of any other features and at least 50% improvement of acute-phase reactants. Patients treated with corticosteroids as first line were differentiated into two groups: high dosage (0.8 to 1 mg/kg/day of prednisone-equivalent) and low dosage. USAID diagnosis was considered concomitant with MDS/CMML or AML when the diagnosis of both diseases was made within ±3 months before or after MDS/CMML were diagnosed. The overall survival, the cause of death and the progression toward AML, were recorded, as well as the date of the last visit.
2.5. Control Group
The control group consisted of 104 patients from the “Groupe Francophone des Myelodysplasies” registry of MDS/CMML which were seen at least once by the internal medicine specialists (AM, OF). These patients did not exhibit any systemic inflammatory or autoimmune features and were selected without matching.
2.6. Ethics
All patients provided informed consent, and the study followed the Helsinki declaration.
2.7. Statistical Analysis
Descriptive data included medians and interquartile ranges (IQR) for continuous variables and frequencies (expressed in percentages) for categorical variables. To account for missing data, results were expressed as observed data (missing data were not replaced). The Chi-square or Fischer’s exact tests were used to compare categorical variables, and the Student’s t-test or Mann–Whitney U test were applied for the comparison of continuous variables. The significance of findings was determined by a p-value of 0.05 or less. Statistical analyses were performed using 2009 GraphPad software, San Diego, CA, USA v6.1.
3. Results
3.1. Characteristics of Patients
All 26 patients with USAID presented with recurrent unexplained fever and elevated acute phase reactants (Figure 1). The median age of appearance of USAID’s symptoms was 70.5 years (IQR: 64.3–78.9) with 76% being male (Table 1). Besides unexplained recurrent fever, clinical features of USAID included arthritis (n = 16, 62%) and skin rash (n = 11, 42%). Severe complications were noted at the time of diagnosis or during the follow-up period in nine patients (35%). These included RHS (n = 5), myopericarditis (n = 3), interstitial lung disease (n = 3), and ARDS (n = 1) (Table 1). Five patients among the initially identified USAID, presented symptoms concordant with a diagnosis of AOSD according to Yamaguchi (n = 5) and Fautrel (n = 4) criteria [22,23]. Nine patients with USAID, reported atypical signs for AOSD including other skin lesions (n = 7, 78%) such as ulcers, nodules, angioedema, erythema nodosum, urticaria, eczematous lesions; non-infectious ileitis (n = 2, 25%), recurrent superficial venous thrombosis (n = 1, 11%), and periorbital headache (n = 1, 11%).
MDS/CMML characteristics (WHO classification, cytogenetics, and prognostic scores) are shown in Table 2. The most frequent subtype was MDS with excess blasts (30.8% of the patients) (MDS EB-1: 11.5%, MDS EB-2: 19.2%), with a median R-IPSS of 3.7 (IQR: 2–5). NGS somatic mutations screening was available for 17 patients and showed TET2 (n = 5), ASXL1 (n = 4), IDH1 (n = 3), and KRAS (n = 3) mutations (Supplementary Table S1). The diagnosis of USAID co-occurred with preceded and appeared after respectively the diagnosis of MDS/CMML in eight (32%), twelve patients (48%), and five patients (24%). The median time between USAID and MDS/CMML diagnosis was one year (IQR: 0.2–2). Specific hematological treatments were initiated in seventeen cases (65%) within half a year (IQR: 0.2–1.2) after the diagnosis of MDS. First-line treatment mostly consisted of azacytidine (Supplementary Table S2).
Among the 26 patients included, 18 had samples available to be tested for UBA1 mutation was tested in 18 patients and revealed six 33% positive cases, five out six were males (Figure 1 and Table 3). None of these patients progressed to AML during the 2.2 median years of follow up (ranges 1.2 to 5.6 years). Among these six individuals with VEXAS syndrome, none had a confirmed AOSD, including one with incomplete AOSD criteria sets and five remainders presenting additional unusual clinical features for AOSD. None had polychondritis, one patient hand interstitial pneumonia, one alveolitis, and five had cutaneous features distinct from a rash.
Compared to MDS/CMML controls without any inflammatory features (n = 104), USAID-associated MDS/CMML patients were younger (71.4 (IQR: 36–85) vs. 78 years (IQR: 42–92); p = 0.0005), without any other statistically significant differences for demography, MDS/CMML subtype, survival. Even if the rates of deaths were higher in the study group (46% vs. 25%; p = 0.02), the overall survival and the time to progression to AML were not significantly different between the groups (Figure 2).
3.2. Treatment and Outcomes
Twenty-two patients (85%) received specific treatment for USAID. Corticosteroids were used as a first-line treatment in 19 cases (86%) alone (n = 17) or combined with anakinra or infliximab in the other 2 cases. A complete clinical and biological response to first-line treatment was observed in 14 cases (64%) but 5 cases of secondary steroid dependency were described. Thirteen patients (59%) required a second-line treatment because of a resistance to steroids, primary inefficiency, or relapse, with a response in eight (73%) patients. Targeted biological therapy alone or in association with corticosteroids enabled either a partial or complete response in 9 out of 11 patients (anakinra n = 8/9, tocilizumab n = 0/1, and infliximab n = 1/1). Azacytidine used for MDS or steroid dependent autoinflammatory disease (n = 12) resulted in a complete or partial response of systemic features in 10 (83%) cases. Seven patients (26%) progressed to AML and 12 died (46%), all except one in the VEXAS negative group during the follow-up (Supplementary Table S2 and Figure S1).
Among the six patients with VEXAS, four responded temporarily and/or partially to corticosteroids: relapses and steroid dependency were observed in all cases. Anakinra was used in five cases with a complete or partial response in four cases. Tocilizumab was ineffective in one remaining case. When available, azacytidine led to a response on systemic features in all 3 cases.
4. Discussion
Patients with MDS/CMML can develop USAID with various extra hematological features including pattern suggestive of AOSD. This is the first multidisciplinary series (involving both rheumatologists, hematologists, and clinical immunologists) reporting on USAID associated with MDS/CMML features and the prevalence of VEXAS in such cohort(s). The results of the present study have several important implications. In the case of MDS/CMML with recurrent and unexplained fever, our cohort, although limited, shows that VEXAS syndrome represents 33% (6/18) of cases, these inflammatory situations remaining rare. Moreover, over a median follow-up of 26 month, none of the 6 cases of MDS/CMML VEXAS + progressed to AML, versus 23% of MDS/CMML with USAID and 40% of classic MDS/CMML without inflammatory manifestations. At last, although the numbers are small therefore caution must remain prevalent, there could be a potential interest of biological therapies or even azacytidine when UBA1 is mutated.
Patients with MDS and unexplained recurrent fever should be first tested for the UBA1 mutation. The recent work by Beck et al. which identified VEXAS, implying that somatic mutations may be a more frequent cause of human disease than previously recognized [18,24]. A third of our patients screened for UBA1 were positive for this mutation (including one woman). As a cohort of comparison, in relapsing chondritis, a frequently associated clinical picture usually described with VEXAS, only 7.6% had UBA1 mutations [25]. USAID appeared as a new pattern of VEXAS. Interestingly, 50% of our VEXAS patients experienced RHS. In the future, the order of UBA1 screening could be debated: integrated into the first-line genetic exploration of MDS as well as the MDS/SMP NGS panel or rather screened in the case of MDS/CMML with systemic features in particular USAID.
In contrast to other dysimmune manifestations with a near equal frequency distribution before, simultaneously, and after the diagnosis of MDS/CMML (USAID and systemic features of VEXAS tend to precede the diagnosis of hematological diseases) [9]; hence, the importance of an early identification of warning signs to carefully consider an underlying neoplasia, in particular hematological malignancy. Nearly 20% of the patients matched with the criteria concordant with AOSD, but some atypia should raise the physicians’ attention in patients with newly-diagnosed AOSD, with some features such as late-onset disease [26], male sex [27] as well as cytopenia in particular the absence of leukocytosis (a hallmark feature of AOSD), and macrocytosis and monocytosis [9,11]. In a recent Dutch case series of VEXAS, among patients with unclassified autoinflammation, two among the twelve retrospectively identified were initially suspected with AOSD [28]. Thus, elderly patients with late AOSD diagnosis or suspicion as described in some series [29,30] could also benefit from UBA1 mutation screening.
As described previously for systemic inflammatory and autoimmune disorders associated with MDS/CMML, MDS EB, and MDS MLD were the most frequently associated subtypes in USAID patients not UBA1 mutated [6,31]. No association with a specific karyotype was identified but interestingly TET2 and IDH mutation already associated with systemic inflammatory and auto immune disease and T cell dysregulation in a recent work [32] were also frequently found in our cohort. Two out of the six VEXAS patients presented DNMT3A also described in other VEXAS patients [18,28,33,34], but significance is yet unclear. None of the patients with VEXAS had CMML, which is consistent with the recent report published by Zhao et al. [35]. The prognosis of MDS-associated autoimmune disorders remains unclear, as depending on the types of autoimmune disease in each cohort, the impact on survival could be different [7] but we must notice that in our group, despite a high rate of transformation (more than 25%), the twelve death: only one was UBA1 mutated and none of the VEXAS patients transformed into AML.
The treatment of symptoms of patients with malignant associated features concordant or close to AOSD is challenging. Corticosteroids response was similar to AOSD’s but with a high percentage of steroid dependency or secondary failure [27]. Methotrexate, usually used for its steroid-sparing effect, was rarely applied, presumably due to the risk of cytopenia, explaining the frequent use of biologic agents. The preferential utilization of interleukin-1R antagonists rather than TNF-a antagonists usually used in articular rheumatism is justified by the dominance of the systemic character of the disease with frequent spikes in fever and seemed efficient. Most treatments were only transiently effective, but hematological treatment allowed control of the USAID symptoms for 11 patients in our cohort. As in autoimmune and inflammatory disorders, azacytidine, appears to have a beneficial effect on these systemic manifestations [36,37]. Similarly, in a recent retrospective, Bourbon et al.’s study of the hypomethylating agent and signaling inhibitors seemed to achieve interesting results in VEXAS syndrome patients [38]. The occurrence of USAID or AOSD compatible features over the course of myelodysplastic diseases may prompt a hematological treatment, especially in its refractory form, despite the absence of a direct hematological indication. Thus, azacytidine could be a therapeutical hypothesis for USAID associated with MDS as well as it could be for UBA1 mutated patients.
Our study has several important limitations. First, the retrospective design used here carries an inherited risk of bias and missing data. Second, despite the scarcity of the described clinical syndrome, a small sample size limits the generalizability of the findings reported. Herein we chose to select only patient with occurrence of USAID/AOSD suspicion and MDS/CMML within the period of 5 years to avoid any fortuitous association. Further studies should aim at improving study designs with a prospective nature, larger sample size, and detailed comprehensive information collection.
5. Conclusions
Systemic form of VEXAS syndrome can mimic AOSD, especially in the elderly. USAID symptoms including a pattern suggestive of AOSD associated with MDS/CMML was identified in 33% cases with VEXAS syndrome, thereby further expanding the spectrum of this new syndrome. UBA1 should be sequenced in this population, especially in case of macrocytic associated anemia and chronically elevated CRP among old males, but not exclusively. Although the optimal management of UBA1/MDS overlap patients remains to be determined in larger scale cohorts, biological therapies and/or hypomethylating agents seem promising in this situation.
Key messages:
Patients with MDS/CMML can develop a recurrent fever with various extra hematological features suggestive of USAID;
Pseudo-Still disease or USAID associated with a myelodysplastic syndrome are a new phenotype of VEXAS syndrome;
UBA1 mutation should be screened in case of such association.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/jcm10235586/s1, Figure S1: Different lines of USAID treatments and treatment responses. Twenty-two patient (85%) received specific treatment for USAID and 14 (64%) experienced complete response. Fifty-nine percent of the patient needed a second line treatment and 54% a third line, Table S1: Main features of MDS/CMML patients with USAID, Table S2: USAID including pattern suggestive of AOSD natural history and therapeutical management.
Click here for additional data file.
Author Contributions
Conceptualization, M.D. (Marion Delplanque), S.G.-L. and A.M.; Supervision, S.G.-L. and A.M.; Writing—original draft, M.D. (Marion Delplanque); Writing—review & editing, M.D. (Marion Delplanque), A.A., P.H., P.F., J.G., F.M., D.R.-W., N.B., L.D., A.O., M.G., M.M., J.R. (Jerome Razanamahery), G.M., M.D. (Matthieu Décamp), S.M., T.Q., J.R. (Julien Rossignol), L.S., M.S., L.T., A.S., Y.H., S.G.-L. and A.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Cochin Hospital Institutional Review Board (CLEP Decision N°: AAA-2021-08040).
Informed Consent Statement
In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion.
Data Availability Statement
Data are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
A Arthritis/arthralgia
AML Acute myeloid leukemia
ANA Antinuclear antibody
AOSD Adult-onset Still’s disease
ARDS Acute respiratory distress syndrome
C Cytolysis
CBC Complete blood count
CC Corticosteroids
CMML Chronic myelomonocytic leukemia
CPSS CMML-specific prognostic scoring system
CR Complete remission
CRP C-reactive protein
DIC Disseminated intravascular coagulation
F Female
F Fever
Fr High ferritin
G Low glycosylated ferritin
IL Interleukin
ILD interstitial lung disease
L Lymph nodes and splenomegaly
M Male
M/F Male-to-female ratio
MAS Macrophage activation syndrome
MDS Myelodysplastic syndrome
MDS MLD MDS with multilineage dysplasia
MDS SLD MDS with single lineage dysplasia
MDS-EB1 MDS with excess of blasts <5%
MDS-EB2 MDS with excess of blasts >5%
MDS-RS MDS with ring sideroblasts
MM Myelodysplastic malignancy
MTX Methotrexate
PNN Polymorphonuclear neutrophils >80%
PET scan Positron emission tomography scan
PR Partial remission
RF Rheumatoid factor
RHS Reactive hemophagocytic syndrome
R-IPPS Revised International Prognostic Scoring System
SAID Systemic autoinflammatory disorder
S Skin rash
T Sore throat
TNF Tumor necrosis factor
UBA1 Ubiquitin-like modifier activating enzyme 1
USAID Undifferentiated systemic autoinflammatory disorder
VEXAS Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome
W Leukocytosis
Yrs Years
Figure 1 Flow-chart depicting patient selection. From the 46 patients screened, 26 were included. Six UBA1 mutated patients identified from the included patients.
Figure 2 Kaplan–Meier curves of overall survival (a), progression to AML (b) in MDS patients with and without USAID. Data were censored at time of last visit or death. The response MDS control group is in blue and the one with autoinflammatory features is in red.
jcm-10-05586-t001_Table 1 Table 1 Baseline characteristics of USAID including pattern suggestive of AOSD.
Patients (n = 26) No VEXAS (n = 18) VEXAS (n = 6)
Epidemiology
Male-to-female ratio 3.16 2.8 4
Age at 1st signs (years) (range) 70.5 (64.3–78.9) 71 (65.5–79.3) 64.3 (63.6–68.2)
Time between USAID and MDS (years) (range) 1.0 (0.2–2) 0.9 (1.8–0.2) 1.2 (1.1–3)
Medical history (%)
Personal or familial history of autoimmunity 2 (9) 1 (6) 1 (25)
Symptoms (%)
Fever 26 (100) 18(100) 6 (100)
Skin rash 11 (42) 6 (33) 5 (83)
Arthritis/arthralgia 16 (62) 14 (78) 2 (33)
Pharyngitis/sore throat 5 (19) 1 (22) 1 (17)
Myalgia 5 (19) 3 (17) 2 (33)
Lymph nodes or splenomegaly 12 (46) 8 (44) 4 (67)
Blood test results (%)
Leukocytosis > 10,000/mm3 10 (38) 9 (50) 1 (17)
Granulocytes ≥ 80% 7 (26) 6 (67) 1 (17)
CRP >30 mg/L 26 (100) 18 (100) 6 (100)
Elevated liver enzymes 9 (35) 7 (39) 2 (67)
High ferritin 19/20 (95) 15 (94) 4 (100)
>2000 µg/L 14/20 (70) 13 (81) 1 (25)
Glycosylated ferritin < 20% 4/11 (36) 3 (30) 1 (50)
Severe complications
Pericarditis 3 (12) 3 (18) 0 (0)
Myocarditis 0 (0) 0 (0) 0 (0)
DIC 0 (0) 0 (0) 0 (0)
RHS 5 (19) 2 (11) 3 (50)
ARDS 1 (4) 1 (4) 0 (0)
ILD, alveolitis 3 (12) 1 (4) 2 (67)
Pleurisy 6 (23) 6 (33) 0 (0)
AOSD, adult-onset Still’s disease; ARDS, acute respiratory distress syndrome; CRP, C-reactive protein; DIC, disseminated intravascular syndrome; ILD, interstitial lung disease; MDS, myelodysplastic syndrome; RHS, reactive hemophagocytic syndrome.
jcm-10-05586-t002_Table 2 Table 2 Main features of MDS/CMML patients with USAID.
MDS-Related USAID
n = 26 (%) MDS/CMML Controls
n = 104 (%)
Mean age at diagnosis (range) 71.4 (36–85) 78 (42–92) *
Male 19 (76) 79 (76)
Myelodysplastic syndrome (MDS) 23 (89) 83 (80)
MDS with single lineage dysplasia 3 (12) 14 (13)
MDS with ring sideroblasts (MDS-RS) 2 (8) 6 (6)
MDS with multilineage dysplasia 5 (19) 33 (32)
MDS with excess blasts (EB) 8 (31) 14 (13)
MDS with isolated del(5q) 0 4 (4)
MDS, unclassifiable/missing data 5 (19) 7 (7)
Chronic myelomonocytic leukemia (CMML) 3 (12) 21 (20)
Acute myeloid leukemia (AML) (progressed to) 7 (27) 11 (10)
IPPS-R (IQR) 3.7 (2–5) 2.5 (0–8)
Deaths 12 (46) 26 (25) *
Follow-up (range) 16.8 (0–104) 21.5 (0–86)
* p value < 0.05.
jcm-10-05586-t003_Table 3 Table 3 Main features of the patients with UBA1 mutations (VEXAS syndrome).
Patient Sex Type MDS Age at Diagnosis of MDS Characteristics of MDS Age at USAID Onset Signs of USAID Other Symptoms Evolution
Patient #1 * M MDS UL 59.8 IPPS = NS 58.8 Fever, rash, cytolysis, high ferritin, RHS Recurrent superficial veinous thrombosis, cutaneous atypia Azacytidine for MDS just begun
NGS: DNMT3A, BRCA2, and ZRSR2 mutated
Bone marrow: vacuoles in myeloid precursor cells No response to CTC high dose rapidly completed with cyclosporine permitting, PR
Del 6q Blasts: NS Alive under azacytidine, CTC 20 mg and cyclosporine
Patient #2 * M MDS EB1 64.5 IPPS = 4 63.3 Fever, arthralgia, leukocytosis, lymphadenopathy, splenomegaly, granulocytes, cytolysis CR under azacytidine for MDS
NGS: Normal Periorbital headache, skin nodules, edema, diarrhea, abdominal pain Multiple lines of treatments: response and relapses to high-dose CTC and anakinra; no response to infliximab, tocilizumab, IV Ig, cyclosporine
Blasts: 7% Alive and disappearance of systemic features under azacytidine and CTC 20 mg/day
Patient #3 * M Unclassifiable MDS 73.5 IPPS-R: 2 73.5 Fever, rash, lymphadenopathy, splenomegaly, high ferritin, RHS Recurrent face edema, urticaria, skin nodules and eczematous skin lesions PR with azacytidine for MDS
NGS: DNMT3A mutated 31.7% No response to high-dose CTC and anakinra
Blasts: 0% Alive, PR and systemic symptoms with azacytidine
Patient #4 F Unclassifiable MDS 64.3 IPPS-R: NS NS Fever, rash, RHS Unknown response with hydroxyurea
Del X Blasts: NS Interstitial pneumonia, diarrhea CR with high-dose CTC, steroid dependence; CR with anakinra and CTC
Alive at last visit
Patient #5 * M MDS MLD 69.4 IPPS-R: 2
NGS: TET2 mutated 3% 65.8 Fever, rash, arthritis, sore throat, lymphadenopathy, splenomegaly, high ferritin, myalgia Pustular eruption and other cutaneous atypia CR with azacytidine; failure with methotrexate; leflunomide stopped early due to cytopenia; CR (with few relapses) with CTC and anakinra
Patient #6 M Unclassifiable MDS NS IPPS-R: NS
NGS: normal 69 Fever, rash, high ferritin, myalgia Oedema, angioedema chronic urticaria, alveolitis No hematological treatment CR under high dose CTC but CTC dependency, CR under anakinra and CTC stopped for neutropenia
Death at 73 years from sepsis and cardiac failure and anakinra
Median (yrs) (IQ 25;75) n = (%) M/F = 5:1 Follow up 2.2 (1.5; 3.3) 64.5 (64.3; 69.4) Fever (n = 6, 100%), skin rash (n = 5, 83%), arthralgia arthritis (n = 2, 33%), lymph nodes/splenomegaly n = 3 (50), sore throat (n = 1, 17%), RHS n = 3 (50), leukocytosis (n = 1, 17%), granulocytosis (n = 1, 17%), cytolysis (n = 2, 33%), high ferritin (n = 4, 67%)
CR, complete remission; CTC, corticosteroids; Ig, immunoglobulin; IPPS-R, Revised International Prognostic Scoring System; IV, intravenous; MDS, myelodysplastic syndrome; MDS EB1, MDS with excess of blasts < 5%; MDS: myelodysplastic syndrome; NGS, next-generation sequencing; NS, not significant; PR, partial response; RHS, reactive hemophagocytic syndrome; MDS SLD, MDS with single lineage dysplasia; MDS UL. Patients marked with an * were identified and included in French VEXAS group cohort and could have been used in other published studies.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 34884286 | 20,184,789 | 2021-11-27 |
What was the outcome of reaction 'Sepsis'? | USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still's Disease in Elderly Patients.
BACKGROUND
Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS).
OBJECTIVE
To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome.
METHODS
A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML.
RESULTS
Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS.
CONCLUSIONS
Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.
pmc1. Introduction
Recently, the concept of autoinflammatory disorders keep evolving and an increasing number of new monogenic diseases are identified but numerous autoinflammatory diseases are still to be characterized. Systemic autoinflammatory disorders (SAID) are unprovoked episodic or chronic sterile inflammation which are secondary to innate immune system dysregulation [1]. If well-characterized monogenic diseases such as familial Mediterranean fever are part of it, more than 50% patients presenting with clinical features resembling SAIDs still do not carry any of the know pathogenic mutations in autoinflammatory disease genes [2]. Some patients with SAID fit the criteria for polygenic forms of autoinflammatory diseases, such as adult-onset Still’s disease (AOSD); however, some of them do not. They are defined as undifferentiated systemic autoinflammatory disorders (USAID) [1,3].
Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are part of a heterogeneous group of clonal hematopoietic stem cell diseases characterized by ineffective hematopoiesis, peripheral cytopenia with an increased risk of progression, to acute myeloid leukemia (AML) [4]. About 10 to 20% of MDS/CMML could be associated with various extra hematological features, e.g., neutrophilic dermatoses, systemic vasculitis, inflammatory arthritis, pseudo-Behçet’s disease, and relapsing polychondritis [5,6,7,8]. For years now, the state of autoinflammatory disorders associated with neoplasia reported in the literature were mainly associated with solid cancer but also MDS/CMML, myeloproliferative disorders, and lymphoma, and identified in the literature as “paraneoplastic AOSD” or “malignant associated AOSD” [8,9,10,11,12,13,14,15,16,17].
Recently, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), a newly established X-linked disease associated with a somatic mutation in a gene encoding ubiquitin-like modifier activating enzyme 1 (UBA1) characterized by lipid vacuole inclusions in myeloid precursors of bone marrow examination, has been described [18]. These patients often develop hematologic malignancies, and especially MDS.
In this French nationwide study, our objective was to describe patients with MDS/CMML with unexplained recurrent fever and extra hematological signs, concordant or close to AOSD, and fulfilling the definition of USAID, their management, outcomes, overall survival, and the specific risk of progression to AML. We evaluated the prevalence of the newly described VEXAS syndrome in this group of patients and specifically reported their features.
2. Materials and Methods
2.1. Study Design
Data for patients with MDS or CMML and unexplained recurrent fever associated or not to extra hematological signs, concordant with USAID diagnosed between 2010 and June 2020 were retrospectively collected. All patients provided informed consent, and the study followed the Helsinki declaration and received the approval from the Institutional Review Board of Cochin Hospital (CLEP Decision N°: AAA-2021-08040). In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion. Three hundred and ninety patients were included in the MINHEMON registry across France for extra-hematological features associated to MDS/CMML. From this cohort, we selected patients which presented at least fever of unknown origin and elevated phase reactant. Physicians were also asked by Société Nationale Française de Médecine Interne” (SNFMI), “Club Rhumatisme et Inflammation” group (CRI), “Club Médecine INterne, HEMatologie et ONcologie” (MINHEMON) and the “Centre de référence des maladies auto-inflammatoires et des amyloses d’origine inflammatoire” CEREMAIA to report cases of patients with these features associated with MDS or CMML. Inclusion criteria were as follows: (1) MDS or CMML (WHO criteria); (2) AOSD with complete criteria (Yamaguchi and/or Fautrel criteria), or suspicion of AOSD (at least 3 from 5 criteria including fever) consistent with USAID; and (3) an established diagnosis of AOSD and MDS/CMML within the period of 5 years to avoid any fortuitous association. Exclusion criteria was defined as a diagnosis compatible with another autoimmune, infectious, drug-induced or systemic disease at the time of the inclusion. The diagnosis of suspected AOSD or USAID was made based on a consensus by two specialists (MD, AM) and a senior physician from the reference center of autoinflammatory diseases (SG). We compared our patients with a control group of MDS without extra hematological symptoms. Finally, we decided to screen the included patients for the newly described VEXAS to identify if it could be a new phenotype of this disease.
2.2. MDS, CMML
MDS and CMML were diagnosed based on peripheral blood and bone marrow examinations and classified according to the WHO 2016 criteria [19]. Patients were graded using the Revised International Prognostic Scoring System (IPSS-R) [20] for MDS: very low, low, intermediate, high, and very high risk groups; and the new CMML-specific Prognostic Scoring System (CPSS) for CMML: low, intermediate, and high. Karyotypes, the percentage of medullar blasts, and somatic mutations were assessed at the time of MDS diagnosis.
2.3. Genetic Analysis for VEXAS
Somatic UBA1 mutation was explored by incorporating the targeted gene in a homemade 75-gene panel for the next generation sequencing (NGS) of circulating mononucleated cells with a 2% threshold of detection already used in previous work [21]. Only patients alive or dead with available DNA were tested for UBA1. Tested samples were collected in a single center except for one tested in his reference center. UBA1 exon 3 sequences were determined by specific PCR followed by Sanger sequencing reaction using BigDye ™ Terminator (Applied Biosystems, Waltham, MA, USA) according to the manufacturer’s instructions and using the following primers: (forward) 5′-GTGGGTGGGAAAGTCTTTTGT-3′ and (reverse) 5′-TTACAGCTGCCGGGAGTAAAG-3′. A 3500xL-Dx Genetic Analyzer sequencing system was used, and sequences were analyzed with SeqScape software (Applied Biosystems). As MDS patients from the control group did not show any extra hematological features, they were not screened for UBA1 mutation. UBA1 mutated patients were identified and included in French VEXAS group cohort whom data could be used for other studies. The patients used in different studies are represented with an asterisk* in corresponding table.
2.4. USAID
Patient’s clinical files were screened for other autoinflammatory diagnostics. Symptoms of AOSD were specifically recorded and highlighted: fever, skin rash, arthritis or arthralgia, myalgia, pharyngitis or sore throat, nodes, or splenomegaly as well as these severe complications pericarditis, pleuritis, myocarditis, reactive hemophagocytic syndrome (RHS), disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and interstitial lung disease (ILD).
Data from the laboratory test included complete blood count, liver enzymes, C-reactive protein (CRP), ferritin, and glycosylated ferritin levels.
USAID complete clinical and biological response was defined as a total disappearance of all clinical features present at baseline in exclusion of those possible reliable to MDS and/or CMML and a complete normalization of acute-phase reactants. Partial response was defined as an improvement of at least one the clinical sign without an increase of any other features and at least 50% improvement of acute-phase reactants. Patients treated with corticosteroids as first line were differentiated into two groups: high dosage (0.8 to 1 mg/kg/day of prednisone-equivalent) and low dosage. USAID diagnosis was considered concomitant with MDS/CMML or AML when the diagnosis of both diseases was made within ±3 months before or after MDS/CMML were diagnosed. The overall survival, the cause of death and the progression toward AML, were recorded, as well as the date of the last visit.
2.5. Control Group
The control group consisted of 104 patients from the “Groupe Francophone des Myelodysplasies” registry of MDS/CMML which were seen at least once by the internal medicine specialists (AM, OF). These patients did not exhibit any systemic inflammatory or autoimmune features and were selected without matching.
2.6. Ethics
All patients provided informed consent, and the study followed the Helsinki declaration.
2.7. Statistical Analysis
Descriptive data included medians and interquartile ranges (IQR) for continuous variables and frequencies (expressed in percentages) for categorical variables. To account for missing data, results were expressed as observed data (missing data were not replaced). The Chi-square or Fischer’s exact tests were used to compare categorical variables, and the Student’s t-test or Mann–Whitney U test were applied for the comparison of continuous variables. The significance of findings was determined by a p-value of 0.05 or less. Statistical analyses were performed using 2009 GraphPad software, San Diego, CA, USA v6.1.
3. Results
3.1. Characteristics of Patients
All 26 patients with USAID presented with recurrent unexplained fever and elevated acute phase reactants (Figure 1). The median age of appearance of USAID’s symptoms was 70.5 years (IQR: 64.3–78.9) with 76% being male (Table 1). Besides unexplained recurrent fever, clinical features of USAID included arthritis (n = 16, 62%) and skin rash (n = 11, 42%). Severe complications were noted at the time of diagnosis or during the follow-up period in nine patients (35%). These included RHS (n = 5), myopericarditis (n = 3), interstitial lung disease (n = 3), and ARDS (n = 1) (Table 1). Five patients among the initially identified USAID, presented symptoms concordant with a diagnosis of AOSD according to Yamaguchi (n = 5) and Fautrel (n = 4) criteria [22,23]. Nine patients with USAID, reported atypical signs for AOSD including other skin lesions (n = 7, 78%) such as ulcers, nodules, angioedema, erythema nodosum, urticaria, eczematous lesions; non-infectious ileitis (n = 2, 25%), recurrent superficial venous thrombosis (n = 1, 11%), and periorbital headache (n = 1, 11%).
MDS/CMML characteristics (WHO classification, cytogenetics, and prognostic scores) are shown in Table 2. The most frequent subtype was MDS with excess blasts (30.8% of the patients) (MDS EB-1: 11.5%, MDS EB-2: 19.2%), with a median R-IPSS of 3.7 (IQR: 2–5). NGS somatic mutations screening was available for 17 patients and showed TET2 (n = 5), ASXL1 (n = 4), IDH1 (n = 3), and KRAS (n = 3) mutations (Supplementary Table S1). The diagnosis of USAID co-occurred with preceded and appeared after respectively the diagnosis of MDS/CMML in eight (32%), twelve patients (48%), and five patients (24%). The median time between USAID and MDS/CMML diagnosis was one year (IQR: 0.2–2). Specific hematological treatments were initiated in seventeen cases (65%) within half a year (IQR: 0.2–1.2) after the diagnosis of MDS. First-line treatment mostly consisted of azacytidine (Supplementary Table S2).
Among the 26 patients included, 18 had samples available to be tested for UBA1 mutation was tested in 18 patients and revealed six 33% positive cases, five out six were males (Figure 1 and Table 3). None of these patients progressed to AML during the 2.2 median years of follow up (ranges 1.2 to 5.6 years). Among these six individuals with VEXAS syndrome, none had a confirmed AOSD, including one with incomplete AOSD criteria sets and five remainders presenting additional unusual clinical features for AOSD. None had polychondritis, one patient hand interstitial pneumonia, one alveolitis, and five had cutaneous features distinct from a rash.
Compared to MDS/CMML controls without any inflammatory features (n = 104), USAID-associated MDS/CMML patients were younger (71.4 (IQR: 36–85) vs. 78 years (IQR: 42–92); p = 0.0005), without any other statistically significant differences for demography, MDS/CMML subtype, survival. Even if the rates of deaths were higher in the study group (46% vs. 25%; p = 0.02), the overall survival and the time to progression to AML were not significantly different between the groups (Figure 2).
3.2. Treatment and Outcomes
Twenty-two patients (85%) received specific treatment for USAID. Corticosteroids were used as a first-line treatment in 19 cases (86%) alone (n = 17) or combined with anakinra or infliximab in the other 2 cases. A complete clinical and biological response to first-line treatment was observed in 14 cases (64%) but 5 cases of secondary steroid dependency were described. Thirteen patients (59%) required a second-line treatment because of a resistance to steroids, primary inefficiency, or relapse, with a response in eight (73%) patients. Targeted biological therapy alone or in association with corticosteroids enabled either a partial or complete response in 9 out of 11 patients (anakinra n = 8/9, tocilizumab n = 0/1, and infliximab n = 1/1). Azacytidine used for MDS or steroid dependent autoinflammatory disease (n = 12) resulted in a complete or partial response of systemic features in 10 (83%) cases. Seven patients (26%) progressed to AML and 12 died (46%), all except one in the VEXAS negative group during the follow-up (Supplementary Table S2 and Figure S1).
Among the six patients with VEXAS, four responded temporarily and/or partially to corticosteroids: relapses and steroid dependency were observed in all cases. Anakinra was used in five cases with a complete or partial response in four cases. Tocilizumab was ineffective in one remaining case. When available, azacytidine led to a response on systemic features in all 3 cases.
4. Discussion
Patients with MDS/CMML can develop USAID with various extra hematological features including pattern suggestive of AOSD. This is the first multidisciplinary series (involving both rheumatologists, hematologists, and clinical immunologists) reporting on USAID associated with MDS/CMML features and the prevalence of VEXAS in such cohort(s). The results of the present study have several important implications. In the case of MDS/CMML with recurrent and unexplained fever, our cohort, although limited, shows that VEXAS syndrome represents 33% (6/18) of cases, these inflammatory situations remaining rare. Moreover, over a median follow-up of 26 month, none of the 6 cases of MDS/CMML VEXAS + progressed to AML, versus 23% of MDS/CMML with USAID and 40% of classic MDS/CMML without inflammatory manifestations. At last, although the numbers are small therefore caution must remain prevalent, there could be a potential interest of biological therapies or even azacytidine when UBA1 is mutated.
Patients with MDS and unexplained recurrent fever should be first tested for the UBA1 mutation. The recent work by Beck et al. which identified VEXAS, implying that somatic mutations may be a more frequent cause of human disease than previously recognized [18,24]. A third of our patients screened for UBA1 were positive for this mutation (including one woman). As a cohort of comparison, in relapsing chondritis, a frequently associated clinical picture usually described with VEXAS, only 7.6% had UBA1 mutations [25]. USAID appeared as a new pattern of VEXAS. Interestingly, 50% of our VEXAS patients experienced RHS. In the future, the order of UBA1 screening could be debated: integrated into the first-line genetic exploration of MDS as well as the MDS/SMP NGS panel or rather screened in the case of MDS/CMML with systemic features in particular USAID.
In contrast to other dysimmune manifestations with a near equal frequency distribution before, simultaneously, and after the diagnosis of MDS/CMML (USAID and systemic features of VEXAS tend to precede the diagnosis of hematological diseases) [9]; hence, the importance of an early identification of warning signs to carefully consider an underlying neoplasia, in particular hematological malignancy. Nearly 20% of the patients matched with the criteria concordant with AOSD, but some atypia should raise the physicians’ attention in patients with newly-diagnosed AOSD, with some features such as late-onset disease [26], male sex [27] as well as cytopenia in particular the absence of leukocytosis (a hallmark feature of AOSD), and macrocytosis and monocytosis [9,11]. In a recent Dutch case series of VEXAS, among patients with unclassified autoinflammation, two among the twelve retrospectively identified were initially suspected with AOSD [28]. Thus, elderly patients with late AOSD diagnosis or suspicion as described in some series [29,30] could also benefit from UBA1 mutation screening.
As described previously for systemic inflammatory and autoimmune disorders associated with MDS/CMML, MDS EB, and MDS MLD were the most frequently associated subtypes in USAID patients not UBA1 mutated [6,31]. No association with a specific karyotype was identified but interestingly TET2 and IDH mutation already associated with systemic inflammatory and auto immune disease and T cell dysregulation in a recent work [32] were also frequently found in our cohort. Two out of the six VEXAS patients presented DNMT3A also described in other VEXAS patients [18,28,33,34], but significance is yet unclear. None of the patients with VEXAS had CMML, which is consistent with the recent report published by Zhao et al. [35]. The prognosis of MDS-associated autoimmune disorders remains unclear, as depending on the types of autoimmune disease in each cohort, the impact on survival could be different [7] but we must notice that in our group, despite a high rate of transformation (more than 25%), the twelve death: only one was UBA1 mutated and none of the VEXAS patients transformed into AML.
The treatment of symptoms of patients with malignant associated features concordant or close to AOSD is challenging. Corticosteroids response was similar to AOSD’s but with a high percentage of steroid dependency or secondary failure [27]. Methotrexate, usually used for its steroid-sparing effect, was rarely applied, presumably due to the risk of cytopenia, explaining the frequent use of biologic agents. The preferential utilization of interleukin-1R antagonists rather than TNF-a antagonists usually used in articular rheumatism is justified by the dominance of the systemic character of the disease with frequent spikes in fever and seemed efficient. Most treatments were only transiently effective, but hematological treatment allowed control of the USAID symptoms for 11 patients in our cohort. As in autoimmune and inflammatory disorders, azacytidine, appears to have a beneficial effect on these systemic manifestations [36,37]. Similarly, in a recent retrospective, Bourbon et al.’s study of the hypomethylating agent and signaling inhibitors seemed to achieve interesting results in VEXAS syndrome patients [38]. The occurrence of USAID or AOSD compatible features over the course of myelodysplastic diseases may prompt a hematological treatment, especially in its refractory form, despite the absence of a direct hematological indication. Thus, azacytidine could be a therapeutical hypothesis for USAID associated with MDS as well as it could be for UBA1 mutated patients.
Our study has several important limitations. First, the retrospective design used here carries an inherited risk of bias and missing data. Second, despite the scarcity of the described clinical syndrome, a small sample size limits the generalizability of the findings reported. Herein we chose to select only patient with occurrence of USAID/AOSD suspicion and MDS/CMML within the period of 5 years to avoid any fortuitous association. Further studies should aim at improving study designs with a prospective nature, larger sample size, and detailed comprehensive information collection.
5. Conclusions
Systemic form of VEXAS syndrome can mimic AOSD, especially in the elderly. USAID symptoms including a pattern suggestive of AOSD associated with MDS/CMML was identified in 33% cases with VEXAS syndrome, thereby further expanding the spectrum of this new syndrome. UBA1 should be sequenced in this population, especially in case of macrocytic associated anemia and chronically elevated CRP among old males, but not exclusively. Although the optimal management of UBA1/MDS overlap patients remains to be determined in larger scale cohorts, biological therapies and/or hypomethylating agents seem promising in this situation.
Key messages:
Patients with MDS/CMML can develop a recurrent fever with various extra hematological features suggestive of USAID;
Pseudo-Still disease or USAID associated with a myelodysplastic syndrome are a new phenotype of VEXAS syndrome;
UBA1 mutation should be screened in case of such association.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/jcm10235586/s1, Figure S1: Different lines of USAID treatments and treatment responses. Twenty-two patient (85%) received specific treatment for USAID and 14 (64%) experienced complete response. Fifty-nine percent of the patient needed a second line treatment and 54% a third line, Table S1: Main features of MDS/CMML patients with USAID, Table S2: USAID including pattern suggestive of AOSD natural history and therapeutical management.
Click here for additional data file.
Author Contributions
Conceptualization, M.D. (Marion Delplanque), S.G.-L. and A.M.; Supervision, S.G.-L. and A.M.; Writing—original draft, M.D. (Marion Delplanque); Writing—review & editing, M.D. (Marion Delplanque), A.A., P.H., P.F., J.G., F.M., D.R.-W., N.B., L.D., A.O., M.G., M.M., J.R. (Jerome Razanamahery), G.M., M.D. (Matthieu Décamp), S.M., T.Q., J.R. (Julien Rossignol), L.S., M.S., L.T., A.S., Y.H., S.G.-L. and A.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Cochin Hospital Institutional Review Board (CLEP Decision N°: AAA-2021-08040).
Informed Consent Statement
In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion.
Data Availability Statement
Data are available on request from the corresponding author.
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
A Arthritis/arthralgia
AML Acute myeloid leukemia
ANA Antinuclear antibody
AOSD Adult-onset Still’s disease
ARDS Acute respiratory distress syndrome
C Cytolysis
CBC Complete blood count
CC Corticosteroids
CMML Chronic myelomonocytic leukemia
CPSS CMML-specific prognostic scoring system
CR Complete remission
CRP C-reactive protein
DIC Disseminated intravascular coagulation
F Female
F Fever
Fr High ferritin
G Low glycosylated ferritin
IL Interleukin
ILD interstitial lung disease
L Lymph nodes and splenomegaly
M Male
M/F Male-to-female ratio
MAS Macrophage activation syndrome
MDS Myelodysplastic syndrome
MDS MLD MDS with multilineage dysplasia
MDS SLD MDS with single lineage dysplasia
MDS-EB1 MDS with excess of blasts <5%
MDS-EB2 MDS with excess of blasts >5%
MDS-RS MDS with ring sideroblasts
MM Myelodysplastic malignancy
MTX Methotrexate
PNN Polymorphonuclear neutrophils >80%
PET scan Positron emission tomography scan
PR Partial remission
RF Rheumatoid factor
RHS Reactive hemophagocytic syndrome
R-IPPS Revised International Prognostic Scoring System
SAID Systemic autoinflammatory disorder
S Skin rash
T Sore throat
TNF Tumor necrosis factor
UBA1 Ubiquitin-like modifier activating enzyme 1
USAID Undifferentiated systemic autoinflammatory disorder
VEXAS Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome
W Leukocytosis
Yrs Years
Figure 1 Flow-chart depicting patient selection. From the 46 patients screened, 26 were included. Six UBA1 mutated patients identified from the included patients.
Figure 2 Kaplan–Meier curves of overall survival (a), progression to AML (b) in MDS patients with and without USAID. Data were censored at time of last visit or death. The response MDS control group is in blue and the one with autoinflammatory features is in red.
jcm-10-05586-t001_Table 1 Table 1 Baseline characteristics of USAID including pattern suggestive of AOSD.
Patients (n = 26) No VEXAS (n = 18) VEXAS (n = 6)
Epidemiology
Male-to-female ratio 3.16 2.8 4
Age at 1st signs (years) (range) 70.5 (64.3–78.9) 71 (65.5–79.3) 64.3 (63.6–68.2)
Time between USAID and MDS (years) (range) 1.0 (0.2–2) 0.9 (1.8–0.2) 1.2 (1.1–3)
Medical history (%)
Personal or familial history of autoimmunity 2 (9) 1 (6) 1 (25)
Symptoms (%)
Fever 26 (100) 18(100) 6 (100)
Skin rash 11 (42) 6 (33) 5 (83)
Arthritis/arthralgia 16 (62) 14 (78) 2 (33)
Pharyngitis/sore throat 5 (19) 1 (22) 1 (17)
Myalgia 5 (19) 3 (17) 2 (33)
Lymph nodes or splenomegaly 12 (46) 8 (44) 4 (67)
Blood test results (%)
Leukocytosis > 10,000/mm3 10 (38) 9 (50) 1 (17)
Granulocytes ≥ 80% 7 (26) 6 (67) 1 (17)
CRP >30 mg/L 26 (100) 18 (100) 6 (100)
Elevated liver enzymes 9 (35) 7 (39) 2 (67)
High ferritin 19/20 (95) 15 (94) 4 (100)
>2000 µg/L 14/20 (70) 13 (81) 1 (25)
Glycosylated ferritin < 20% 4/11 (36) 3 (30) 1 (50)
Severe complications
Pericarditis 3 (12) 3 (18) 0 (0)
Myocarditis 0 (0) 0 (0) 0 (0)
DIC 0 (0) 0 (0) 0 (0)
RHS 5 (19) 2 (11) 3 (50)
ARDS 1 (4) 1 (4) 0 (0)
ILD, alveolitis 3 (12) 1 (4) 2 (67)
Pleurisy 6 (23) 6 (33) 0 (0)
AOSD, adult-onset Still’s disease; ARDS, acute respiratory distress syndrome; CRP, C-reactive protein; DIC, disseminated intravascular syndrome; ILD, interstitial lung disease; MDS, myelodysplastic syndrome; RHS, reactive hemophagocytic syndrome.
jcm-10-05586-t002_Table 2 Table 2 Main features of MDS/CMML patients with USAID.
MDS-Related USAID
n = 26 (%) MDS/CMML Controls
n = 104 (%)
Mean age at diagnosis (range) 71.4 (36–85) 78 (42–92) *
Male 19 (76) 79 (76)
Myelodysplastic syndrome (MDS) 23 (89) 83 (80)
MDS with single lineage dysplasia 3 (12) 14 (13)
MDS with ring sideroblasts (MDS-RS) 2 (8) 6 (6)
MDS with multilineage dysplasia 5 (19) 33 (32)
MDS with excess blasts (EB) 8 (31) 14 (13)
MDS with isolated del(5q) 0 4 (4)
MDS, unclassifiable/missing data 5 (19) 7 (7)
Chronic myelomonocytic leukemia (CMML) 3 (12) 21 (20)
Acute myeloid leukemia (AML) (progressed to) 7 (27) 11 (10)
IPPS-R (IQR) 3.7 (2–5) 2.5 (0–8)
Deaths 12 (46) 26 (25) *
Follow-up (range) 16.8 (0–104) 21.5 (0–86)
* p value < 0.05.
jcm-10-05586-t003_Table 3 Table 3 Main features of the patients with UBA1 mutations (VEXAS syndrome).
Patient Sex Type MDS Age at Diagnosis of MDS Characteristics of MDS Age at USAID Onset Signs of USAID Other Symptoms Evolution
Patient #1 * M MDS UL 59.8 IPPS = NS 58.8 Fever, rash, cytolysis, high ferritin, RHS Recurrent superficial veinous thrombosis, cutaneous atypia Azacytidine for MDS just begun
NGS: DNMT3A, BRCA2, and ZRSR2 mutated
Bone marrow: vacuoles in myeloid precursor cells No response to CTC high dose rapidly completed with cyclosporine permitting, PR
Del 6q Blasts: NS Alive under azacytidine, CTC 20 mg and cyclosporine
Patient #2 * M MDS EB1 64.5 IPPS = 4 63.3 Fever, arthralgia, leukocytosis, lymphadenopathy, splenomegaly, granulocytes, cytolysis CR under azacytidine for MDS
NGS: Normal Periorbital headache, skin nodules, edema, diarrhea, abdominal pain Multiple lines of treatments: response and relapses to high-dose CTC and anakinra; no response to infliximab, tocilizumab, IV Ig, cyclosporine
Blasts: 7% Alive and disappearance of systemic features under azacytidine and CTC 20 mg/day
Patient #3 * M Unclassifiable MDS 73.5 IPPS-R: 2 73.5 Fever, rash, lymphadenopathy, splenomegaly, high ferritin, RHS Recurrent face edema, urticaria, skin nodules and eczematous skin lesions PR with azacytidine for MDS
NGS: DNMT3A mutated 31.7% No response to high-dose CTC and anakinra
Blasts: 0% Alive, PR and systemic symptoms with azacytidine
Patient #4 F Unclassifiable MDS 64.3 IPPS-R: NS NS Fever, rash, RHS Unknown response with hydroxyurea
Del X Blasts: NS Interstitial pneumonia, diarrhea CR with high-dose CTC, steroid dependence; CR with anakinra and CTC
Alive at last visit
Patient #5 * M MDS MLD 69.4 IPPS-R: 2
NGS: TET2 mutated 3% 65.8 Fever, rash, arthritis, sore throat, lymphadenopathy, splenomegaly, high ferritin, myalgia Pustular eruption and other cutaneous atypia CR with azacytidine; failure with methotrexate; leflunomide stopped early due to cytopenia; CR (with few relapses) with CTC and anakinra
Patient #6 M Unclassifiable MDS NS IPPS-R: NS
NGS: normal 69 Fever, rash, high ferritin, myalgia Oedema, angioedema chronic urticaria, alveolitis No hematological treatment CR under high dose CTC but CTC dependency, CR under anakinra and CTC stopped for neutropenia
Death at 73 years from sepsis and cardiac failure and anakinra
Median (yrs) (IQ 25;75) n = (%) M/F = 5:1 Follow up 2.2 (1.5; 3.3) 64.5 (64.3; 69.4) Fever (n = 6, 100%), skin rash (n = 5, 83%), arthralgia arthritis (n = 2, 33%), lymph nodes/splenomegaly n = 3 (50), sore throat (n = 1, 17%), RHS n = 3 (50), leukocytosis (n = 1, 17%), granulocytosis (n = 1, 17%), cytolysis (n = 2, 33%), high ferritin (n = 4, 67%)
CR, complete remission; CTC, corticosteroids; Ig, immunoglobulin; IPPS-R, Revised International Prognostic Scoring System; IV, intravenous; MDS, myelodysplastic syndrome; MDS EB1, MDS with excess of blasts < 5%; MDS: myelodysplastic syndrome; NGS, next-generation sequencing; NS, not significant; PR, partial response; RHS, reactive hemophagocytic syndrome; MDS SLD, MDS with single lineage dysplasia; MDS UL. Patients marked with an * were identified and included in French VEXAS group cohort and could have been used in other published studies.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 34884286 | 20,184,789 | 2021-11-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac disorder'. | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BENDAMUSTINE, CYTARABINE, RITUXIMAB | DrugsGivenReaction | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BENDAMUSTINE, CYTARABINE, RITUXIMAB | DrugsGivenReaction | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BENDAMUSTINE, CYTARABINE, RITUXIMAB | DrugsGivenReaction | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BENDAMUSTINE, BORTEZOMIB, CYTARABINE, IBRUTINIB, LENALIDOMIDE, RITUXIMAB | DrugsGivenReaction | CC BY | 34885198 | 20,252,357 | 2021-12-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'. | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BENDAMUSTINE, BORTEZOMIB, CYTARABINE, IBRUTINIB, LENALIDOMIDE, RITUXIMAB | DrugsGivenReaction | CC BY | 34885198 | 20,252,357 | 2021-12-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BENDAMUSTINE, RITUXIMAB | DrugsGivenReaction | CC BY | 34885198 | 20,215,473 | 2021-12-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Performance status decreased'. | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BENDAMUSTINE, BORTEZOMIB, CYTARABINE, IBRUTINIB, LENALIDOMIDE, RITUXIMAB | DrugsGivenReaction | CC BY | 34885198 | 20,252,357 | 2021-12-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Prostate cancer'. | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BENDAMUSTINE, CYTARABINE, RITUXIMAB | DrugsGivenReaction | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sarcoma'. | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BENDAMUSTINE, CYTARABINE, RITUXIMAB | DrugsGivenReaction | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
What was the dosage of drug 'BORTEZOMIB'? | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BORTEZOMIB-BASED REGIMEN (N=4) | DrugDosageText | CC BY | 34885198 | 20,252,357 | 2021-12-03 |
What was the dosage of drug 'IBRUTINIB'? | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 33 RECEIVED IBRUTINIB AS SECOND LINE THERAPY | DrugDosageText | CC BY | 34885198 | 20,252,357 | 2021-12-03 |
What was the dosage of drug 'LENALIDOMIDE'? | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | LENALIDOMIDE 2ND-LINE THERAPY(N=2) | DrugDosageText | CC BY | 34885198 | 20,252,357 | 2021-12-03 |
What was the outcome of reaction 'Cardiac disorder'? | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
What was the outcome of reaction 'Death'? | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
What was the outcome of reaction 'Disease progression'? | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
What was the outcome of reaction 'Prostate cancer'? | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
What was the outcome of reaction 'Sarcoma'? | Rituximab and Bendamustine (BR) Compared with Rituximab, Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell Lymphoma.
BACKGROUND
Rituximab plus bendamustine (BR), and rituximab, bendamustine, and cytarabine (R-BAC) are well-known induction therapies in elderly patients with mantle cell lymphoma (MCL), according to clinical guidelines. However, a direct comparison between the two regimens has never been performed.
METHODS
In this multicentre retrospective study, we compared the outcome of patients with newly diagnosed MCL, treated with BR or R-BAC. Primary endpoint was 2-year progression-free survival (PFS). Inclusion bias was assessed using a propensity score stratified by gender, age, MCL morphology, and MIPI score.
RESULTS
After adjusting by propensity score, we identified 156 patients (53 BR, 103 R-BAC) with median age of 72 (53-90). Median follow-up was 46 months (range 12-133). R-BAC was administered in a 2-day schedule or with attenuated dose in 51% of patients. Patients treated with R-BAC achieved CR in 91% of cases, as compared with 60% for BR (p < 0.0001). The 2-year PFS was 87 ± 3% and 64 ± 7% for R-BAC and BR, respectively (p = 0.001). In terms of toxicity, R-BAC was associated with significantly more pronounced grade 3-4 thrombocytopenia than BR (50% vs. 17%).
CONCLUSIONS
This study indicates that R-BAC, even when administered with judiciously attenuated doses, is associated with significantly prolonged 2-year PFS than BR in elderly patients with previously untreated MCL.
pmc1. Introduction
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma characterized by continuous relapses over time, with no standard initial therapy for patients who are not eligible for an autologous transplant [1]. Furthermore, many patients cannot be eligible for intensive therapies because of their older age, or medical comorbidities. [2] The standard-of-care upfront therapy for elderly or frail patients was represented by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by maintenance with rituximab [3] or by the VR-CAP regimen, where vincristine is replaced by bortezomib [4]. Alternatively, in the last decades, bendamustine-based therapies have been increasingly adopted worldwide for elderly patients with MCL. Two phase 3 randomized studies have investigated the role of the bendamustine and rituximab (BR) in this setting as opposite to R-CHOP. The first study reported that BR had fewer toxicities and significantly improved progression-free survival (PFS) in comparison with R-CHOP [5]; the second study showed that BR had better long-term disease control than R-CHOP/R-CVP, confirming that BR represents a suitable first-line option for patients with MCL [6]. With the aim of improving the efficacy of the BR regimen, the R-BAC regimen (rituximab, bendamustine, and intermediate dose cytarabine) has been proposed by the Fondazione Italiana Linfomi (FIL) as a very active alternative induction regimen for elderly patients with MCL [7]. When indirectly comparing historical results, with the limitations of such analysis, it appears that BR was less toxic than R-BAC (especially on blood counts), but also less active. The STiL [5], and FIL study [7] had apparently similar populations, with median age of 70 (64.5–74) and 71 (67–75), respectively, but in the first patients treated with BR had a median PFS of 35.4 months, as opposite to 76% 3-year PFS of R-BAC [7]. Similarly, in the Bright study [6], median PFS after long-term follow up for the BR arm approximated 48 months [8].
European and international clinical guidelines [9,10] list the two bendamustine-based regimens as feasible options in MCL patients who are not eligible for autologous transplant. However, to the best of our knowledge no study so far has compared face-to-face the efficacy of these two regimens.
As in the Veneto region both BR and R-BAC represent standard induction treatment for elderly patients with MCL, we performed a retrospective survey with the aim of comparing the two regimens in similar populations of patients from our geographical area.
2. Materials and Methods
2.1. Study Design and Partecipants
This was a multicentre, observational, retrospective study that enrolled patients from eight centres of the Rete Ematologica Veneta (REV). The two regimens (BR and R-BAC) represented routine induction regimens in the selected centres for patients with MCL not eligible for autologous transplant. Due to the retrospective nature of the study, treatment assignment to one therapy instead of the other was based on local doctor decision. Patients were included if they: (i) were previously untreated; (ii) were not eligible for upfront autologous transplant; (iii) had established histological diagnosis of MCL, made by an expert pathologist according to the criteria of the WHO classification [11]. Reasons for not being eligible for upfront autologous transplant in patients less than 65 years-old were represented by coexisting comorbidities or medical conditions, since all enrolling institutions routinely treat with BR or R-BAC transplant ineligible patients.
Clinical and pathological data of each included patient were retrieved by local investigator from medical records, after obtaining written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The study was denominated “BE-ve-BAC study”, and was approved by the Ethics Committee of Verona University on 24 March 2021, protocol number 18448.
2.2. Efficacy and Toxicity Outcomes
The primary efficacy outcome was 2-year PFS defined as progression, relapse or death from any cause two years after diagnosis. Secondary outcomes were overall survival (OS), defined as the time from diagnosis until death from any cause, response to treatment (either overall response and complete remission rate), and toxicity. OS from time of first relapse (OS-2) was defined as the time from first relapse to death for any cause. Tumour response was assessed at the end of induction treatment irrespective of the number of administered cycles. For response assessment, since not all included patients were staged with PET at the end of therapy, we adopted Cheson 2008 criteria [12]. Toxicity was measured by means of number of patients that interrupted treatment prematurely for reasons not related to tumour response, or by registered episodes of relevant toxicity, defined as grade 3–4 haematological toxicity, grade 3–4 nonhaematological toxicity.
2.3. Statistical Analysis
Demographics and clinical patient characteristics were summarized using descriptive statistical methods. All patients treated with at least one cycle of either BR or R-BAC were included, provided they had a minimum follow-up of 12 months since start of treatment. Inclusion bias was addressed by using a propensity score (PS), that was calculated based on possible known confounding factors, which were gender, age, MCL blastoid morphology, and MIPI score. In order to reduce selection bias, we applied an inverse probability of treatment weight (IPTW). The PS was estimated using a multivariate logistic model, with the type of treatment (BR versus R-BAC) that represented the dependent variable and the covariates listed above were the possible confounding factors.
The survival analysis was estimated using the Kaplan–Meier method and the groups were compared using log-rank test. Multivariate analysis was performed using Cox regression models. Toxicity, completed treatment rates and treatment response rates were compared with the chi-square or Fisher’s test.
3. Results
3.1. Patients
Overall, 180 patients with MCL with a median age of 72 years (range 53–90) were identified and included in the database. According to our IPTW calculation, the probability of receiving R-BAC instead of BR was significantly higher in younger patients (p < 0.0001), with no additional significant difference in the distribution of other computed prognostic variables (p = 0.31 for gender, p = 0.73 for morphology, p = 0.15 for MIPI score). Therefore, we performed our comparative analysis in patients who were 80 years old or younger, in order to smooth this significant age difference between the two cohorts, and to obtain a fair comparison between the two groups. This final cohort included 156 patients (53 BR, 103 R-BAC), which represented the subject of the present analysis. The clinical and pathological characteristics of these patients, then divided for treatment allocation, are shown in Table 1. Of them, 109 (70%) were males, MIPI was elevated in 64.1%, 11.5% had blastoid or pleomorphic morphology, 47% had high Ki 67 index. As reported in Table 1, the BR and R-BAC group appeared comparable in terms of disease characteristics and main prognostic factors at presentation, except for age, as previously discussed.
3.2. Administered Cycles, Dose Reductions, and Tumor Response
Overall, 146 patients (94%) received at least four induction cycles. Of the 10 patients who were treated with less than four cycles, eight were treated with BR (15%), and two with R-BAC (2%, p = 0.002). The main reasons for not administering at least four cycles were tumour progression (seven patients: six BR, one R-BAC) or toxicity (three patients: two BR, one R-BAC).
Cycles were reduced in total dose in 62 patients. Approximately half (51%) of patients treated with R-BAC had substantial dose reductions, which were mainly represented by the 2-day schedule (instead of 3-day), meaning that the third day of cytarabine was skipped. The detailed distribution of administered cycles and dose reductions are reported in Table 2. A similar proportion of patients in the two study groups (12% for BR, 14% for R-BAC) delayed the interval between cycles of more than 2 weeks.
Complete response (CR) was achieved in 126 patients (81%); 12 patients (8%) were primary refractory to induction therapy. According to Cheson 2008 criteria, patients treated with R-BAC achieved CR in 76% of cases, as compared to 47% of patients treated with BR (p = 0.0004). When we analysed patients staged by PET-scan (N = 80), according to Lugano criteria, patients treated with R-BAC achieved CR in 91% of cases, as compared to 60% of patients treated with BR (p < 0.0001). Accordingly, only three patients treated with R-BAC had refractory disease (3%), as opposed to nine patients treated with BR (17%, p = 0.001).
3.3. Survival Analysis
Overall, 49 patients died during the study period. Of them, 32 (65%) died of progressive disease, four (8%) of second neoplasms (three prostatic carcinoma and one sarcoma), two of cardiac complications, and 11 of a miscellanea of other causes. None of the patients died of infection. Median follow-up for survivors from MCL diagnosis was 46 months (range 12–135), with no statistical difference between BR (42 months, range 12–135) and R-BAC (52 months, range 12–133) cohorts (p = 0.12 by Mann–Whitney test). The 2-year PFS was 87% ± 3% and 64% ± 7% for R-BAC and BR, respectively (p = 0.001). Median overall survival (OS) was 121 months for R-BAC and 78 months for BR (p = 0.08, Figure 1).
For the whole series of 156 patients, high MIPI score was the only predictive significant variable both in terms of PFS and OS (p = 0.001 and p = 0.003, respectively). The same high MIPI score was predictive of adverse PFS (but not OS) in patients treated with R-BAC, while it was associated with significantly inferior PFS and OS in patients treated with BR.
We analysed survival of the 127 patients > 65 years (50 treated with BR, 77 with R-BAC) matched across the treatment programs, and we found that R-BAC was associated with significantly superior PFS (p = 0.01), but not OS (p = 0.386).
Patients treated with R-BAC who had dose reductions had similar outcome than those who received full dose.
3.4. Toxicity
As mentioned above, three patients interrupted prematurely the induction therapy due to toxicity. Reasons were prolonged neutropenia grade 4 (one patient), and erythematous skin reaction grade 4 (two patients).
As shown in Table 2, we registered 208 episodes of relevant toxicity, which were evenly distributed among the two treatment groups. Patients receiving R-BAC experienced 133 episodes of grade 3–4 haematological toxicity: 32 grade 3–4 anaemia, 49 grade 3–4 neutropenia and 52 grade 3–4 thrombocytopenia. After R-BAC, we registered eight cases of febrile neutropenia as compared to two in the BR group (p = NS). Other causes of nonhaematological toxicity in the R-BAC group were infections (four patients), skin reactions (five patients), or miscellaneous other causes in the remaining 15 patients.
Of note, in the BR group we recorded significantly less cases of severe thrombocytopenia (p = 0.004).
3.5. Second Line Treatments and Survival, POD-24
Of the 64 patients who experienced first-relapse during the study period, 10 patients did not receive second line therapy, and were managed with supportive therapy or palliative care due to rapid tumour progression or old age and poor performance status.
Thirty-three of the 54 treated patients (61%) were treated in second line with ibrutinib. Remaining patients were treated with anthracycline-based therapy (7), bortezomib-based regimens (4), lenalidomide (2), bendamustine-based (5), and other different chemotherapeutic regimens (3). Overall, OS-2 was 8.2 months (Figure 2a). The median OS-2 for patients treated with ibrutinib was significantly longer than for patients treated with other approaches (15.2 months versus 6.0 months, p = 0.05, Figure 2b).
Furthermore, patients that were refractory to induction therapy or who experienced early progression of disease (POD), defined as POD within 24 months from start of therapy (POD-24, n = 31), had significantly inferior median OS-2 than patients with late-POD (5 months versus 21 months, p = 0.005, Figure 2c). When divided according to first line, patients with POD-24 were more represented among the BR patients (21 of 28 POD, 75%), than among the R-BAC patients (10 of 36 POD, 28%, p = 0.0002). The detrimental effect of POD-24 on patient final outcome was observed both in the BR and in the R-BAC treated patients.
4. Discussion
With the present report, we show that R-BAC was more effective than BR in an unselected series of consecutive elderly patients with MCL from our geographical area. This difference was particularly pronounced in terms of PFS, while curves showed only a trend in favor of R-BAC in terms of OS. This improvement in efficacy was at the cost of increased haematotoxicity, specifically thrombocytopenia.
Available comparison of historical results had suggested that R-BAC was associated with superior survival, but with increased haematotoxicity than BR. However, to our knowledge, the present study represents the first attempt of face-to-face comparison between BR and R-BAC, since the two regimens had never been compared before, either retrospectively or prospectively. Our results may assist physicians’ choice when allocating patients to a bendamustine-based approach, as opposite to R-CHOP-based induction therapy. According to our observations, R-BAC may then be considered the best choice in terms of efficacy, but be destined cautiously to relatively younger or fit patient populations. Since toxicity of R-BAC was mainly limited to blood counts, and was transient, we believe that judicious dose reductions may be applied to the R-BAC regimens in less fit or elderly patients, facilitating a wider use of this regimen. Indeed, the 2-day schedule was widely adopted in the everyday practice described in this trial, and did not hamper efficacy results, while sparing toxicity, as previously reported [7]. It is not surprising that most of the included patients received R-BAC and not BR, since R-BAC has been conceived in this territory, and well used by most centers in or outside trials of the FIL (Fondazione Italiana Linfomi).
We acknowledge that the major limitation of our study was represented by the retrospective collection of patients. Propensity score matching and other statistical methods cannot incorporate unmeasurable confounders such as physiological age which is a major factor in making treatment decisions in astute clinicians. However, the concern for a selection bias may have been attenuated by the enrollment of consecutive patients from centers where the two regimens were routinely used as standard induction. Moreover, it is likely that the use of propensity score further smoothed the selection bias, although we cannot exclude the contribution of unknown confounders.
The fact that the survival advantage of R-BAC was limited to PFS was not surprising since the median age of our patients was 72 years, and only 65% of our patients died of progressive disease, meaning that in many cases the cause of death had little to do with the type of first line regimen.
We have shown that ibrutinib represents a valid second-line option for patients relapsing after bendamustine-based induction. The survival expectancy of relapsing patients was significantly improved by the availability of ibrutinib as a second line option. Ibrutinib monotherapy had similar efficacy after BR or R-BAC (p = 0.25 for OS-2). Overall, our real-life data show a relatively inferior OS-2 than other series of patients enrolled in clinical trials [13,14].
In parallel to what has been described in younger patients [15,16], POD24 confirmed its high discriminative power in elderly patients, as shown in Figure 2c; as observed by others [17], and mirroring results of younger cohorts [15], ibrutinib was the best choice in early-POD (p = 0.006 in favor of ibrutinib versus other choices), but not in late-POD (p = 0.42).
With the CAR-T cell therapy era at the door, the use of bendamustine-based regimens before T-cell lymphocyte harvest has been debated, due to the detrimental impact on lymphocyte health and functions. Therefore, this drug may be dedicated to elderly population, especially above 70 years, due to its excellent activity and overall toxicity profile. Furthermore, since median PFS with both regimens exceeded 3 years, most patients will benefit from a sufficient time interval to allow T-lymphocytes to recover their initial function.
5. Conclusions
The BE vs. BAC study indicates that R-BAC, even when administered in the 2-day schedule or with attenuated dose, was associated with significantly more prolonged PFS than BR in elderly patients with previously untreated MCL. As hypothesized hematological toxicity was significantly higher for R-BAC regimen.
Long term follow-up of the R-BAC500 prospective study (NCT01662050, reference number 7) of the Fondazione Italiana Linfomi (FIL) is awaited to confirm our findings in an independent prospective setting.
Acknowledgments
The authors acknowledge AIL Verona Section, and Emilia Elizbieta Florea for the administrative assistance.
Author Contributions
Conceptualization, C.V. and G.B.; methodology, C.V.; recruited patients, G.B., J.O., M.R., G.S., R.P., S.F., R.S., E.L., G.G., D.F., M.C.T., M.B., L.B., F.P., I.F. and C.V.; formal analysis, C.V.; data curation, C.V. and G.B.; writing—original draft preparation, C.V. and G.B.; writing—review and editing, C.V. and G.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Verona University (protocol code 18448, date of approval 24 March 2021).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 PFS (a) and OS (b) of all 156 MCL patients. PFS (c) and OS (d) of all 156 MCL patients divided according to administered upfront treatment.
Figure 2 Overall survival from time of first relapse (OS-2) of MCL patients: (a) all 64 relapsed or refractory patients; (b) patients who had ibrutinib as second line (n = 33) versus other treated patients (n = 21); (c) patients experiencing early- (n = 31) versus late-POD (n = 33) after first line.
cancers-13-06089-t001_Table 1 Table 1 Baseline characteristics.
Variation Data (n = 156) BR (n = 53) R-BAC (n = 103) p-Values
Median age (years) 72 (53–80) 73 (53–80) 69 (54–80) 0.012
Sex
Male 109 (70%) 37 (70%) 72 (70%) 0.890
Female 47 (30%) 16 (30%) 31 (30%)
Ann Arbor stage
I–II 11 (10%) 4 (8%) 7 (7%) 0.862
III–IV 145 (90%) 49 (92%) 96 (93%)
Bone marrow involvement
Yes 127 (81%) 52 (98%) 75 (73%) 0.623
No 29 (19%) 1 (2%) 28 (27%)
Morphological variants
Classical 138 (89%) 46 (87%) 92 (89%) 0.901
Pleomorphic-Blastoid 18 (11%) 7 (13%) 11 (11%)
Ki 67 index
<30% 73 (47%) 21 (40%) 52 (50%) 0.442
≥30% 47 (30%) 14 (26%) 33 (32%)
n.d. 36 (23%) 18 (34%) 18 (18%)
MIPI
Low risk 11 (7%) 5 (10%) 6 (6%) 0.751 *
Intermediate risk 45 (29%) 15 (28%) 30 (29%)
High risk 100 (64%) 33 (62%) 67 (65%)
Data are n (%) unless indicated otherwise. MIPI = Mantle Cell Limphoma International Prognostic Index. * calculated as MIPI high vs. others.
cancers-13-06089-t002_Table 2 Table 2 Administered cycles, premature interruptions, and toxicity.
Variation BR (n = 53) R-BAC (n = 103) p-Value
Number of cycles
<4 8 (15%) 2 (2%) 0.001
≥4 11 (21%) 41 (40%) 0.016
6 34 (64%) 60 (58%) 0.474
Dose reduction
≥25% 10 (19%) 52 (51%) 0.008
Two-day schedule 42 (41%)
Toxicities
Anaemia grade 3–4 8 (15%) 32 (31%) 0.121
Neutropenia grade 3–4 20 (38%) 49 (48%) 0.531
Thrombocytopenia grade 3–4 9 (17%) 52 (50%) 0.004
Nonhaematological toxicity grade 3–4 13 (24%) 25 (24%) 1.000
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 34885198 | 20,232,219 | 2021-12-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Deep vein thrombosis'. | Mechanical thrombectomy of COVID-19 DVT with congenital heart disease leading to phlegmasia cerulea dolens: a case report.
BACKGROUND
COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both.
METHODS
A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated.
CONCLUSIONS
This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity.
pmcBackground
COVID-associated coagulopathy has recently been described [1] and COVID VTE is recognized to be significantly elevated in critically ill patients [2–4]. Patients with altered Fontan physiology have independently elevated risks of developing VTE due to decreased pulmonary arterial pressures. Meta-analyses are now reporting risk factors for DVT development including hypoalbuminemia and higher Sequential Organ Failure Assessment (SOFA) scores [5]. However the risk for VTE in the context of altered cardiopulmonary circulation due to congential heart disease (CHD) remains largely unknown.
Case presentation
A 51-year-old male with tricuspid atresia, status post atriopulmonary Fontan at 6 years of age with subsequent urgent surgical conversion to an extracardiac Fontan (Fig. 1) in the setting of a right atrial thrombus at 30 years of age. The patient initially presented to an outpatient clinic with cough and diarrhea. He was diagnosed with SARS-CoV-2 infection via nasopharyngeal swab. Six days later, he presented to a rural emergency room with progressive exertional dyspnea, and was found to be hypoxic and hypotensive. He was diagnosed with COVID-19 pneumonia (Fig. 2), the patient was placed on bilevel positive airway pressure (BiPAP) and vasopressor support. He received a course of remdesivir and was continued on tadalafil. Warfarin was held due to a supratherapeutic international normalized ratio (INR) greater than 14. His respiratory status improved and he was weaned to a non-rebreather mask. He developed bilateral leg pain during the hospitalization, and lower extremity venous ultrasound detected bilateral deep vein thromboses. Given these findings, he was urgently transferred to our institution on hospital day (HD) 7 for higher level of care (Table 1).Fig. 1 Central venogram highlighting Fontan circulation with extracardiac shunt. EC extracardiac Fontan conduit, RA right atrium, RPA right pulmonary artery, LPA left pulmonary artery
Fig. 2 Multifocal pneumonia consistent with clinical presentation and laboratory studies for COVID-19 (A, B). Subsequent axial and coronal slices showing resolution of COVID-19 pneumonia with pulmonary fibrosis (C, D)
Table 1 Timeline for the key events from initial presentation, hospitalization, and transfer to our institution
Day 1 Patient presentation to outpatient clinic with upper respiratory and gastrointestinal symptoms, diagnosed with SARS-CoV-2 infection via nasopharyngeal swab
Day 7 (OSH HD 1) Presentation to community hospital with hypoxia and hypotension with COVID-19 pneumonia requiring BiPAP and vasopressor support
Day 12 (HD 1) Patient transfered to our healthcare facility for higher level of care with subsequent mechanical thrombectomy of bilateral lower extremities
Day 13 Bilateral iliac filters retrieved with patent IVC and iliac veins
Day 41 Left below the knee amputation was performed
Day 50 Patient discharged to rehabilitation facility
OSHD Outside Hospital Day, HD Hospital Day (our institution)
Upon transfer, his INR was down-trending, but remained supratherapeutic at 6.6, and computed tomography venogram (CTV) demonstrated bilateral deep venous thrombosis from the iliac to calf veins, excluding the inferior vena cava (IVC). There was no evidence of pulmonary embolus. Physical exam was notable left lower leg findings pitting edema, purple discoloration (Figs. 3, 4), decreased sensation, and mobility. The laboratory workup was notable in particular for the supratherapeutic INR that was reduced to 1.6 by the second day of hospitalization at our institution, following treatment with Vitamin K. DIC panel and prothrombotic workup, including β-2 glycoprotein and cardiolipin antibodies, were negative (Table 2).Fig. 3 Painful, violaceous foot, concerning for venous outflow obstruction resulting in PCD
Fig. 4 Color-rendered 3D reconstruction of the pelvis outlining the patent arterial vasculature (aorta and bilateral iliac arteries) and IVC with bilateral venous thromboses. The white, green, and blue arrows indicate the abrupt completely occlusive thrombus of the proximal left common iliac vein, the occlusive thrombus of the right common femoral vein, and the iliac confluence into the IVC, respectively
Table 2 Relevant laboratory values on admission (Day 12/HD 1)
Value Normal range
White blood cell count 8.17 4.16–9.95 × 10E3/uL
Red blood cell count 3.22 4.41–5.95 × 10E6/uL
Hemoglobin 11.6 13.5–17.1 g/dL
Hematocrit 35.7 38.5–52.0%
Mean corpuscular volume 91.5 79.3–98.6 fL
Mean corpuscular hemoglobin 30.7 26.4–33.4 pg
MCH concentration 33.3 31.5–35.5 g/dL
Platelet count 137 143–398 × 10E3/uL
Ferritin 522 8–350 ng/mL
Prothrombin time 16.7 11.5–14.4 s
INR 6.6 < 1.1
APTT 78.5 24.4–36.2 s
D-dimer 5,164 ≤ 499 ng/mL FEU
Factor V (5) activity 113 > 50% act
Fibrinogen 526 235–490 mg/dL
Sodium 138 135–146 mmol/L
Potassium 4.1 3.6–5.3 mmol/L
Chloride 101 96–106 mmol/L
Total CO2 25 20–30 mmol/L
Anion gap 12 8–19 mmol/L
Glucose 115 65–99 mg/dL
GFR estimate for non-African American > 89 > 89 mL/min/1.73m2
Creatinine 0.96 0.60–1.30 mg/dL
Urea Nitrogen 24 7–22 mg/dL
Calcium 7.6 8.6–10.4 mg/dL
Magnesium 1.9 1.4–1.9 mEq/L
Phosphorus 2.7 2.3–4.4 mg/dL
Phosphorus 2.7 2.3–4.4 mg/dL
Lactate dehydrogenase 336 125–256 U/L
Total protein 5.8 6.1–8.2 g/dL
Albumin 2.2 3.9–5.0 g/dL
Bilirubin, total 3.2 0.1–1.2 mg/dL
Bilirubin, conjugated 2.6 ≤ 0.3 mg/dL
Alkaline phosphatase 63 37–113 U/L
Aspartate aminotransferase 32 13–47 U/L
Alanine aminotransferase 11 8–64 U/L
While the differential diagnosis of limb ischemia in the setting of COVID-19 infection includes arterial thrombosis, the demonstration of venous outflow obstruction (Fig. 4), violaceous discoloration of the lower extremity, pronounced edema, and pain confirmed the diagnosis of phlegmasia cerulea dolens (PCD). A heparin drip was initiated with vitamin K reversal of warfarin. Since his partial thromboplastin time (PTT) values were abnormal (Table 2), anti-Xa levels were used to titrate the heparin infusion. He also received convalescent plasma [6]. Arterial Doppler was notable for biphasic waveforms with excessive diastolic reversed flow concerning for developing compartment syndrome, without evidence of arterial thrombosis.
Following multidisciplinary evaluation, the decision was made undergo an emergent transvenous thrombectomy to salvage the left leg. Given the inflammatory nature of the clot and development of PCD in spite of supratherapeutic INR, mechanical thrombectomy was felt to be the most appropriate course of action [7] as opposed to ‘lyse and wait’ strategies that could prolong vascular compromise and also subject the patient to increased adverse bleeding events and the potential development of compartment syndrome.
Bilateral popliteal vein access was obtained for catheter directed mechanical thrombectomy using the ClotTriever® system (Inari Medical). Popliteal and Fontan pressures were 19 and 17 mmHg, respectively; pulmonary angiography did not demonstrate any emboli. Five thrombectomy passes of the left lower extremity from the popliteal vein to the IVC and four passes of the right leg successfully restored flow from the bilateral popliteal veins to the IVC (Fig. 5) and yielded thrombus that was positive for SARS-CoV-2 by polymerase chain reaction (PCR). In order to protect the cardiopulmonary circulation peri-procedurally during anticoagulation optimization, bilateral retrievable iliac vein filters (Optease) were placed. An IVC filter was not placed due to the large size of the cava. The iliac filters were retrieved on HD 12 via femoral approach (the right internal jugular vein was chronically occluded) following venograms confirming patent femoral and iliac veins. A left lower extremity cellulitis developed and empirically managed with antibiotics. The patient unfortunately did not have reversal of the ischemic changes post-procedure, requiring below-the-knee amputation (BKA) for dry gangrene of the left foot.Fig. 5 Post-thrombectomy lower extremity venograms (A) with corresponding photographs of the pathology-confirmed COVID-19-positive extracted thrombus from the left (B) and right (C) lower extremities
He experienced epistaxis while on heparin, that was treated with nasal packing. There was evidence of post-pneumonia fibrosis [8] (Fig. 2C and 2D); the associated increase in pulmonary vascular resistance is often not well tolerated in Fontan patients [9]. His tadalafil was increased to 40 mg daily from 20 mg daily to improve hemodynamics. His oxygen saturation was eventually maintained on room air and he never required mechanical ventilation. The BKA was well tolerated and on HD 50 he was discharged to an acute rehabilitation unit on warfarin.
Discussion and conclusions
Patients with a Fontan circulation are at higher risk for thrombus formation [10]. The systemic venous return drains directly into the pulmonary arteries, and the lack of a subpulmonary ventricle results in a low-flow state through the pulmonary arterial circuit. Pulmonary venous return thus depends on negative inspiratory intrathoracic pressure, low pulmonary vascular resistance, and diastolic function of the systemic ventricle. Increases in pulmonary vascular resistance due to pulmonary infections, positive-pressure ventilation, and/or atrial arrhythmias can all decrease pulmonary blood flow [10, 11]. Patients with COVID-19 infection are at higher risk for thrombosis due to multiple theorized factors, including an increased inflammatory state and endothelial cell dysfunction secondary to viral invasion [12, 13]. PCD in patients with COVID-19 has been reported [1], but thus far only in patients predisposed to thrombosis. In our case, our patient’s cardiac anatomy and physiology placed him in a higher risk category, and despite treatment with a vitamin K antagonist with supratherapeutic levels, he developed extensive bilateral venous thromboses. Interestingly his pulmonary circulation was intact and he did not develop any evidence of pulmonary emboli on CTA or pulmonary angiography.
PCD requires aggressive therapy for limb salvage [14], but resource limitations in heavily impacted hospitals during the COVID pandemic may result in delays in diagnosis and treatment. Nevertheless, the treatment this patient received likely prevented further leg ischemia and limited his amputation to below-the-knee instead of above-the-knee, which is associated with improved functionality and long-term outcomes [15].
Presently, the most effective anticoagulation strategy for patients with COVID-19 related thrombosis is unclear. Our patient developed no further thrombosis while on heparin, though notably this change was made after the COVID pneumonia was already improving.
Patients with comorbidities that place them in higher-risk categories for various disease states, such as Fontan circulation, are potentially at higher risk of complications from COVID-19. PCD is a rare but devastating complication, and must be recognized early and treated aggressively; mechanical thrombectomy may be indicated to expedite restoration of venous outflow, particularly when anticoagulation may be contraindicated. Pulmonary fibrosis secondary to COVID-19 may lead to increased pulmonary vascular resistance, which may further complicate the long-term course of Fontan patients in particular. Despite the presence of acute lung injury and extensive deep venous thromboses, our patient did not require mechanical ventilation or develop decompensated heart failure, reflecting a reassuring degree of resilience of this patient’s Fontan circulation in the face of COVID-19 infection.
Abbreviations
BKA Below-the-knee amputation
PCD Phlegmasia cerulea dolens
PTT Partial thromboplastin time
CTV Computed tomography venogram
IVC Inferior vena cava
HD Hospital day
BiPAP Bilevel positive airway pressure
VTE Venous thromboembolism
DIC Disseminated intravascular coagulation
PCR Polymerase chain reaction
Acknowledgements
Not applicable.
Authors' contributions
NJ, DF, JM were involved with acquisition of and interpretation of patient data. LR, GL, JA, and JL were involved with acquisition of data. NJ, DF, and WW drafted the manuscript with substantial revisions by JL. All authors contributed to the editing of the manuscript and agreed on the final content. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding authors on reasonable request.
Declarations
Ethics approval and consent to participate
The Institutional Review Board waived full board review for the presentation of this anonymized case report. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines.
Consent for publication
The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.
Competing interests
JM is a consultant for Argon Medical, Angiodynamics Inc, Boston Scientific Inc, Inari Medical, Penumbra Inc, BD Bard, Thrombolex Inc, and Pavmed Inc. The other authors have no conflicts to disclose.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | WARFARIN | DrugsGivenReaction | CC BY | 34886795 | 20,416,963 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Mechanical thrombectomy of COVID-19 DVT with congenital heart disease leading to phlegmasia cerulea dolens: a case report.
BACKGROUND
COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both.
METHODS
A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated.
CONCLUSIONS
This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity.
pmcBackground
COVID-associated coagulopathy has recently been described [1] and COVID VTE is recognized to be significantly elevated in critically ill patients [2–4]. Patients with altered Fontan physiology have independently elevated risks of developing VTE due to decreased pulmonary arterial pressures. Meta-analyses are now reporting risk factors for DVT development including hypoalbuminemia and higher Sequential Organ Failure Assessment (SOFA) scores [5]. However the risk for VTE in the context of altered cardiopulmonary circulation due to congential heart disease (CHD) remains largely unknown.
Case presentation
A 51-year-old male with tricuspid atresia, status post atriopulmonary Fontan at 6 years of age with subsequent urgent surgical conversion to an extracardiac Fontan (Fig. 1) in the setting of a right atrial thrombus at 30 years of age. The patient initially presented to an outpatient clinic with cough and diarrhea. He was diagnosed with SARS-CoV-2 infection via nasopharyngeal swab. Six days later, he presented to a rural emergency room with progressive exertional dyspnea, and was found to be hypoxic and hypotensive. He was diagnosed with COVID-19 pneumonia (Fig. 2), the patient was placed on bilevel positive airway pressure (BiPAP) and vasopressor support. He received a course of remdesivir and was continued on tadalafil. Warfarin was held due to a supratherapeutic international normalized ratio (INR) greater than 14. His respiratory status improved and he was weaned to a non-rebreather mask. He developed bilateral leg pain during the hospitalization, and lower extremity venous ultrasound detected bilateral deep vein thromboses. Given these findings, he was urgently transferred to our institution on hospital day (HD) 7 for higher level of care (Table 1).Fig. 1 Central venogram highlighting Fontan circulation with extracardiac shunt. EC extracardiac Fontan conduit, RA right atrium, RPA right pulmonary artery, LPA left pulmonary artery
Fig. 2 Multifocal pneumonia consistent with clinical presentation and laboratory studies for COVID-19 (A, B). Subsequent axial and coronal slices showing resolution of COVID-19 pneumonia with pulmonary fibrosis (C, D)
Table 1 Timeline for the key events from initial presentation, hospitalization, and transfer to our institution
Day 1 Patient presentation to outpatient clinic with upper respiratory and gastrointestinal symptoms, diagnosed with SARS-CoV-2 infection via nasopharyngeal swab
Day 7 (OSH HD 1) Presentation to community hospital with hypoxia and hypotension with COVID-19 pneumonia requiring BiPAP and vasopressor support
Day 12 (HD 1) Patient transfered to our healthcare facility for higher level of care with subsequent mechanical thrombectomy of bilateral lower extremities
Day 13 Bilateral iliac filters retrieved with patent IVC and iliac veins
Day 41 Left below the knee amputation was performed
Day 50 Patient discharged to rehabilitation facility
OSHD Outside Hospital Day, HD Hospital Day (our institution)
Upon transfer, his INR was down-trending, but remained supratherapeutic at 6.6, and computed tomography venogram (CTV) demonstrated bilateral deep venous thrombosis from the iliac to calf veins, excluding the inferior vena cava (IVC). There was no evidence of pulmonary embolus. Physical exam was notable left lower leg findings pitting edema, purple discoloration (Figs. 3, 4), decreased sensation, and mobility. The laboratory workup was notable in particular for the supratherapeutic INR that was reduced to 1.6 by the second day of hospitalization at our institution, following treatment with Vitamin K. DIC panel and prothrombotic workup, including β-2 glycoprotein and cardiolipin antibodies, were negative (Table 2).Fig. 3 Painful, violaceous foot, concerning for venous outflow obstruction resulting in PCD
Fig. 4 Color-rendered 3D reconstruction of the pelvis outlining the patent arterial vasculature (aorta and bilateral iliac arteries) and IVC with bilateral venous thromboses. The white, green, and blue arrows indicate the abrupt completely occlusive thrombus of the proximal left common iliac vein, the occlusive thrombus of the right common femoral vein, and the iliac confluence into the IVC, respectively
Table 2 Relevant laboratory values on admission (Day 12/HD 1)
Value Normal range
White blood cell count 8.17 4.16–9.95 × 10E3/uL
Red blood cell count 3.22 4.41–5.95 × 10E6/uL
Hemoglobin 11.6 13.5–17.1 g/dL
Hematocrit 35.7 38.5–52.0%
Mean corpuscular volume 91.5 79.3–98.6 fL
Mean corpuscular hemoglobin 30.7 26.4–33.4 pg
MCH concentration 33.3 31.5–35.5 g/dL
Platelet count 137 143–398 × 10E3/uL
Ferritin 522 8–350 ng/mL
Prothrombin time 16.7 11.5–14.4 s
INR 6.6 < 1.1
APTT 78.5 24.4–36.2 s
D-dimer 5,164 ≤ 499 ng/mL FEU
Factor V (5) activity 113 > 50% act
Fibrinogen 526 235–490 mg/dL
Sodium 138 135–146 mmol/L
Potassium 4.1 3.6–5.3 mmol/L
Chloride 101 96–106 mmol/L
Total CO2 25 20–30 mmol/L
Anion gap 12 8–19 mmol/L
Glucose 115 65–99 mg/dL
GFR estimate for non-African American > 89 > 89 mL/min/1.73m2
Creatinine 0.96 0.60–1.30 mg/dL
Urea Nitrogen 24 7–22 mg/dL
Calcium 7.6 8.6–10.4 mg/dL
Magnesium 1.9 1.4–1.9 mEq/L
Phosphorus 2.7 2.3–4.4 mg/dL
Phosphorus 2.7 2.3–4.4 mg/dL
Lactate dehydrogenase 336 125–256 U/L
Total protein 5.8 6.1–8.2 g/dL
Albumin 2.2 3.9–5.0 g/dL
Bilirubin, total 3.2 0.1–1.2 mg/dL
Bilirubin, conjugated 2.6 ≤ 0.3 mg/dL
Alkaline phosphatase 63 37–113 U/L
Aspartate aminotransferase 32 13–47 U/L
Alanine aminotransferase 11 8–64 U/L
While the differential diagnosis of limb ischemia in the setting of COVID-19 infection includes arterial thrombosis, the demonstration of venous outflow obstruction (Fig. 4), violaceous discoloration of the lower extremity, pronounced edema, and pain confirmed the diagnosis of phlegmasia cerulea dolens (PCD). A heparin drip was initiated with vitamin K reversal of warfarin. Since his partial thromboplastin time (PTT) values were abnormal (Table 2), anti-Xa levels were used to titrate the heparin infusion. He also received convalescent plasma [6]. Arterial Doppler was notable for biphasic waveforms with excessive diastolic reversed flow concerning for developing compartment syndrome, without evidence of arterial thrombosis.
Following multidisciplinary evaluation, the decision was made undergo an emergent transvenous thrombectomy to salvage the left leg. Given the inflammatory nature of the clot and development of PCD in spite of supratherapeutic INR, mechanical thrombectomy was felt to be the most appropriate course of action [7] as opposed to ‘lyse and wait’ strategies that could prolong vascular compromise and also subject the patient to increased adverse bleeding events and the potential development of compartment syndrome.
Bilateral popliteal vein access was obtained for catheter directed mechanical thrombectomy using the ClotTriever® system (Inari Medical). Popliteal and Fontan pressures were 19 and 17 mmHg, respectively; pulmonary angiography did not demonstrate any emboli. Five thrombectomy passes of the left lower extremity from the popliteal vein to the IVC and four passes of the right leg successfully restored flow from the bilateral popliteal veins to the IVC (Fig. 5) and yielded thrombus that was positive for SARS-CoV-2 by polymerase chain reaction (PCR). In order to protect the cardiopulmonary circulation peri-procedurally during anticoagulation optimization, bilateral retrievable iliac vein filters (Optease) were placed. An IVC filter was not placed due to the large size of the cava. The iliac filters were retrieved on HD 12 via femoral approach (the right internal jugular vein was chronically occluded) following venograms confirming patent femoral and iliac veins. A left lower extremity cellulitis developed and empirically managed with antibiotics. The patient unfortunately did not have reversal of the ischemic changes post-procedure, requiring below-the-knee amputation (BKA) for dry gangrene of the left foot.Fig. 5 Post-thrombectomy lower extremity venograms (A) with corresponding photographs of the pathology-confirmed COVID-19-positive extracted thrombus from the left (B) and right (C) lower extremities
He experienced epistaxis while on heparin, that was treated with nasal packing. There was evidence of post-pneumonia fibrosis [8] (Fig. 2C and 2D); the associated increase in pulmonary vascular resistance is often not well tolerated in Fontan patients [9]. His tadalafil was increased to 40 mg daily from 20 mg daily to improve hemodynamics. His oxygen saturation was eventually maintained on room air and he never required mechanical ventilation. The BKA was well tolerated and on HD 50 he was discharged to an acute rehabilitation unit on warfarin.
Discussion and conclusions
Patients with a Fontan circulation are at higher risk for thrombus formation [10]. The systemic venous return drains directly into the pulmonary arteries, and the lack of a subpulmonary ventricle results in a low-flow state through the pulmonary arterial circuit. Pulmonary venous return thus depends on negative inspiratory intrathoracic pressure, low pulmonary vascular resistance, and diastolic function of the systemic ventricle. Increases in pulmonary vascular resistance due to pulmonary infections, positive-pressure ventilation, and/or atrial arrhythmias can all decrease pulmonary blood flow [10, 11]. Patients with COVID-19 infection are at higher risk for thrombosis due to multiple theorized factors, including an increased inflammatory state and endothelial cell dysfunction secondary to viral invasion [12, 13]. PCD in patients with COVID-19 has been reported [1], but thus far only in patients predisposed to thrombosis. In our case, our patient’s cardiac anatomy and physiology placed him in a higher risk category, and despite treatment with a vitamin K antagonist with supratherapeutic levels, he developed extensive bilateral venous thromboses. Interestingly his pulmonary circulation was intact and he did not develop any evidence of pulmonary emboli on CTA or pulmonary angiography.
PCD requires aggressive therapy for limb salvage [14], but resource limitations in heavily impacted hospitals during the COVID pandemic may result in delays in diagnosis and treatment. Nevertheless, the treatment this patient received likely prevented further leg ischemia and limited his amputation to below-the-knee instead of above-the-knee, which is associated with improved functionality and long-term outcomes [15].
Presently, the most effective anticoagulation strategy for patients with COVID-19 related thrombosis is unclear. Our patient developed no further thrombosis while on heparin, though notably this change was made after the COVID pneumonia was already improving.
Patients with comorbidities that place them in higher-risk categories for various disease states, such as Fontan circulation, are potentially at higher risk of complications from COVID-19. PCD is a rare but devastating complication, and must be recognized early and treated aggressively; mechanical thrombectomy may be indicated to expedite restoration of venous outflow, particularly when anticoagulation may be contraindicated. Pulmonary fibrosis secondary to COVID-19 may lead to increased pulmonary vascular resistance, which may further complicate the long-term course of Fontan patients in particular. Despite the presence of acute lung injury and extensive deep venous thromboses, our patient did not require mechanical ventilation or develop decompensated heart failure, reflecting a reassuring degree of resilience of this patient’s Fontan circulation in the face of COVID-19 infection.
Abbreviations
BKA Below-the-knee amputation
PCD Phlegmasia cerulea dolens
PTT Partial thromboplastin time
CTV Computed tomography venogram
IVC Inferior vena cava
HD Hospital day
BiPAP Bilevel positive airway pressure
VTE Venous thromboembolism
DIC Disseminated intravascular coagulation
PCR Polymerase chain reaction
Acknowledgements
Not applicable.
Authors' contributions
NJ, DF, JM were involved with acquisition of and interpretation of patient data. LR, GL, JA, and JL were involved with acquisition of data. NJ, DF, and WW drafted the manuscript with substantial revisions by JL. All authors contributed to the editing of the manuscript and agreed on the final content. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding authors on reasonable request.
Declarations
Ethics approval and consent to participate
The Institutional Review Board waived full board review for the presentation of this anonymized case report. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines.
Consent for publication
The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.
Competing interests
JM is a consultant for Argon Medical, Angiodynamics Inc, Boston Scientific Inc, Inari Medical, Penumbra Inc, BD Bard, Thrombolex Inc, and Pavmed Inc. The other authors have no conflicts to disclose.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | HEPARIN SODIUM, HUMAN PLASMA, REMDESIVIR, TADALAFIL, WARFARIN | DrugsGivenReaction | CC BY | 34886795 | 20,391,609 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epistaxis'. | Mechanical thrombectomy of COVID-19 DVT with congenital heart disease leading to phlegmasia cerulea dolens: a case report.
BACKGROUND
COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both.
METHODS
A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated.
CONCLUSIONS
This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity.
pmcBackground
COVID-associated coagulopathy has recently been described [1] and COVID VTE is recognized to be significantly elevated in critically ill patients [2–4]. Patients with altered Fontan physiology have independently elevated risks of developing VTE due to decreased pulmonary arterial pressures. Meta-analyses are now reporting risk factors for DVT development including hypoalbuminemia and higher Sequential Organ Failure Assessment (SOFA) scores [5]. However the risk for VTE in the context of altered cardiopulmonary circulation due to congential heart disease (CHD) remains largely unknown.
Case presentation
A 51-year-old male with tricuspid atresia, status post atriopulmonary Fontan at 6 years of age with subsequent urgent surgical conversion to an extracardiac Fontan (Fig. 1) in the setting of a right atrial thrombus at 30 years of age. The patient initially presented to an outpatient clinic with cough and diarrhea. He was diagnosed with SARS-CoV-2 infection via nasopharyngeal swab. Six days later, he presented to a rural emergency room with progressive exertional dyspnea, and was found to be hypoxic and hypotensive. He was diagnosed with COVID-19 pneumonia (Fig. 2), the patient was placed on bilevel positive airway pressure (BiPAP) and vasopressor support. He received a course of remdesivir and was continued on tadalafil. Warfarin was held due to a supratherapeutic international normalized ratio (INR) greater than 14. His respiratory status improved and he was weaned to a non-rebreather mask. He developed bilateral leg pain during the hospitalization, and lower extremity venous ultrasound detected bilateral deep vein thromboses. Given these findings, he was urgently transferred to our institution on hospital day (HD) 7 for higher level of care (Table 1).Fig. 1 Central venogram highlighting Fontan circulation with extracardiac shunt. EC extracardiac Fontan conduit, RA right atrium, RPA right pulmonary artery, LPA left pulmonary artery
Fig. 2 Multifocal pneumonia consistent with clinical presentation and laboratory studies for COVID-19 (A, B). Subsequent axial and coronal slices showing resolution of COVID-19 pneumonia with pulmonary fibrosis (C, D)
Table 1 Timeline for the key events from initial presentation, hospitalization, and transfer to our institution
Day 1 Patient presentation to outpatient clinic with upper respiratory and gastrointestinal symptoms, diagnosed with SARS-CoV-2 infection via nasopharyngeal swab
Day 7 (OSH HD 1) Presentation to community hospital with hypoxia and hypotension with COVID-19 pneumonia requiring BiPAP and vasopressor support
Day 12 (HD 1) Patient transfered to our healthcare facility for higher level of care with subsequent mechanical thrombectomy of bilateral lower extremities
Day 13 Bilateral iliac filters retrieved with patent IVC and iliac veins
Day 41 Left below the knee amputation was performed
Day 50 Patient discharged to rehabilitation facility
OSHD Outside Hospital Day, HD Hospital Day (our institution)
Upon transfer, his INR was down-trending, but remained supratherapeutic at 6.6, and computed tomography venogram (CTV) demonstrated bilateral deep venous thrombosis from the iliac to calf veins, excluding the inferior vena cava (IVC). There was no evidence of pulmonary embolus. Physical exam was notable left lower leg findings pitting edema, purple discoloration (Figs. 3, 4), decreased sensation, and mobility. The laboratory workup was notable in particular for the supratherapeutic INR that was reduced to 1.6 by the second day of hospitalization at our institution, following treatment with Vitamin K. DIC panel and prothrombotic workup, including β-2 glycoprotein and cardiolipin antibodies, were negative (Table 2).Fig. 3 Painful, violaceous foot, concerning for venous outflow obstruction resulting in PCD
Fig. 4 Color-rendered 3D reconstruction of the pelvis outlining the patent arterial vasculature (aorta and bilateral iliac arteries) and IVC with bilateral venous thromboses. The white, green, and blue arrows indicate the abrupt completely occlusive thrombus of the proximal left common iliac vein, the occlusive thrombus of the right common femoral vein, and the iliac confluence into the IVC, respectively
Table 2 Relevant laboratory values on admission (Day 12/HD 1)
Value Normal range
White blood cell count 8.17 4.16–9.95 × 10E3/uL
Red blood cell count 3.22 4.41–5.95 × 10E6/uL
Hemoglobin 11.6 13.5–17.1 g/dL
Hematocrit 35.7 38.5–52.0%
Mean corpuscular volume 91.5 79.3–98.6 fL
Mean corpuscular hemoglobin 30.7 26.4–33.4 pg
MCH concentration 33.3 31.5–35.5 g/dL
Platelet count 137 143–398 × 10E3/uL
Ferritin 522 8–350 ng/mL
Prothrombin time 16.7 11.5–14.4 s
INR 6.6 < 1.1
APTT 78.5 24.4–36.2 s
D-dimer 5,164 ≤ 499 ng/mL FEU
Factor V (5) activity 113 > 50% act
Fibrinogen 526 235–490 mg/dL
Sodium 138 135–146 mmol/L
Potassium 4.1 3.6–5.3 mmol/L
Chloride 101 96–106 mmol/L
Total CO2 25 20–30 mmol/L
Anion gap 12 8–19 mmol/L
Glucose 115 65–99 mg/dL
GFR estimate for non-African American > 89 > 89 mL/min/1.73m2
Creatinine 0.96 0.60–1.30 mg/dL
Urea Nitrogen 24 7–22 mg/dL
Calcium 7.6 8.6–10.4 mg/dL
Magnesium 1.9 1.4–1.9 mEq/L
Phosphorus 2.7 2.3–4.4 mg/dL
Phosphorus 2.7 2.3–4.4 mg/dL
Lactate dehydrogenase 336 125–256 U/L
Total protein 5.8 6.1–8.2 g/dL
Albumin 2.2 3.9–5.0 g/dL
Bilirubin, total 3.2 0.1–1.2 mg/dL
Bilirubin, conjugated 2.6 ≤ 0.3 mg/dL
Alkaline phosphatase 63 37–113 U/L
Aspartate aminotransferase 32 13–47 U/L
Alanine aminotransferase 11 8–64 U/L
While the differential diagnosis of limb ischemia in the setting of COVID-19 infection includes arterial thrombosis, the demonstration of venous outflow obstruction (Fig. 4), violaceous discoloration of the lower extremity, pronounced edema, and pain confirmed the diagnosis of phlegmasia cerulea dolens (PCD). A heparin drip was initiated with vitamin K reversal of warfarin. Since his partial thromboplastin time (PTT) values were abnormal (Table 2), anti-Xa levels were used to titrate the heparin infusion. He also received convalescent plasma [6]. Arterial Doppler was notable for biphasic waveforms with excessive diastolic reversed flow concerning for developing compartment syndrome, without evidence of arterial thrombosis.
Following multidisciplinary evaluation, the decision was made undergo an emergent transvenous thrombectomy to salvage the left leg. Given the inflammatory nature of the clot and development of PCD in spite of supratherapeutic INR, mechanical thrombectomy was felt to be the most appropriate course of action [7] as opposed to ‘lyse and wait’ strategies that could prolong vascular compromise and also subject the patient to increased adverse bleeding events and the potential development of compartment syndrome.
Bilateral popliteal vein access was obtained for catheter directed mechanical thrombectomy using the ClotTriever® system (Inari Medical). Popliteal and Fontan pressures were 19 and 17 mmHg, respectively; pulmonary angiography did not demonstrate any emboli. Five thrombectomy passes of the left lower extremity from the popliteal vein to the IVC and four passes of the right leg successfully restored flow from the bilateral popliteal veins to the IVC (Fig. 5) and yielded thrombus that was positive for SARS-CoV-2 by polymerase chain reaction (PCR). In order to protect the cardiopulmonary circulation peri-procedurally during anticoagulation optimization, bilateral retrievable iliac vein filters (Optease) were placed. An IVC filter was not placed due to the large size of the cava. The iliac filters were retrieved on HD 12 via femoral approach (the right internal jugular vein was chronically occluded) following venograms confirming patent femoral and iliac veins. A left lower extremity cellulitis developed and empirically managed with antibiotics. The patient unfortunately did not have reversal of the ischemic changes post-procedure, requiring below-the-knee amputation (BKA) for dry gangrene of the left foot.Fig. 5 Post-thrombectomy lower extremity venograms (A) with corresponding photographs of the pathology-confirmed COVID-19-positive extracted thrombus from the left (B) and right (C) lower extremities
He experienced epistaxis while on heparin, that was treated with nasal packing. There was evidence of post-pneumonia fibrosis [8] (Fig. 2C and 2D); the associated increase in pulmonary vascular resistance is often not well tolerated in Fontan patients [9]. His tadalafil was increased to 40 mg daily from 20 mg daily to improve hemodynamics. His oxygen saturation was eventually maintained on room air and he never required mechanical ventilation. The BKA was well tolerated and on HD 50 he was discharged to an acute rehabilitation unit on warfarin.
Discussion and conclusions
Patients with a Fontan circulation are at higher risk for thrombus formation [10]. The systemic venous return drains directly into the pulmonary arteries, and the lack of a subpulmonary ventricle results in a low-flow state through the pulmonary arterial circuit. Pulmonary venous return thus depends on negative inspiratory intrathoracic pressure, low pulmonary vascular resistance, and diastolic function of the systemic ventricle. Increases in pulmonary vascular resistance due to pulmonary infections, positive-pressure ventilation, and/or atrial arrhythmias can all decrease pulmonary blood flow [10, 11]. Patients with COVID-19 infection are at higher risk for thrombosis due to multiple theorized factors, including an increased inflammatory state and endothelial cell dysfunction secondary to viral invasion [12, 13]. PCD in patients with COVID-19 has been reported [1], but thus far only in patients predisposed to thrombosis. In our case, our patient’s cardiac anatomy and physiology placed him in a higher risk category, and despite treatment with a vitamin K antagonist with supratherapeutic levels, he developed extensive bilateral venous thromboses. Interestingly his pulmonary circulation was intact and he did not develop any evidence of pulmonary emboli on CTA or pulmonary angiography.
PCD requires aggressive therapy for limb salvage [14], but resource limitations in heavily impacted hospitals during the COVID pandemic may result in delays in diagnosis and treatment. Nevertheless, the treatment this patient received likely prevented further leg ischemia and limited his amputation to below-the-knee instead of above-the-knee, which is associated with improved functionality and long-term outcomes [15].
Presently, the most effective anticoagulation strategy for patients with COVID-19 related thrombosis is unclear. Our patient developed no further thrombosis while on heparin, though notably this change was made after the COVID pneumonia was already improving.
Patients with comorbidities that place them in higher-risk categories for various disease states, such as Fontan circulation, are potentially at higher risk of complications from COVID-19. PCD is a rare but devastating complication, and must be recognized early and treated aggressively; mechanical thrombectomy may be indicated to expedite restoration of venous outflow, particularly when anticoagulation may be contraindicated. Pulmonary fibrosis secondary to COVID-19 may lead to increased pulmonary vascular resistance, which may further complicate the long-term course of Fontan patients in particular. Despite the presence of acute lung injury and extensive deep venous thromboses, our patient did not require mechanical ventilation or develop decompensated heart failure, reflecting a reassuring degree of resilience of this patient’s Fontan circulation in the face of COVID-19 infection.
Abbreviations
BKA Below-the-knee amputation
PCD Phlegmasia cerulea dolens
PTT Partial thromboplastin time
CTV Computed tomography venogram
IVC Inferior vena cava
HD Hospital day
BiPAP Bilevel positive airway pressure
VTE Venous thromboembolism
DIC Disseminated intravascular coagulation
PCR Polymerase chain reaction
Acknowledgements
Not applicable.
Authors' contributions
NJ, DF, JM were involved with acquisition of and interpretation of patient data. LR, GL, JA, and JL were involved with acquisition of data. NJ, DF, and WW drafted the manuscript with substantial revisions by JL. All authors contributed to the editing of the manuscript and agreed on the final content. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding authors on reasonable request.
Declarations
Ethics approval and consent to participate
The Institutional Review Board waived full board review for the presentation of this anonymized case report. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines.
Consent for publication
The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.
Competing interests
JM is a consultant for Argon Medical, Angiodynamics Inc, Boston Scientific Inc, Inari Medical, Penumbra Inc, BD Bard, Thrombolex Inc, and Pavmed Inc. The other authors have no conflicts to disclose.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | HEPARIN SODIUM, HUMAN PLASMA, REMDESIVIR, TADALAFIL, WARFARIN | DrugsGivenReaction | CC BY | 34886795 | 20,391,609 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'International normalised ratio increased'. | Mechanical thrombectomy of COVID-19 DVT with congenital heart disease leading to phlegmasia cerulea dolens: a case report.
BACKGROUND
COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both.
METHODS
A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated.
CONCLUSIONS
This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity.
pmcBackground
COVID-associated coagulopathy has recently been described [1] and COVID VTE is recognized to be significantly elevated in critically ill patients [2–4]. Patients with altered Fontan physiology have independently elevated risks of developing VTE due to decreased pulmonary arterial pressures. Meta-analyses are now reporting risk factors for DVT development including hypoalbuminemia and higher Sequential Organ Failure Assessment (SOFA) scores [5]. However the risk for VTE in the context of altered cardiopulmonary circulation due to congential heart disease (CHD) remains largely unknown.
Case presentation
A 51-year-old male with tricuspid atresia, status post atriopulmonary Fontan at 6 years of age with subsequent urgent surgical conversion to an extracardiac Fontan (Fig. 1) in the setting of a right atrial thrombus at 30 years of age. The patient initially presented to an outpatient clinic with cough and diarrhea. He was diagnosed with SARS-CoV-2 infection via nasopharyngeal swab. Six days later, he presented to a rural emergency room with progressive exertional dyspnea, and was found to be hypoxic and hypotensive. He was diagnosed with COVID-19 pneumonia (Fig. 2), the patient was placed on bilevel positive airway pressure (BiPAP) and vasopressor support. He received a course of remdesivir and was continued on tadalafil. Warfarin was held due to a supratherapeutic international normalized ratio (INR) greater than 14. His respiratory status improved and he was weaned to a non-rebreather mask. He developed bilateral leg pain during the hospitalization, and lower extremity venous ultrasound detected bilateral deep vein thromboses. Given these findings, he was urgently transferred to our institution on hospital day (HD) 7 for higher level of care (Table 1).Fig. 1 Central venogram highlighting Fontan circulation with extracardiac shunt. EC extracardiac Fontan conduit, RA right atrium, RPA right pulmonary artery, LPA left pulmonary artery
Fig. 2 Multifocal pneumonia consistent with clinical presentation and laboratory studies for COVID-19 (A, B). Subsequent axial and coronal slices showing resolution of COVID-19 pneumonia with pulmonary fibrosis (C, D)
Table 1 Timeline for the key events from initial presentation, hospitalization, and transfer to our institution
Day 1 Patient presentation to outpatient clinic with upper respiratory and gastrointestinal symptoms, diagnosed with SARS-CoV-2 infection via nasopharyngeal swab
Day 7 (OSH HD 1) Presentation to community hospital with hypoxia and hypotension with COVID-19 pneumonia requiring BiPAP and vasopressor support
Day 12 (HD 1) Patient transfered to our healthcare facility for higher level of care with subsequent mechanical thrombectomy of bilateral lower extremities
Day 13 Bilateral iliac filters retrieved with patent IVC and iliac veins
Day 41 Left below the knee amputation was performed
Day 50 Patient discharged to rehabilitation facility
OSHD Outside Hospital Day, HD Hospital Day (our institution)
Upon transfer, his INR was down-trending, but remained supratherapeutic at 6.6, and computed tomography venogram (CTV) demonstrated bilateral deep venous thrombosis from the iliac to calf veins, excluding the inferior vena cava (IVC). There was no evidence of pulmonary embolus. Physical exam was notable left lower leg findings pitting edema, purple discoloration (Figs. 3, 4), decreased sensation, and mobility. The laboratory workup was notable in particular for the supratherapeutic INR that was reduced to 1.6 by the second day of hospitalization at our institution, following treatment with Vitamin K. DIC panel and prothrombotic workup, including β-2 glycoprotein and cardiolipin antibodies, were negative (Table 2).Fig. 3 Painful, violaceous foot, concerning for venous outflow obstruction resulting in PCD
Fig. 4 Color-rendered 3D reconstruction of the pelvis outlining the patent arterial vasculature (aorta and bilateral iliac arteries) and IVC with bilateral venous thromboses. The white, green, and blue arrows indicate the abrupt completely occlusive thrombus of the proximal left common iliac vein, the occlusive thrombus of the right common femoral vein, and the iliac confluence into the IVC, respectively
Table 2 Relevant laboratory values on admission (Day 12/HD 1)
Value Normal range
White blood cell count 8.17 4.16–9.95 × 10E3/uL
Red blood cell count 3.22 4.41–5.95 × 10E6/uL
Hemoglobin 11.6 13.5–17.1 g/dL
Hematocrit 35.7 38.5–52.0%
Mean corpuscular volume 91.5 79.3–98.6 fL
Mean corpuscular hemoglobin 30.7 26.4–33.4 pg
MCH concentration 33.3 31.5–35.5 g/dL
Platelet count 137 143–398 × 10E3/uL
Ferritin 522 8–350 ng/mL
Prothrombin time 16.7 11.5–14.4 s
INR 6.6 < 1.1
APTT 78.5 24.4–36.2 s
D-dimer 5,164 ≤ 499 ng/mL FEU
Factor V (5) activity 113 > 50% act
Fibrinogen 526 235–490 mg/dL
Sodium 138 135–146 mmol/L
Potassium 4.1 3.6–5.3 mmol/L
Chloride 101 96–106 mmol/L
Total CO2 25 20–30 mmol/L
Anion gap 12 8–19 mmol/L
Glucose 115 65–99 mg/dL
GFR estimate for non-African American > 89 > 89 mL/min/1.73m2
Creatinine 0.96 0.60–1.30 mg/dL
Urea Nitrogen 24 7–22 mg/dL
Calcium 7.6 8.6–10.4 mg/dL
Magnesium 1.9 1.4–1.9 mEq/L
Phosphorus 2.7 2.3–4.4 mg/dL
Phosphorus 2.7 2.3–4.4 mg/dL
Lactate dehydrogenase 336 125–256 U/L
Total protein 5.8 6.1–8.2 g/dL
Albumin 2.2 3.9–5.0 g/dL
Bilirubin, total 3.2 0.1–1.2 mg/dL
Bilirubin, conjugated 2.6 ≤ 0.3 mg/dL
Alkaline phosphatase 63 37–113 U/L
Aspartate aminotransferase 32 13–47 U/L
Alanine aminotransferase 11 8–64 U/L
While the differential diagnosis of limb ischemia in the setting of COVID-19 infection includes arterial thrombosis, the demonstration of venous outflow obstruction (Fig. 4), violaceous discoloration of the lower extremity, pronounced edema, and pain confirmed the diagnosis of phlegmasia cerulea dolens (PCD). A heparin drip was initiated with vitamin K reversal of warfarin. Since his partial thromboplastin time (PTT) values were abnormal (Table 2), anti-Xa levels were used to titrate the heparin infusion. He also received convalescent plasma [6]. Arterial Doppler was notable for biphasic waveforms with excessive diastolic reversed flow concerning for developing compartment syndrome, without evidence of arterial thrombosis.
Following multidisciplinary evaluation, the decision was made undergo an emergent transvenous thrombectomy to salvage the left leg. Given the inflammatory nature of the clot and development of PCD in spite of supratherapeutic INR, mechanical thrombectomy was felt to be the most appropriate course of action [7] as opposed to ‘lyse and wait’ strategies that could prolong vascular compromise and also subject the patient to increased adverse bleeding events and the potential development of compartment syndrome.
Bilateral popliteal vein access was obtained for catheter directed mechanical thrombectomy using the ClotTriever® system (Inari Medical). Popliteal and Fontan pressures were 19 and 17 mmHg, respectively; pulmonary angiography did not demonstrate any emboli. Five thrombectomy passes of the left lower extremity from the popliteal vein to the IVC and four passes of the right leg successfully restored flow from the bilateral popliteal veins to the IVC (Fig. 5) and yielded thrombus that was positive for SARS-CoV-2 by polymerase chain reaction (PCR). In order to protect the cardiopulmonary circulation peri-procedurally during anticoagulation optimization, bilateral retrievable iliac vein filters (Optease) were placed. An IVC filter was not placed due to the large size of the cava. The iliac filters were retrieved on HD 12 via femoral approach (the right internal jugular vein was chronically occluded) following venograms confirming patent femoral and iliac veins. A left lower extremity cellulitis developed and empirically managed with antibiotics. The patient unfortunately did not have reversal of the ischemic changes post-procedure, requiring below-the-knee amputation (BKA) for dry gangrene of the left foot.Fig. 5 Post-thrombectomy lower extremity venograms (A) with corresponding photographs of the pathology-confirmed COVID-19-positive extracted thrombus from the left (B) and right (C) lower extremities
He experienced epistaxis while on heparin, that was treated with nasal packing. There was evidence of post-pneumonia fibrosis [8] (Fig. 2C and 2D); the associated increase in pulmonary vascular resistance is often not well tolerated in Fontan patients [9]. His tadalafil was increased to 40 mg daily from 20 mg daily to improve hemodynamics. His oxygen saturation was eventually maintained on room air and he never required mechanical ventilation. The BKA was well tolerated and on HD 50 he was discharged to an acute rehabilitation unit on warfarin.
Discussion and conclusions
Patients with a Fontan circulation are at higher risk for thrombus formation [10]. The systemic venous return drains directly into the pulmonary arteries, and the lack of a subpulmonary ventricle results in a low-flow state through the pulmonary arterial circuit. Pulmonary venous return thus depends on negative inspiratory intrathoracic pressure, low pulmonary vascular resistance, and diastolic function of the systemic ventricle. Increases in pulmonary vascular resistance due to pulmonary infections, positive-pressure ventilation, and/or atrial arrhythmias can all decrease pulmonary blood flow [10, 11]. Patients with COVID-19 infection are at higher risk for thrombosis due to multiple theorized factors, including an increased inflammatory state and endothelial cell dysfunction secondary to viral invasion [12, 13]. PCD in patients with COVID-19 has been reported [1], but thus far only in patients predisposed to thrombosis. In our case, our patient’s cardiac anatomy and physiology placed him in a higher risk category, and despite treatment with a vitamin K antagonist with supratherapeutic levels, he developed extensive bilateral venous thromboses. Interestingly his pulmonary circulation was intact and he did not develop any evidence of pulmonary emboli on CTA or pulmonary angiography.
PCD requires aggressive therapy for limb salvage [14], but resource limitations in heavily impacted hospitals during the COVID pandemic may result in delays in diagnosis and treatment. Nevertheless, the treatment this patient received likely prevented further leg ischemia and limited his amputation to below-the-knee instead of above-the-knee, which is associated with improved functionality and long-term outcomes [15].
Presently, the most effective anticoagulation strategy for patients with COVID-19 related thrombosis is unclear. Our patient developed no further thrombosis while on heparin, though notably this change was made after the COVID pneumonia was already improving.
Patients with comorbidities that place them in higher-risk categories for various disease states, such as Fontan circulation, are potentially at higher risk of complications from COVID-19. PCD is a rare but devastating complication, and must be recognized early and treated aggressively; mechanical thrombectomy may be indicated to expedite restoration of venous outflow, particularly when anticoagulation may be contraindicated. Pulmonary fibrosis secondary to COVID-19 may lead to increased pulmonary vascular resistance, which may further complicate the long-term course of Fontan patients in particular. Despite the presence of acute lung injury and extensive deep venous thromboses, our patient did not require mechanical ventilation or develop decompensated heart failure, reflecting a reassuring degree of resilience of this patient’s Fontan circulation in the face of COVID-19 infection.
Abbreviations
BKA Below-the-knee amputation
PCD Phlegmasia cerulea dolens
PTT Partial thromboplastin time
CTV Computed tomography venogram
IVC Inferior vena cava
HD Hospital day
BiPAP Bilevel positive airway pressure
VTE Venous thromboembolism
DIC Disseminated intravascular coagulation
PCR Polymerase chain reaction
Acknowledgements
Not applicable.
Authors' contributions
NJ, DF, JM were involved with acquisition of and interpretation of patient data. LR, GL, JA, and JL were involved with acquisition of data. NJ, DF, and WW drafted the manuscript with substantial revisions by JL. All authors contributed to the editing of the manuscript and agreed on the final content. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding authors on reasonable request.
Declarations
Ethics approval and consent to participate
The Institutional Review Board waived full board review for the presentation of this anonymized case report. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines.
Consent for publication
The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.
Competing interests
JM is a consultant for Argon Medical, Angiodynamics Inc, Boston Scientific Inc, Inari Medical, Penumbra Inc, BD Bard, Thrombolex Inc, and Pavmed Inc. The other authors have no conflicts to disclose.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | WARFARIN | DrugsGivenReaction | CC BY | 34886795 | 20,416,963 | 2021-12-09 |
What was the dosage of drug 'HEPARIN SODIUM'? | Mechanical thrombectomy of COVID-19 DVT with congenital heart disease leading to phlegmasia cerulea dolens: a case report.
BACKGROUND
COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both.
METHODS
A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated.
CONCLUSIONS
This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity.
pmcBackground
COVID-associated coagulopathy has recently been described [1] and COVID VTE is recognized to be significantly elevated in critically ill patients [2–4]. Patients with altered Fontan physiology have independently elevated risks of developing VTE due to decreased pulmonary arterial pressures. Meta-analyses are now reporting risk factors for DVT development including hypoalbuminemia and higher Sequential Organ Failure Assessment (SOFA) scores [5]. However the risk for VTE in the context of altered cardiopulmonary circulation due to congential heart disease (CHD) remains largely unknown.
Case presentation
A 51-year-old male with tricuspid atresia, status post atriopulmonary Fontan at 6 years of age with subsequent urgent surgical conversion to an extracardiac Fontan (Fig. 1) in the setting of a right atrial thrombus at 30 years of age. The patient initially presented to an outpatient clinic with cough and diarrhea. He was diagnosed with SARS-CoV-2 infection via nasopharyngeal swab. Six days later, he presented to a rural emergency room with progressive exertional dyspnea, and was found to be hypoxic and hypotensive. He was diagnosed with COVID-19 pneumonia (Fig. 2), the patient was placed on bilevel positive airway pressure (BiPAP) and vasopressor support. He received a course of remdesivir and was continued on tadalafil. Warfarin was held due to a supratherapeutic international normalized ratio (INR) greater than 14. His respiratory status improved and he was weaned to a non-rebreather mask. He developed bilateral leg pain during the hospitalization, and lower extremity venous ultrasound detected bilateral deep vein thromboses. Given these findings, he was urgently transferred to our institution on hospital day (HD) 7 for higher level of care (Table 1).Fig. 1 Central venogram highlighting Fontan circulation with extracardiac shunt. EC extracardiac Fontan conduit, RA right atrium, RPA right pulmonary artery, LPA left pulmonary artery
Fig. 2 Multifocal pneumonia consistent with clinical presentation and laboratory studies for COVID-19 (A, B). Subsequent axial and coronal slices showing resolution of COVID-19 pneumonia with pulmonary fibrosis (C, D)
Table 1 Timeline for the key events from initial presentation, hospitalization, and transfer to our institution
Day 1 Patient presentation to outpatient clinic with upper respiratory and gastrointestinal symptoms, diagnosed with SARS-CoV-2 infection via nasopharyngeal swab
Day 7 (OSH HD 1) Presentation to community hospital with hypoxia and hypotension with COVID-19 pneumonia requiring BiPAP and vasopressor support
Day 12 (HD 1) Patient transfered to our healthcare facility for higher level of care with subsequent mechanical thrombectomy of bilateral lower extremities
Day 13 Bilateral iliac filters retrieved with patent IVC and iliac veins
Day 41 Left below the knee amputation was performed
Day 50 Patient discharged to rehabilitation facility
OSHD Outside Hospital Day, HD Hospital Day (our institution)
Upon transfer, his INR was down-trending, but remained supratherapeutic at 6.6, and computed tomography venogram (CTV) demonstrated bilateral deep venous thrombosis from the iliac to calf veins, excluding the inferior vena cava (IVC). There was no evidence of pulmonary embolus. Physical exam was notable left lower leg findings pitting edema, purple discoloration (Figs. 3, 4), decreased sensation, and mobility. The laboratory workup was notable in particular for the supratherapeutic INR that was reduced to 1.6 by the second day of hospitalization at our institution, following treatment with Vitamin K. DIC panel and prothrombotic workup, including β-2 glycoprotein and cardiolipin antibodies, were negative (Table 2).Fig. 3 Painful, violaceous foot, concerning for venous outflow obstruction resulting in PCD
Fig. 4 Color-rendered 3D reconstruction of the pelvis outlining the patent arterial vasculature (aorta and bilateral iliac arteries) and IVC with bilateral venous thromboses. The white, green, and blue arrows indicate the abrupt completely occlusive thrombus of the proximal left common iliac vein, the occlusive thrombus of the right common femoral vein, and the iliac confluence into the IVC, respectively
Table 2 Relevant laboratory values on admission (Day 12/HD 1)
Value Normal range
White blood cell count 8.17 4.16–9.95 × 10E3/uL
Red blood cell count 3.22 4.41–5.95 × 10E6/uL
Hemoglobin 11.6 13.5–17.1 g/dL
Hematocrit 35.7 38.5–52.0%
Mean corpuscular volume 91.5 79.3–98.6 fL
Mean corpuscular hemoglobin 30.7 26.4–33.4 pg
MCH concentration 33.3 31.5–35.5 g/dL
Platelet count 137 143–398 × 10E3/uL
Ferritin 522 8–350 ng/mL
Prothrombin time 16.7 11.5–14.4 s
INR 6.6 < 1.1
APTT 78.5 24.4–36.2 s
D-dimer 5,164 ≤ 499 ng/mL FEU
Factor V (5) activity 113 > 50% act
Fibrinogen 526 235–490 mg/dL
Sodium 138 135–146 mmol/L
Potassium 4.1 3.6–5.3 mmol/L
Chloride 101 96–106 mmol/L
Total CO2 25 20–30 mmol/L
Anion gap 12 8–19 mmol/L
Glucose 115 65–99 mg/dL
GFR estimate for non-African American > 89 > 89 mL/min/1.73m2
Creatinine 0.96 0.60–1.30 mg/dL
Urea Nitrogen 24 7–22 mg/dL
Calcium 7.6 8.6–10.4 mg/dL
Magnesium 1.9 1.4–1.9 mEq/L
Phosphorus 2.7 2.3–4.4 mg/dL
Phosphorus 2.7 2.3–4.4 mg/dL
Lactate dehydrogenase 336 125–256 U/L
Total protein 5.8 6.1–8.2 g/dL
Albumin 2.2 3.9–5.0 g/dL
Bilirubin, total 3.2 0.1–1.2 mg/dL
Bilirubin, conjugated 2.6 ≤ 0.3 mg/dL
Alkaline phosphatase 63 37–113 U/L
Aspartate aminotransferase 32 13–47 U/L
Alanine aminotransferase 11 8–64 U/L
While the differential diagnosis of limb ischemia in the setting of COVID-19 infection includes arterial thrombosis, the demonstration of venous outflow obstruction (Fig. 4), violaceous discoloration of the lower extremity, pronounced edema, and pain confirmed the diagnosis of phlegmasia cerulea dolens (PCD). A heparin drip was initiated with vitamin K reversal of warfarin. Since his partial thromboplastin time (PTT) values were abnormal (Table 2), anti-Xa levels were used to titrate the heparin infusion. He also received convalescent plasma [6]. Arterial Doppler was notable for biphasic waveforms with excessive diastolic reversed flow concerning for developing compartment syndrome, without evidence of arterial thrombosis.
Following multidisciplinary evaluation, the decision was made undergo an emergent transvenous thrombectomy to salvage the left leg. Given the inflammatory nature of the clot and development of PCD in spite of supratherapeutic INR, mechanical thrombectomy was felt to be the most appropriate course of action [7] as opposed to ‘lyse and wait’ strategies that could prolong vascular compromise and also subject the patient to increased adverse bleeding events and the potential development of compartment syndrome.
Bilateral popliteal vein access was obtained for catheter directed mechanical thrombectomy using the ClotTriever® system (Inari Medical). Popliteal and Fontan pressures were 19 and 17 mmHg, respectively; pulmonary angiography did not demonstrate any emboli. Five thrombectomy passes of the left lower extremity from the popliteal vein to the IVC and four passes of the right leg successfully restored flow from the bilateral popliteal veins to the IVC (Fig. 5) and yielded thrombus that was positive for SARS-CoV-2 by polymerase chain reaction (PCR). In order to protect the cardiopulmonary circulation peri-procedurally during anticoagulation optimization, bilateral retrievable iliac vein filters (Optease) were placed. An IVC filter was not placed due to the large size of the cava. The iliac filters were retrieved on HD 12 via femoral approach (the right internal jugular vein was chronically occluded) following venograms confirming patent femoral and iliac veins. A left lower extremity cellulitis developed and empirically managed with antibiotics. The patient unfortunately did not have reversal of the ischemic changes post-procedure, requiring below-the-knee amputation (BKA) for dry gangrene of the left foot.Fig. 5 Post-thrombectomy lower extremity venograms (A) with corresponding photographs of the pathology-confirmed COVID-19-positive extracted thrombus from the left (B) and right (C) lower extremities
He experienced epistaxis while on heparin, that was treated with nasal packing. There was evidence of post-pneumonia fibrosis [8] (Fig. 2C and 2D); the associated increase in pulmonary vascular resistance is often not well tolerated in Fontan patients [9]. His tadalafil was increased to 40 mg daily from 20 mg daily to improve hemodynamics. His oxygen saturation was eventually maintained on room air and he never required mechanical ventilation. The BKA was well tolerated and on HD 50 he was discharged to an acute rehabilitation unit on warfarin.
Discussion and conclusions
Patients with a Fontan circulation are at higher risk for thrombus formation [10]. The systemic venous return drains directly into the pulmonary arteries, and the lack of a subpulmonary ventricle results in a low-flow state through the pulmonary arterial circuit. Pulmonary venous return thus depends on negative inspiratory intrathoracic pressure, low pulmonary vascular resistance, and diastolic function of the systemic ventricle. Increases in pulmonary vascular resistance due to pulmonary infections, positive-pressure ventilation, and/or atrial arrhythmias can all decrease pulmonary blood flow [10, 11]. Patients with COVID-19 infection are at higher risk for thrombosis due to multiple theorized factors, including an increased inflammatory state and endothelial cell dysfunction secondary to viral invasion [12, 13]. PCD in patients with COVID-19 has been reported [1], but thus far only in patients predisposed to thrombosis. In our case, our patient’s cardiac anatomy and physiology placed him in a higher risk category, and despite treatment with a vitamin K antagonist with supratherapeutic levels, he developed extensive bilateral venous thromboses. Interestingly his pulmonary circulation was intact and he did not develop any evidence of pulmonary emboli on CTA or pulmonary angiography.
PCD requires aggressive therapy for limb salvage [14], but resource limitations in heavily impacted hospitals during the COVID pandemic may result in delays in diagnosis and treatment. Nevertheless, the treatment this patient received likely prevented further leg ischemia and limited his amputation to below-the-knee instead of above-the-knee, which is associated with improved functionality and long-term outcomes [15].
Presently, the most effective anticoagulation strategy for patients with COVID-19 related thrombosis is unclear. Our patient developed no further thrombosis while on heparin, though notably this change was made after the COVID pneumonia was already improving.
Patients with comorbidities that place them in higher-risk categories for various disease states, such as Fontan circulation, are potentially at higher risk of complications from COVID-19. PCD is a rare but devastating complication, and must be recognized early and treated aggressively; mechanical thrombectomy may be indicated to expedite restoration of venous outflow, particularly when anticoagulation may be contraindicated. Pulmonary fibrosis secondary to COVID-19 may lead to increased pulmonary vascular resistance, which may further complicate the long-term course of Fontan patients in particular. Despite the presence of acute lung injury and extensive deep venous thromboses, our patient did not require mechanical ventilation or develop decompensated heart failure, reflecting a reassuring degree of resilience of this patient’s Fontan circulation in the face of COVID-19 infection.
Abbreviations
BKA Below-the-knee amputation
PCD Phlegmasia cerulea dolens
PTT Partial thromboplastin time
CTV Computed tomography venogram
IVC Inferior vena cava
HD Hospital day
BiPAP Bilevel positive airway pressure
VTE Venous thromboembolism
DIC Disseminated intravascular coagulation
PCR Polymerase chain reaction
Acknowledgements
Not applicable.
Authors' contributions
NJ, DF, JM were involved with acquisition of and interpretation of patient data. LR, GL, JA, and JL were involved with acquisition of data. NJ, DF, and WW drafted the manuscript with substantial revisions by JL. All authors contributed to the editing of the manuscript and agreed on the final content. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding authors on reasonable request.
Declarations
Ethics approval and consent to participate
The Institutional Review Board waived full board review for the presentation of this anonymized case report. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines.
Consent for publication
The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.
Competing interests
JM is a consultant for Argon Medical, Angiodynamics Inc, Boston Scientific Inc, Inari Medical, Penumbra Inc, BD Bard, Thrombolex Inc, and Pavmed Inc. The other authors have no conflicts to disclose.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | DRIP | DrugDosageText | CC BY | 34886795 | 20,391,609 | 2021-12-09 |
What was the outcome of reaction 'Deep vein thrombosis'? | Mechanical thrombectomy of COVID-19 DVT with congenital heart disease leading to phlegmasia cerulea dolens: a case report.
BACKGROUND
COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both.
METHODS
A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated.
CONCLUSIONS
This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity.
pmcBackground
COVID-associated coagulopathy has recently been described [1] and COVID VTE is recognized to be significantly elevated in critically ill patients [2–4]. Patients with altered Fontan physiology have independently elevated risks of developing VTE due to decreased pulmonary arterial pressures. Meta-analyses are now reporting risk factors for DVT development including hypoalbuminemia and higher Sequential Organ Failure Assessment (SOFA) scores [5]. However the risk for VTE in the context of altered cardiopulmonary circulation due to congential heart disease (CHD) remains largely unknown.
Case presentation
A 51-year-old male with tricuspid atresia, status post atriopulmonary Fontan at 6 years of age with subsequent urgent surgical conversion to an extracardiac Fontan (Fig. 1) in the setting of a right atrial thrombus at 30 years of age. The patient initially presented to an outpatient clinic with cough and diarrhea. He was diagnosed with SARS-CoV-2 infection via nasopharyngeal swab. Six days later, he presented to a rural emergency room with progressive exertional dyspnea, and was found to be hypoxic and hypotensive. He was diagnosed with COVID-19 pneumonia (Fig. 2), the patient was placed on bilevel positive airway pressure (BiPAP) and vasopressor support. He received a course of remdesivir and was continued on tadalafil. Warfarin was held due to a supratherapeutic international normalized ratio (INR) greater than 14. His respiratory status improved and he was weaned to a non-rebreather mask. He developed bilateral leg pain during the hospitalization, and lower extremity venous ultrasound detected bilateral deep vein thromboses. Given these findings, he was urgently transferred to our institution on hospital day (HD) 7 for higher level of care (Table 1).Fig. 1 Central venogram highlighting Fontan circulation with extracardiac shunt. EC extracardiac Fontan conduit, RA right atrium, RPA right pulmonary artery, LPA left pulmonary artery
Fig. 2 Multifocal pneumonia consistent with clinical presentation and laboratory studies for COVID-19 (A, B). Subsequent axial and coronal slices showing resolution of COVID-19 pneumonia with pulmonary fibrosis (C, D)
Table 1 Timeline for the key events from initial presentation, hospitalization, and transfer to our institution
Day 1 Patient presentation to outpatient clinic with upper respiratory and gastrointestinal symptoms, diagnosed with SARS-CoV-2 infection via nasopharyngeal swab
Day 7 (OSH HD 1) Presentation to community hospital with hypoxia and hypotension with COVID-19 pneumonia requiring BiPAP and vasopressor support
Day 12 (HD 1) Patient transfered to our healthcare facility for higher level of care with subsequent mechanical thrombectomy of bilateral lower extremities
Day 13 Bilateral iliac filters retrieved with patent IVC and iliac veins
Day 41 Left below the knee amputation was performed
Day 50 Patient discharged to rehabilitation facility
OSHD Outside Hospital Day, HD Hospital Day (our institution)
Upon transfer, his INR was down-trending, but remained supratherapeutic at 6.6, and computed tomography venogram (CTV) demonstrated bilateral deep venous thrombosis from the iliac to calf veins, excluding the inferior vena cava (IVC). There was no evidence of pulmonary embolus. Physical exam was notable left lower leg findings pitting edema, purple discoloration (Figs. 3, 4), decreased sensation, and mobility. The laboratory workup was notable in particular for the supratherapeutic INR that was reduced to 1.6 by the second day of hospitalization at our institution, following treatment with Vitamin K. DIC panel and prothrombotic workup, including β-2 glycoprotein and cardiolipin antibodies, were negative (Table 2).Fig. 3 Painful, violaceous foot, concerning for venous outflow obstruction resulting in PCD
Fig. 4 Color-rendered 3D reconstruction of the pelvis outlining the patent arterial vasculature (aorta and bilateral iliac arteries) and IVC with bilateral venous thromboses. The white, green, and blue arrows indicate the abrupt completely occlusive thrombus of the proximal left common iliac vein, the occlusive thrombus of the right common femoral vein, and the iliac confluence into the IVC, respectively
Table 2 Relevant laboratory values on admission (Day 12/HD 1)
Value Normal range
White blood cell count 8.17 4.16–9.95 × 10E3/uL
Red blood cell count 3.22 4.41–5.95 × 10E6/uL
Hemoglobin 11.6 13.5–17.1 g/dL
Hematocrit 35.7 38.5–52.0%
Mean corpuscular volume 91.5 79.3–98.6 fL
Mean corpuscular hemoglobin 30.7 26.4–33.4 pg
MCH concentration 33.3 31.5–35.5 g/dL
Platelet count 137 143–398 × 10E3/uL
Ferritin 522 8–350 ng/mL
Prothrombin time 16.7 11.5–14.4 s
INR 6.6 < 1.1
APTT 78.5 24.4–36.2 s
D-dimer 5,164 ≤ 499 ng/mL FEU
Factor V (5) activity 113 > 50% act
Fibrinogen 526 235–490 mg/dL
Sodium 138 135–146 mmol/L
Potassium 4.1 3.6–5.3 mmol/L
Chloride 101 96–106 mmol/L
Total CO2 25 20–30 mmol/L
Anion gap 12 8–19 mmol/L
Glucose 115 65–99 mg/dL
GFR estimate for non-African American > 89 > 89 mL/min/1.73m2
Creatinine 0.96 0.60–1.30 mg/dL
Urea Nitrogen 24 7–22 mg/dL
Calcium 7.6 8.6–10.4 mg/dL
Magnesium 1.9 1.4–1.9 mEq/L
Phosphorus 2.7 2.3–4.4 mg/dL
Phosphorus 2.7 2.3–4.4 mg/dL
Lactate dehydrogenase 336 125–256 U/L
Total protein 5.8 6.1–8.2 g/dL
Albumin 2.2 3.9–5.0 g/dL
Bilirubin, total 3.2 0.1–1.2 mg/dL
Bilirubin, conjugated 2.6 ≤ 0.3 mg/dL
Alkaline phosphatase 63 37–113 U/L
Aspartate aminotransferase 32 13–47 U/L
Alanine aminotransferase 11 8–64 U/L
While the differential diagnosis of limb ischemia in the setting of COVID-19 infection includes arterial thrombosis, the demonstration of venous outflow obstruction (Fig. 4), violaceous discoloration of the lower extremity, pronounced edema, and pain confirmed the diagnosis of phlegmasia cerulea dolens (PCD). A heparin drip was initiated with vitamin K reversal of warfarin. Since his partial thromboplastin time (PTT) values were abnormal (Table 2), anti-Xa levels were used to titrate the heparin infusion. He also received convalescent plasma [6]. Arterial Doppler was notable for biphasic waveforms with excessive diastolic reversed flow concerning for developing compartment syndrome, without evidence of arterial thrombosis.
Following multidisciplinary evaluation, the decision was made undergo an emergent transvenous thrombectomy to salvage the left leg. Given the inflammatory nature of the clot and development of PCD in spite of supratherapeutic INR, mechanical thrombectomy was felt to be the most appropriate course of action [7] as opposed to ‘lyse and wait’ strategies that could prolong vascular compromise and also subject the patient to increased adverse bleeding events and the potential development of compartment syndrome.
Bilateral popliteal vein access was obtained for catheter directed mechanical thrombectomy using the ClotTriever® system (Inari Medical). Popliteal and Fontan pressures were 19 and 17 mmHg, respectively; pulmonary angiography did not demonstrate any emboli. Five thrombectomy passes of the left lower extremity from the popliteal vein to the IVC and four passes of the right leg successfully restored flow from the bilateral popliteal veins to the IVC (Fig. 5) and yielded thrombus that was positive for SARS-CoV-2 by polymerase chain reaction (PCR). In order to protect the cardiopulmonary circulation peri-procedurally during anticoagulation optimization, bilateral retrievable iliac vein filters (Optease) were placed. An IVC filter was not placed due to the large size of the cava. The iliac filters were retrieved on HD 12 via femoral approach (the right internal jugular vein was chronically occluded) following venograms confirming patent femoral and iliac veins. A left lower extremity cellulitis developed and empirically managed with antibiotics. The patient unfortunately did not have reversal of the ischemic changes post-procedure, requiring below-the-knee amputation (BKA) for dry gangrene of the left foot.Fig. 5 Post-thrombectomy lower extremity venograms (A) with corresponding photographs of the pathology-confirmed COVID-19-positive extracted thrombus from the left (B) and right (C) lower extremities
He experienced epistaxis while on heparin, that was treated with nasal packing. There was evidence of post-pneumonia fibrosis [8] (Fig. 2C and 2D); the associated increase in pulmonary vascular resistance is often not well tolerated in Fontan patients [9]. His tadalafil was increased to 40 mg daily from 20 mg daily to improve hemodynamics. His oxygen saturation was eventually maintained on room air and he never required mechanical ventilation. The BKA was well tolerated and on HD 50 he was discharged to an acute rehabilitation unit on warfarin.
Discussion and conclusions
Patients with a Fontan circulation are at higher risk for thrombus formation [10]. The systemic venous return drains directly into the pulmonary arteries, and the lack of a subpulmonary ventricle results in a low-flow state through the pulmonary arterial circuit. Pulmonary venous return thus depends on negative inspiratory intrathoracic pressure, low pulmonary vascular resistance, and diastolic function of the systemic ventricle. Increases in pulmonary vascular resistance due to pulmonary infections, positive-pressure ventilation, and/or atrial arrhythmias can all decrease pulmonary blood flow [10, 11]. Patients with COVID-19 infection are at higher risk for thrombosis due to multiple theorized factors, including an increased inflammatory state and endothelial cell dysfunction secondary to viral invasion [12, 13]. PCD in patients with COVID-19 has been reported [1], but thus far only in patients predisposed to thrombosis. In our case, our patient’s cardiac anatomy and physiology placed him in a higher risk category, and despite treatment with a vitamin K antagonist with supratherapeutic levels, he developed extensive bilateral venous thromboses. Interestingly his pulmonary circulation was intact and he did not develop any evidence of pulmonary emboli on CTA or pulmonary angiography.
PCD requires aggressive therapy for limb salvage [14], but resource limitations in heavily impacted hospitals during the COVID pandemic may result in delays in diagnosis and treatment. Nevertheless, the treatment this patient received likely prevented further leg ischemia and limited his amputation to below-the-knee instead of above-the-knee, which is associated with improved functionality and long-term outcomes [15].
Presently, the most effective anticoagulation strategy for patients with COVID-19 related thrombosis is unclear. Our patient developed no further thrombosis while on heparin, though notably this change was made after the COVID pneumonia was already improving.
Patients with comorbidities that place them in higher-risk categories for various disease states, such as Fontan circulation, are potentially at higher risk of complications from COVID-19. PCD is a rare but devastating complication, and must be recognized early and treated aggressively; mechanical thrombectomy may be indicated to expedite restoration of venous outflow, particularly when anticoagulation may be contraindicated. Pulmonary fibrosis secondary to COVID-19 may lead to increased pulmonary vascular resistance, which may further complicate the long-term course of Fontan patients in particular. Despite the presence of acute lung injury and extensive deep venous thromboses, our patient did not require mechanical ventilation or develop decompensated heart failure, reflecting a reassuring degree of resilience of this patient’s Fontan circulation in the face of COVID-19 infection.
Abbreviations
BKA Below-the-knee amputation
PCD Phlegmasia cerulea dolens
PTT Partial thromboplastin time
CTV Computed tomography venogram
IVC Inferior vena cava
HD Hospital day
BiPAP Bilevel positive airway pressure
VTE Venous thromboembolism
DIC Disseminated intravascular coagulation
PCR Polymerase chain reaction
Acknowledgements
Not applicable.
Authors' contributions
NJ, DF, JM were involved with acquisition of and interpretation of patient data. LR, GL, JA, and JL were involved with acquisition of data. NJ, DF, and WW drafted the manuscript with substantial revisions by JL. All authors contributed to the editing of the manuscript and agreed on the final content. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding authors on reasonable request.
Declarations
Ethics approval and consent to participate
The Institutional Review Board waived full board review for the presentation of this anonymized case report. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines.
Consent for publication
The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.
Competing interests
JM is a consultant for Argon Medical, Angiodynamics Inc, Boston Scientific Inc, Inari Medical, Penumbra Inc, BD Bard, Thrombolex Inc, and Pavmed Inc. The other authors have no conflicts to disclose.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 34886795 | 20,416,963 | 2021-12-09 |
What was the outcome of reaction 'Epistaxis'? | Mechanical thrombectomy of COVID-19 DVT with congenital heart disease leading to phlegmasia cerulea dolens: a case report.
BACKGROUND
COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both.
METHODS
A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated.
CONCLUSIONS
This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity.
pmcBackground
COVID-associated coagulopathy has recently been described [1] and COVID VTE is recognized to be significantly elevated in critically ill patients [2–4]. Patients with altered Fontan physiology have independently elevated risks of developing VTE due to decreased pulmonary arterial pressures. Meta-analyses are now reporting risk factors for DVT development including hypoalbuminemia and higher Sequential Organ Failure Assessment (SOFA) scores [5]. However the risk for VTE in the context of altered cardiopulmonary circulation due to congential heart disease (CHD) remains largely unknown.
Case presentation
A 51-year-old male with tricuspid atresia, status post atriopulmonary Fontan at 6 years of age with subsequent urgent surgical conversion to an extracardiac Fontan (Fig. 1) in the setting of a right atrial thrombus at 30 years of age. The patient initially presented to an outpatient clinic with cough and diarrhea. He was diagnosed with SARS-CoV-2 infection via nasopharyngeal swab. Six days later, he presented to a rural emergency room with progressive exertional dyspnea, and was found to be hypoxic and hypotensive. He was diagnosed with COVID-19 pneumonia (Fig. 2), the patient was placed on bilevel positive airway pressure (BiPAP) and vasopressor support. He received a course of remdesivir and was continued on tadalafil. Warfarin was held due to a supratherapeutic international normalized ratio (INR) greater than 14. His respiratory status improved and he was weaned to a non-rebreather mask. He developed bilateral leg pain during the hospitalization, and lower extremity venous ultrasound detected bilateral deep vein thromboses. Given these findings, he was urgently transferred to our institution on hospital day (HD) 7 for higher level of care (Table 1).Fig. 1 Central venogram highlighting Fontan circulation with extracardiac shunt. EC extracardiac Fontan conduit, RA right atrium, RPA right pulmonary artery, LPA left pulmonary artery
Fig. 2 Multifocal pneumonia consistent with clinical presentation and laboratory studies for COVID-19 (A, B). Subsequent axial and coronal slices showing resolution of COVID-19 pneumonia with pulmonary fibrosis (C, D)
Table 1 Timeline for the key events from initial presentation, hospitalization, and transfer to our institution
Day 1 Patient presentation to outpatient clinic with upper respiratory and gastrointestinal symptoms, diagnosed with SARS-CoV-2 infection via nasopharyngeal swab
Day 7 (OSH HD 1) Presentation to community hospital with hypoxia and hypotension with COVID-19 pneumonia requiring BiPAP and vasopressor support
Day 12 (HD 1) Patient transfered to our healthcare facility for higher level of care with subsequent mechanical thrombectomy of bilateral lower extremities
Day 13 Bilateral iliac filters retrieved with patent IVC and iliac veins
Day 41 Left below the knee amputation was performed
Day 50 Patient discharged to rehabilitation facility
OSHD Outside Hospital Day, HD Hospital Day (our institution)
Upon transfer, his INR was down-trending, but remained supratherapeutic at 6.6, and computed tomography venogram (CTV) demonstrated bilateral deep venous thrombosis from the iliac to calf veins, excluding the inferior vena cava (IVC). There was no evidence of pulmonary embolus. Physical exam was notable left lower leg findings pitting edema, purple discoloration (Figs. 3, 4), decreased sensation, and mobility. The laboratory workup was notable in particular for the supratherapeutic INR that was reduced to 1.6 by the second day of hospitalization at our institution, following treatment with Vitamin K. DIC panel and prothrombotic workup, including β-2 glycoprotein and cardiolipin antibodies, were negative (Table 2).Fig. 3 Painful, violaceous foot, concerning for venous outflow obstruction resulting in PCD
Fig. 4 Color-rendered 3D reconstruction of the pelvis outlining the patent arterial vasculature (aorta and bilateral iliac arteries) and IVC with bilateral venous thromboses. The white, green, and blue arrows indicate the abrupt completely occlusive thrombus of the proximal left common iliac vein, the occlusive thrombus of the right common femoral vein, and the iliac confluence into the IVC, respectively
Table 2 Relevant laboratory values on admission (Day 12/HD 1)
Value Normal range
White blood cell count 8.17 4.16–9.95 × 10E3/uL
Red blood cell count 3.22 4.41–5.95 × 10E6/uL
Hemoglobin 11.6 13.5–17.1 g/dL
Hematocrit 35.7 38.5–52.0%
Mean corpuscular volume 91.5 79.3–98.6 fL
Mean corpuscular hemoglobin 30.7 26.4–33.4 pg
MCH concentration 33.3 31.5–35.5 g/dL
Platelet count 137 143–398 × 10E3/uL
Ferritin 522 8–350 ng/mL
Prothrombin time 16.7 11.5–14.4 s
INR 6.6 < 1.1
APTT 78.5 24.4–36.2 s
D-dimer 5,164 ≤ 499 ng/mL FEU
Factor V (5) activity 113 > 50% act
Fibrinogen 526 235–490 mg/dL
Sodium 138 135–146 mmol/L
Potassium 4.1 3.6–5.3 mmol/L
Chloride 101 96–106 mmol/L
Total CO2 25 20–30 mmol/L
Anion gap 12 8–19 mmol/L
Glucose 115 65–99 mg/dL
GFR estimate for non-African American > 89 > 89 mL/min/1.73m2
Creatinine 0.96 0.60–1.30 mg/dL
Urea Nitrogen 24 7–22 mg/dL
Calcium 7.6 8.6–10.4 mg/dL
Magnesium 1.9 1.4–1.9 mEq/L
Phosphorus 2.7 2.3–4.4 mg/dL
Phosphorus 2.7 2.3–4.4 mg/dL
Lactate dehydrogenase 336 125–256 U/L
Total protein 5.8 6.1–8.2 g/dL
Albumin 2.2 3.9–5.0 g/dL
Bilirubin, total 3.2 0.1–1.2 mg/dL
Bilirubin, conjugated 2.6 ≤ 0.3 mg/dL
Alkaline phosphatase 63 37–113 U/L
Aspartate aminotransferase 32 13–47 U/L
Alanine aminotransferase 11 8–64 U/L
While the differential diagnosis of limb ischemia in the setting of COVID-19 infection includes arterial thrombosis, the demonstration of venous outflow obstruction (Fig. 4), violaceous discoloration of the lower extremity, pronounced edema, and pain confirmed the diagnosis of phlegmasia cerulea dolens (PCD). A heparin drip was initiated with vitamin K reversal of warfarin. Since his partial thromboplastin time (PTT) values were abnormal (Table 2), anti-Xa levels were used to titrate the heparin infusion. He also received convalescent plasma [6]. Arterial Doppler was notable for biphasic waveforms with excessive diastolic reversed flow concerning for developing compartment syndrome, without evidence of arterial thrombosis.
Following multidisciplinary evaluation, the decision was made undergo an emergent transvenous thrombectomy to salvage the left leg. Given the inflammatory nature of the clot and development of PCD in spite of supratherapeutic INR, mechanical thrombectomy was felt to be the most appropriate course of action [7] as opposed to ‘lyse and wait’ strategies that could prolong vascular compromise and also subject the patient to increased adverse bleeding events and the potential development of compartment syndrome.
Bilateral popliteal vein access was obtained for catheter directed mechanical thrombectomy using the ClotTriever® system (Inari Medical). Popliteal and Fontan pressures were 19 and 17 mmHg, respectively; pulmonary angiography did not demonstrate any emboli. Five thrombectomy passes of the left lower extremity from the popliteal vein to the IVC and four passes of the right leg successfully restored flow from the bilateral popliteal veins to the IVC (Fig. 5) and yielded thrombus that was positive for SARS-CoV-2 by polymerase chain reaction (PCR). In order to protect the cardiopulmonary circulation peri-procedurally during anticoagulation optimization, bilateral retrievable iliac vein filters (Optease) were placed. An IVC filter was not placed due to the large size of the cava. The iliac filters were retrieved on HD 12 via femoral approach (the right internal jugular vein was chronically occluded) following venograms confirming patent femoral and iliac veins. A left lower extremity cellulitis developed and empirically managed with antibiotics. The patient unfortunately did not have reversal of the ischemic changes post-procedure, requiring below-the-knee amputation (BKA) for dry gangrene of the left foot.Fig. 5 Post-thrombectomy lower extremity venograms (A) with corresponding photographs of the pathology-confirmed COVID-19-positive extracted thrombus from the left (B) and right (C) lower extremities
He experienced epistaxis while on heparin, that was treated with nasal packing. There was evidence of post-pneumonia fibrosis [8] (Fig. 2C and 2D); the associated increase in pulmonary vascular resistance is often not well tolerated in Fontan patients [9]. His tadalafil was increased to 40 mg daily from 20 mg daily to improve hemodynamics. His oxygen saturation was eventually maintained on room air and he never required mechanical ventilation. The BKA was well tolerated and on HD 50 he was discharged to an acute rehabilitation unit on warfarin.
Discussion and conclusions
Patients with a Fontan circulation are at higher risk for thrombus formation [10]. The systemic venous return drains directly into the pulmonary arteries, and the lack of a subpulmonary ventricle results in a low-flow state through the pulmonary arterial circuit. Pulmonary venous return thus depends on negative inspiratory intrathoracic pressure, low pulmonary vascular resistance, and diastolic function of the systemic ventricle. Increases in pulmonary vascular resistance due to pulmonary infections, positive-pressure ventilation, and/or atrial arrhythmias can all decrease pulmonary blood flow [10, 11]. Patients with COVID-19 infection are at higher risk for thrombosis due to multiple theorized factors, including an increased inflammatory state and endothelial cell dysfunction secondary to viral invasion [12, 13]. PCD in patients with COVID-19 has been reported [1], but thus far only in patients predisposed to thrombosis. In our case, our patient’s cardiac anatomy and physiology placed him in a higher risk category, and despite treatment with a vitamin K antagonist with supratherapeutic levels, he developed extensive bilateral venous thromboses. Interestingly his pulmonary circulation was intact and he did not develop any evidence of pulmonary emboli on CTA or pulmonary angiography.
PCD requires aggressive therapy for limb salvage [14], but resource limitations in heavily impacted hospitals during the COVID pandemic may result in delays in diagnosis and treatment. Nevertheless, the treatment this patient received likely prevented further leg ischemia and limited his amputation to below-the-knee instead of above-the-knee, which is associated with improved functionality and long-term outcomes [15].
Presently, the most effective anticoagulation strategy for patients with COVID-19 related thrombosis is unclear. Our patient developed no further thrombosis while on heparin, though notably this change was made after the COVID pneumonia was already improving.
Patients with comorbidities that place them in higher-risk categories for various disease states, such as Fontan circulation, are potentially at higher risk of complications from COVID-19. PCD is a rare but devastating complication, and must be recognized early and treated aggressively; mechanical thrombectomy may be indicated to expedite restoration of venous outflow, particularly when anticoagulation may be contraindicated. Pulmonary fibrosis secondary to COVID-19 may lead to increased pulmonary vascular resistance, which may further complicate the long-term course of Fontan patients in particular. Despite the presence of acute lung injury and extensive deep venous thromboses, our patient did not require mechanical ventilation or develop decompensated heart failure, reflecting a reassuring degree of resilience of this patient’s Fontan circulation in the face of COVID-19 infection.
Abbreviations
BKA Below-the-knee amputation
PCD Phlegmasia cerulea dolens
PTT Partial thromboplastin time
CTV Computed tomography venogram
IVC Inferior vena cava
HD Hospital day
BiPAP Bilevel positive airway pressure
VTE Venous thromboembolism
DIC Disseminated intravascular coagulation
PCR Polymerase chain reaction
Acknowledgements
Not applicable.
Authors' contributions
NJ, DF, JM were involved with acquisition of and interpretation of patient data. LR, GL, JA, and JL were involved with acquisition of data. NJ, DF, and WW drafted the manuscript with substantial revisions by JL. All authors contributed to the editing of the manuscript and agreed on the final content. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding authors on reasonable request.
Declarations
Ethics approval and consent to participate
The Institutional Review Board waived full board review for the presentation of this anonymized case report. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines.
Consent for publication
The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.
Competing interests
JM is a consultant for Argon Medical, Angiodynamics Inc, Boston Scientific Inc, Inari Medical, Penumbra Inc, BD Bard, Thrombolex Inc, and Pavmed Inc. The other authors have no conflicts to disclose.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 34886795 | 20,391,609 | 2021-12-09 |
What was the outcome of reaction 'International normalised ratio increased'? | Mechanical thrombectomy of COVID-19 DVT with congenital heart disease leading to phlegmasia cerulea dolens: a case report.
BACKGROUND
COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both.
METHODS
A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated.
CONCLUSIONS
This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity.
pmcBackground
COVID-associated coagulopathy has recently been described [1] and COVID VTE is recognized to be significantly elevated in critically ill patients [2–4]. Patients with altered Fontan physiology have independently elevated risks of developing VTE due to decreased pulmonary arterial pressures. Meta-analyses are now reporting risk factors for DVT development including hypoalbuminemia and higher Sequential Organ Failure Assessment (SOFA) scores [5]. However the risk for VTE in the context of altered cardiopulmonary circulation due to congential heart disease (CHD) remains largely unknown.
Case presentation
A 51-year-old male with tricuspid atresia, status post atriopulmonary Fontan at 6 years of age with subsequent urgent surgical conversion to an extracardiac Fontan (Fig. 1) in the setting of a right atrial thrombus at 30 years of age. The patient initially presented to an outpatient clinic with cough and diarrhea. He was diagnosed with SARS-CoV-2 infection via nasopharyngeal swab. Six days later, he presented to a rural emergency room with progressive exertional dyspnea, and was found to be hypoxic and hypotensive. He was diagnosed with COVID-19 pneumonia (Fig. 2), the patient was placed on bilevel positive airway pressure (BiPAP) and vasopressor support. He received a course of remdesivir and was continued on tadalafil. Warfarin was held due to a supratherapeutic international normalized ratio (INR) greater than 14. His respiratory status improved and he was weaned to a non-rebreather mask. He developed bilateral leg pain during the hospitalization, and lower extremity venous ultrasound detected bilateral deep vein thromboses. Given these findings, he was urgently transferred to our institution on hospital day (HD) 7 for higher level of care (Table 1).Fig. 1 Central venogram highlighting Fontan circulation with extracardiac shunt. EC extracardiac Fontan conduit, RA right atrium, RPA right pulmonary artery, LPA left pulmonary artery
Fig. 2 Multifocal pneumonia consistent with clinical presentation and laboratory studies for COVID-19 (A, B). Subsequent axial and coronal slices showing resolution of COVID-19 pneumonia with pulmonary fibrosis (C, D)
Table 1 Timeline for the key events from initial presentation, hospitalization, and transfer to our institution
Day 1 Patient presentation to outpatient clinic with upper respiratory and gastrointestinal symptoms, diagnosed with SARS-CoV-2 infection via nasopharyngeal swab
Day 7 (OSH HD 1) Presentation to community hospital with hypoxia and hypotension with COVID-19 pneumonia requiring BiPAP and vasopressor support
Day 12 (HD 1) Patient transfered to our healthcare facility for higher level of care with subsequent mechanical thrombectomy of bilateral lower extremities
Day 13 Bilateral iliac filters retrieved with patent IVC and iliac veins
Day 41 Left below the knee amputation was performed
Day 50 Patient discharged to rehabilitation facility
OSHD Outside Hospital Day, HD Hospital Day (our institution)
Upon transfer, his INR was down-trending, but remained supratherapeutic at 6.6, and computed tomography venogram (CTV) demonstrated bilateral deep venous thrombosis from the iliac to calf veins, excluding the inferior vena cava (IVC). There was no evidence of pulmonary embolus. Physical exam was notable left lower leg findings pitting edema, purple discoloration (Figs. 3, 4), decreased sensation, and mobility. The laboratory workup was notable in particular for the supratherapeutic INR that was reduced to 1.6 by the second day of hospitalization at our institution, following treatment with Vitamin K. DIC panel and prothrombotic workup, including β-2 glycoprotein and cardiolipin antibodies, were negative (Table 2).Fig. 3 Painful, violaceous foot, concerning for venous outflow obstruction resulting in PCD
Fig. 4 Color-rendered 3D reconstruction of the pelvis outlining the patent arterial vasculature (aorta and bilateral iliac arteries) and IVC with bilateral venous thromboses. The white, green, and blue arrows indicate the abrupt completely occlusive thrombus of the proximal left common iliac vein, the occlusive thrombus of the right common femoral vein, and the iliac confluence into the IVC, respectively
Table 2 Relevant laboratory values on admission (Day 12/HD 1)
Value Normal range
White blood cell count 8.17 4.16–9.95 × 10E3/uL
Red blood cell count 3.22 4.41–5.95 × 10E6/uL
Hemoglobin 11.6 13.5–17.1 g/dL
Hematocrit 35.7 38.5–52.0%
Mean corpuscular volume 91.5 79.3–98.6 fL
Mean corpuscular hemoglobin 30.7 26.4–33.4 pg
MCH concentration 33.3 31.5–35.5 g/dL
Platelet count 137 143–398 × 10E3/uL
Ferritin 522 8–350 ng/mL
Prothrombin time 16.7 11.5–14.4 s
INR 6.6 < 1.1
APTT 78.5 24.4–36.2 s
D-dimer 5,164 ≤ 499 ng/mL FEU
Factor V (5) activity 113 > 50% act
Fibrinogen 526 235–490 mg/dL
Sodium 138 135–146 mmol/L
Potassium 4.1 3.6–5.3 mmol/L
Chloride 101 96–106 mmol/L
Total CO2 25 20–30 mmol/L
Anion gap 12 8–19 mmol/L
Glucose 115 65–99 mg/dL
GFR estimate for non-African American > 89 > 89 mL/min/1.73m2
Creatinine 0.96 0.60–1.30 mg/dL
Urea Nitrogen 24 7–22 mg/dL
Calcium 7.6 8.6–10.4 mg/dL
Magnesium 1.9 1.4–1.9 mEq/L
Phosphorus 2.7 2.3–4.4 mg/dL
Phosphorus 2.7 2.3–4.4 mg/dL
Lactate dehydrogenase 336 125–256 U/L
Total protein 5.8 6.1–8.2 g/dL
Albumin 2.2 3.9–5.0 g/dL
Bilirubin, total 3.2 0.1–1.2 mg/dL
Bilirubin, conjugated 2.6 ≤ 0.3 mg/dL
Alkaline phosphatase 63 37–113 U/L
Aspartate aminotransferase 32 13–47 U/L
Alanine aminotransferase 11 8–64 U/L
While the differential diagnosis of limb ischemia in the setting of COVID-19 infection includes arterial thrombosis, the demonstration of venous outflow obstruction (Fig. 4), violaceous discoloration of the lower extremity, pronounced edema, and pain confirmed the diagnosis of phlegmasia cerulea dolens (PCD). A heparin drip was initiated with vitamin K reversal of warfarin. Since his partial thromboplastin time (PTT) values were abnormal (Table 2), anti-Xa levels were used to titrate the heparin infusion. He also received convalescent plasma [6]. Arterial Doppler was notable for biphasic waveforms with excessive diastolic reversed flow concerning for developing compartment syndrome, without evidence of arterial thrombosis.
Following multidisciplinary evaluation, the decision was made undergo an emergent transvenous thrombectomy to salvage the left leg. Given the inflammatory nature of the clot and development of PCD in spite of supratherapeutic INR, mechanical thrombectomy was felt to be the most appropriate course of action [7] as opposed to ‘lyse and wait’ strategies that could prolong vascular compromise and also subject the patient to increased adverse bleeding events and the potential development of compartment syndrome.
Bilateral popliteal vein access was obtained for catheter directed mechanical thrombectomy using the ClotTriever® system (Inari Medical). Popliteal and Fontan pressures were 19 and 17 mmHg, respectively; pulmonary angiography did not demonstrate any emboli. Five thrombectomy passes of the left lower extremity from the popliteal vein to the IVC and four passes of the right leg successfully restored flow from the bilateral popliteal veins to the IVC (Fig. 5) and yielded thrombus that was positive for SARS-CoV-2 by polymerase chain reaction (PCR). In order to protect the cardiopulmonary circulation peri-procedurally during anticoagulation optimization, bilateral retrievable iliac vein filters (Optease) were placed. An IVC filter was not placed due to the large size of the cava. The iliac filters were retrieved on HD 12 via femoral approach (the right internal jugular vein was chronically occluded) following venograms confirming patent femoral and iliac veins. A left lower extremity cellulitis developed and empirically managed with antibiotics. The patient unfortunately did not have reversal of the ischemic changes post-procedure, requiring below-the-knee amputation (BKA) for dry gangrene of the left foot.Fig. 5 Post-thrombectomy lower extremity venograms (A) with corresponding photographs of the pathology-confirmed COVID-19-positive extracted thrombus from the left (B) and right (C) lower extremities
He experienced epistaxis while on heparin, that was treated with nasal packing. There was evidence of post-pneumonia fibrosis [8] (Fig. 2C and 2D); the associated increase in pulmonary vascular resistance is often not well tolerated in Fontan patients [9]. His tadalafil was increased to 40 mg daily from 20 mg daily to improve hemodynamics. His oxygen saturation was eventually maintained on room air and he never required mechanical ventilation. The BKA was well tolerated and on HD 50 he was discharged to an acute rehabilitation unit on warfarin.
Discussion and conclusions
Patients with a Fontan circulation are at higher risk for thrombus formation [10]. The systemic venous return drains directly into the pulmonary arteries, and the lack of a subpulmonary ventricle results in a low-flow state through the pulmonary arterial circuit. Pulmonary venous return thus depends on negative inspiratory intrathoracic pressure, low pulmonary vascular resistance, and diastolic function of the systemic ventricle. Increases in pulmonary vascular resistance due to pulmonary infections, positive-pressure ventilation, and/or atrial arrhythmias can all decrease pulmonary blood flow [10, 11]. Patients with COVID-19 infection are at higher risk for thrombosis due to multiple theorized factors, including an increased inflammatory state and endothelial cell dysfunction secondary to viral invasion [12, 13]. PCD in patients with COVID-19 has been reported [1], but thus far only in patients predisposed to thrombosis. In our case, our patient’s cardiac anatomy and physiology placed him in a higher risk category, and despite treatment with a vitamin K antagonist with supratherapeutic levels, he developed extensive bilateral venous thromboses. Interestingly his pulmonary circulation was intact and he did not develop any evidence of pulmonary emboli on CTA or pulmonary angiography.
PCD requires aggressive therapy for limb salvage [14], but resource limitations in heavily impacted hospitals during the COVID pandemic may result in delays in diagnosis and treatment. Nevertheless, the treatment this patient received likely prevented further leg ischemia and limited his amputation to below-the-knee instead of above-the-knee, which is associated with improved functionality and long-term outcomes [15].
Presently, the most effective anticoagulation strategy for patients with COVID-19 related thrombosis is unclear. Our patient developed no further thrombosis while on heparin, though notably this change was made after the COVID pneumonia was already improving.
Patients with comorbidities that place them in higher-risk categories for various disease states, such as Fontan circulation, are potentially at higher risk of complications from COVID-19. PCD is a rare but devastating complication, and must be recognized early and treated aggressively; mechanical thrombectomy may be indicated to expedite restoration of venous outflow, particularly when anticoagulation may be contraindicated. Pulmonary fibrosis secondary to COVID-19 may lead to increased pulmonary vascular resistance, which may further complicate the long-term course of Fontan patients in particular. Despite the presence of acute lung injury and extensive deep venous thromboses, our patient did not require mechanical ventilation or develop decompensated heart failure, reflecting a reassuring degree of resilience of this patient’s Fontan circulation in the face of COVID-19 infection.
Abbreviations
BKA Below-the-knee amputation
PCD Phlegmasia cerulea dolens
PTT Partial thromboplastin time
CTV Computed tomography venogram
IVC Inferior vena cava
HD Hospital day
BiPAP Bilevel positive airway pressure
VTE Venous thromboembolism
DIC Disseminated intravascular coagulation
PCR Polymerase chain reaction
Acknowledgements
Not applicable.
Authors' contributions
NJ, DF, JM were involved with acquisition of and interpretation of patient data. LR, GL, JA, and JL were involved with acquisition of data. NJ, DF, and WW drafted the manuscript with substantial revisions by JL. All authors contributed to the editing of the manuscript and agreed on the final content. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding authors on reasonable request.
Declarations
Ethics approval and consent to participate
The Institutional Review Board waived full board review for the presentation of this anonymized case report. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines.
Consent for publication
The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidelines.
Competing interests
JM is a consultant for Argon Medical, Angiodynamics Inc, Boston Scientific Inc, Inari Medical, Penumbra Inc, BD Bard, Thrombolex Inc, and Pavmed Inc. The other authors have no conflicts to disclose.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 34886795 | 20,416,963 | 2021-12-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthralgia'. | A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma.
Anti-programmed death (PD)-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, over 50% of patients progress due to resistance. We tested a first-in-class immune-modulatory vaccine (IO102/IO103) against indoleamine 2,3-dioxygenase (IDO) and PD ligand 1 (PD-L1), targeting immunosuppressive cells and tumor cells expressing IDO and/or PD-L1 (IDO/PD-L1), combined with nivolumab. Thirty aPD1 therapy-naive patients with MM were treated in a phase 1/2 study ( https://clinicaltrials.gov/ , NCT03047928). The primary endpoint was feasibility and safety; the systemic toxicity profile was comparable to that of nivolumab monotherapy. Secondary endpoints were efficacy and immunogenicity; an objective response rate (ORR) of 80% (confidence interval (CI), 62.7-90.5%) was reached, with 43% (CI, 27.4-60.8%) complete responses. After a median follow-up of 22.9 months, the median progression-free survival (PFS) was 26 months (CI, 15.4-69 months). Median overall survival (OS) was not reached. Vaccine-specific responses assessed in vitro were detected in the blood of >93% of patients during vaccination. Vaccine-reactive T cells comprised CD4+ and CD8+ T cells with activity against IDO- and PD-L1-expressing cancer and immune cells. T cell influx of peripherally expanded T cells into tumor sites was observed in responding patients, and general enrichment of IDO- and PD-L1-specific clones after treatment was documented. These clinical efficacy and favorable safety data support further validation in a larger randomized trial to confirm the clinical potential of this immunomodulating approach.
pmcMain
Despite remarkable advances in the treatment of MM with immune checkpoint inhibitors (ICIs) targeting PD-1 and cytotoxic T lymphocyte antigen 4 (CTLA-4), around half of patients are resistant to ICI monotherapy1. The combination of anti-CTLA-4 (aCTLA-4) and aPD1 therapy is to date the most effective therapy resulting in a response rate of around 60%; however, 50% of the patients also develop severe adverse events2,3. Therefore, an equally effective but less toxic treatment is highly needed. Several approaches to enhance ICI efficacy are currently being investigated, such as other ICIs, T cell therapy with tumor-infiltrating T cells or innate immunity stimulators such as Toll-like receptor 9 agonists4–6. Treating cancer patients with vaccines that stimulate a targeted immune response is another attractive approach, with very few side effects observed thus far in combination immunotherapy studies7,8.
Immune-modulatory vaccines targeting tumoral immune escape mechanisms offer a new, generalizable strategy compared to patient-specific neoantigen cancer vaccines7,9. The immune-modulatory vaccine strategy in this clinical trial is based on the finding of circulating cytotoxic T cells specific to IDO and PD-L1 in the blood of patients with cancer and, to a lesser extent, in healthy donors. IDO- and PD-L1-specific CD8+ T cells can directly recognize and kill IDO+ and/or PD-L1+ tumor cells and likewise recognize and kill non-malignant cells that express their cognate targets. Furthermore, IDO- and PD-L1-specific CD4+ T cells release pro-inflammatory cytokines in response to IDO- or PD-L1-expressing target cells. IDO and PD-L1 are expressed not only by melanoma cells but also by many other cell types in the tumor microenvironment (TME), which differentiates these antigens from traditional tumor antigens used in other studies10–15. Activation of IDO/PD-L1-specific T cells by vaccination can therefore restrict the range of immunosuppressive signals mediated by immunosuppressive cells and thereby revert the TME from an immune hostile to an immune friendly environment. In animal models of cancer, vaccinations with IDO epitopes resulted in anti-tumor therapeutic effects that were correlated with reductions in IDO expression in myeloid cell populations within the TME16. The IDO/PD-L1 immune-modulating vaccine may lead to a translatable strategy for improving the efficacy of aPD1 therapy through activation of specific T cells. We hypothesize that the IDO/PD-L1 vaccine attracts T cells into the tumor, which induces type 1 helper T (TH1) cell inflammation and reverts the TME into an immune-permissive site, thereby turning the tumor ‘hot’. This would also upregulate PD-L1 expression in cancer and immune cells, generating more susceptible targets to aPD1 therapy (Extended Data Fig. 1a). This theory was confirmed in a mouse model in which aPD1 therapy and IDO vaccination show synergistic effects16.
In this phase 1/2 clinical trial, MM1636, patients with MM received a combination of the IDO/PD-L1 (IO102/IO103) peptide vaccine with the adjuvant Montanide and the aPD1 antibody nivolumab. Patients were included in three cohorts: 30 aPD1 therapy-naive patients (cohort A), ten aPD1 therapy-refractory patients (cohort B, de novo resistance) and ten patients who progressed after aPD1 therapy (cohort C, acquired resistance). Here, we report results from cohort A.
The vaccine was given biweekly for the first six administrations and thereafter every 4th week. A maximum of 15 vaccines were administered. Nivolumab was given in parallel, biweekly (3 mg per kg) or every 4th week (6 mg per kg) for up to 2 years (Extended Data Fig. 1b).
The primary objective was safety and feasibility. Secondary objectives were immunogenicity and clinical efficacy.
Results
Patients and treatment
Thirty patients were enrolled from December 2017 to June 2020. None of the 30 patients dropped out of the study; all received at least three cycles of therapy (Supplementary Fig. 1). At the current database lock (5 October 2020), six patients were still on treatment in the trial.
Of the 24 patients who were not on trial treatment at data cutoff, two are still receiving nivolumab monotherapy (6 mg per kg every 4 weeks). Reasons for stopping treatment for the remaining 22 patients included disease progression (37%), toxicity (20%), maximum benefit or complete response (CR) confirmed on two consecutive scans (17%) or completing 2 years of treatment (7%).
For the 24 patients who were not on trial treatment at data cutoff, the mean number of vaccinations was 10.5 (range, 3–15 vaccinations). Thirteen of these 24 patients continued nivolumab (6 mg per kg, every 4 weeks) as a standard of care. Nine patients received subsequent therapy after progression (Supplementary Table 1).
Baseline characteristics are shown in Table 1. The mean age was 70 years; 37% of patients had elevated lactate dehydrogenase (LDH) levels, 60% were stage M1c, 37% had BRAF mutations, and 43% were negative for PD-L1 (<1%). A total of three patients (10%) had received prior ipilimumab therapy. No patients had brain metastasis (Supplementary Table 2).Table 1 Baseline patient characteristics (n = 30)
Characteristic Number (%)
Mean age, years (range) 70 (46–85)
Sex, male 16 (55%)
ECOG PS 0 26 (87%)
LDH levels
≤ULN 19 (63%)
>ULN 11 (37%)
M stage (AJCC-8)
M1a 6 (20%)
M1b 6 (20%)
M1c 18 (60%)
Number of lesion sites
1 6 (20%)
2–3 17 (57%)
>3 7 (23%)
Liver metastases present 10 (33%)
BRAF status
Mutant 11 (37%)
Wild type 19 (63%)
PD-L1
<1% 13 (43%)
>1% 17 (57%)
Previous systemic therapy
Ipilimumab 3 (10%)
No 27 (90%)
AJCC-8, eighth edition of the American Joint Committee on Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; ULN, upper limit of normal.
Notable clinical responses to the combination therapy
Thirty patients with MM were treated with the IDO/PD-L1 vaccine and nivolumab according to the trial protocol. By investigator review, the ORR reached 80% (CI, 62.7–90.5%), with 43% of patients (CI, 27.4–60.8%) achieving a CR and 37% (CI, 20.9–54.5%) reaching a partial response (PR) as the best overall response, while 20% experienced progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Fig. 1a). Two of the patients with a PR did not have a confirmatory scan stating PR on two consecutive scans. Early onset of response was frequent, with 22 of 30 patients having an objective response at the first evaluation (after 12 weeks on treatment). Median times to PR and CR were 75 d (range, 54–256 d) and 327 d (range, 73–490 d), respectively (Fig. 2a–c).Fig. 1 Clinical response.
a, Pie charts with percent ORR, CR, PR and PD according to RECIST 1.1 by investigator review of all patients (n = 30), PD-L1+ patients (>1%, (n = 17)) and PD-L1− patients (<1%, n = 13)), respectively. Two-sided CIs (95%) were constructed using the Clopper–Pearson method. b, Treatment effect in MM1636 compared with a matched historical control group from the DAMMED database (n = 74). Patients in MM1636 (n = 29) were matched with the exact same combination variable according to age (≤70 years, >70 years), sex, LDH levels (normal, elevated), M stage (M1a, M1b, M1c), BRAF status (wild type, mutated) and PD-L1 status (<1%, ≥1%). Estimates for treatment effects were calculated by weighted logistic regression analyses and weighted Cox proportional hazard model. Bar height indicates the estimated response rate; tops of bars are centers for error bars. Odds ratios (OR), response rates and their corresponding 95% CIs were extracted from the regression model. All P values were two sided, and P values below 0.05 were considered statistically significant. c, Best change in the sum of target lesion size compared with that at baseline (n = 30). The horizontal line at −30 shows the threshold for defining an objective response in the absence of non-target disease progression or new lesions according to RECIST 1.1. Two patients with 100% reduction in target lesion size had non-target lesions present. White stars, six patients had normalization (<10 mm) of fluor-18-deoxyglucose (FDG)-negative lymph nodes (at baseline, lymph nodes were >1.5 cm and FDG+) and 100% reduction of non-lymph node lesions and are considered to have had a CR (green bar). Black star, one patient (MM29) was considered to have had a PR (blue bar), although he had not reached a −30% change in target lesion size. The patient had a single measurable 13-mm lung metastasis at baseline and multiple biopsy-verified cutaneous metastases on the left crus (not detectable by positron-emission tomography–computed tomography (PET–CT) at baseline). The best change in target lesion size was 10 mm, and a post-treatment biopsy from the cutaneous metastases showed no sign of malignancy. Thus, overall, the patient was classified as having a PR. d, Kaplan–Meier curve of the response duration in the 24 patients with an objective response. e, Kaplan–Meier curve of PFS in all 30 treated patients. f, Kaplan–Meier curve of OS in all 30 treated patients.
Fig. 2 Clinical response.
a, Swimmer plot showing response duration and time to response according to RECIST 1.1 for all treated patients (n = 30). Triangles indicate first evidence of PR, while squares indicate first evidence of CR. Closed circles indicate time of progression. Arrows indicate ongoing responses. Patient MM18 died due to nivolumab-induced side effects. b, Spider plot showing response kinetics in all treated patients (n = 30). Red squares indicate time of progression. c, PET–CT images of patient MM42 before and after treatment (after 12 series of treatment) showing FDG metabolism in target lesions. SC, subcutaneous.
The ORR among PD-L1+ (>1% (clone 28.8)) patients (n = 17) was 94.1% (CI, 73–99.7%) and 61.5% (CI, 35.5–82.3%) in PD-L1− patients (n = 13) (Fig. 1a). Objective responses were observed in patients irrespective of human leukocyte antigen (HLA) genotype (Supplementary Fig. 2).
Clinical response data were validated by blinded independent external review, in which an ORR of 76.6% (CI, 57.7–90.1%) was reported, with 53.3% of patients achieving a CR, 23.3% achieving a PR and 3.3% experiencing stable disease. Comparisons between investigator review and external review are outlined in Supplementary Table 3.
To examine whether the very high response rate should be attributed to nivolumab or to the vaccine, we retrieved clinical response information from a matched historical control group using the Danish Metastatic Melanoma Database (DAMMED) from contemporaneously treated patients with stage 3–4 melanoma who received aPD1 monotherapy17. Patients were matched with the exact same combination variable according to age, sex, PD-L1 status, BRAF status, LDH level and M stage (those at stage M1d were excluded from the control group (no patients with brain metastasis)). Matched controls were identified for 29 patients, and the ORR of 79.3% (CI, 61.0–90.4%) observed in MM1636 was found to be significantly higher (P < 0.0012) than that in the matched control group in which an ORR of 41.7% (CI, 31.0–53.3%) was reached. Furthermore, of the 29 patients in MM1636, a significantly (P < 0.0017) higher percentage (41.4% (CI, 25.2–59.6%)) of patients achieved CR in MM1636 than that (12% (CI, 6.3–21.6%)) in the matched historical control group. ORR and complete response rate (CRR) in the matched historical control group were comparable to those of patients treated in randomized phase 3 pivotal trials with aPD1 monotherapy18 (Fig. 1b).
The treatment leads to prolonged PFS
At data cutoff, the median duration of response had not been reached, with 87% of all responding patients being free from progression at 12 months (Fig. 1d).
Patients were followed for up to 35 months with a median follow-up time of 22.9 months (CI, 14.9–26.2 months). OS and PFS were calculated from the first day of treatment to death or progression or to the date of the last follow-up (5 October 2020).
The median PFS (mPFS) for all treated patients was 26 months (CI, 15.4–69 months) and was not reached for responding patients (Fig. 1e). The median OS was not reached at the data cutoff. OS at 12 months was 81.6% (CI, 61.6–92%) (Fig. 1f). One patient (MM18) with a CR died from nivolumab-related severe adverse events; the remaining patients died because of metastatic melanoma. For comparison, the mPFS was 8.3 months (CI, 5.5 months–NR (not reached)) in the matched historical control group (n = 74), while the median OS was 23.2 months (CI, 23.2 months–NR). (Extended Data Fig. 2a,b).
The combination of the IDO/PD-L1 vaccine and nivolumab was safe
Treatment-related adverse events are listed for all 30 patients in Supplementary Table 4. Common treatment-related grade 1–2 toxicities were fatigue (47%), rash (47%), arthralgia (30%), diarrhea (23%), nausea (23%), dry skin (20%), pruritus (20%), infusion reaction (17%), xerostomia (17%) and myalgia (17%).
Four patients (13%) experienced grade 3–4 adverse events: one patient with a grade 3 maculopapular rash (MM01), one patient with grade 3 adrenal insufficiency (MM06) and one patient with grade 3 arthralgia (MM22).
Patient MM18 died from urosepsis with multi-organ failure and severe hyponatremia. This patient had experienced multiple immune-related adverse events with grade 3 colitis, grade 2 pneumonitis, grade 3 arthralgia, grade 2 vasculitis and grade 2 nivolumab infusion-related allergic reaction. Additionally, patient MM18 had symptoms of myocarditis at the time of death with highly elevated cardiac troponin I levels. Bedside echocardiography showed an ejection fraction of 15%, which at baseline was 60%, but an autopsy was not conducted, and myocarditis was never confirmed pathologically.
Patient MM06 had received first-line treatment with ipilimumab before entering the trial and was on substitution corticosteroids at the time of inclusion. Adrenal insufficiency was aggravated by an erysipelas infection with high fever, reaching grade 3 in Common Terminology Criteria for Adverse Events and resolving quickly after appropriate antibiotic therapy was initiated.
As expected, local side effects were common with 77% of the patients who developed injection site reactions. These reactions were classified as granulomas (63%), redness (20%), pain (13%) and pruritus (13%) at the injection site. All local reactions were grade 1–2, most likely related to the Montanide adjuvant and typically transient. However, two patients (MM07 and MM20) decided to discontinue vaccination after eight and 11 injections, respectively, due to granulomas, tenderness and pain that limited instrumental activities of daily living but continued to receive nivolumab (Extended Data Fig. 2c).
Vaccine-specific responses in blood were frequently detected
First, all 30 patients were assessed for the presence of vaccine-specific responses in peripheral blood mononuclear cells (PBMCs) before, on and after vaccination using a modified interferon (IFN)-γ enzyme-linked immune absorbent spot (ELISPOT) assay. This assay is known to expand antigen-specific memory cells and to improve the detection and the correlative power of ELISPOT during treatment19–21.
Prevaccine IDO-specific responses were detectable in ten (33%) patients, while prevaccine PD-L1-specific responses were detectable in eight patients (27%); overlapping (specific to both IDO and PD-L1) prevaccine responses were present in four (13.3%) patients. During vaccination, an increase of IDO-specific T cells or PD-L1-specific T cells in the blood was observed in 28 (93%) and 26 (86%) patients, respectively. In total, 93% of patients had an increase in either PD-L1- or IDO-specific responses on vaccination (Fig. 3a), with a significant (P < 0.0001) median increase from baseline to the post-vaccine response demonstrated for both IDO and PD-L1 (at different time points on treatment), confirming that vaccine-specific immune responses were induced in patients regardless of clinical response (Fig. 3b,c). Immune responses fluctuated in the blood over time (Extended Data Fig. 3a). An increase in IDO- and PD-L1-specific responses in the peripheral blood was also detectable directly ex vivo across the different clinical response groups (Extended Data Fig. 4).Fig. 3 Vaccine-specific responses in blood.
a, IDO- and PD-L1-specific T cell responses in PBMCs at baseline and on vaccination as measured by the IFN-γ ELISPOT assay (n = 30). *Responses were calculated as the difference between the average numbers of spots in wells stimulated with IDO or PD-L1 peptide (triplicates) and those from the corresponding control (DMSO), and statistical analyses of ELISPOT responses were performed using a distribution-free resampling method (Moodie et al.50). DR (double response), response was not statistically confirmed due to replicate number, but the number of spots in peptide wells was two times higher than that in control wells (DMSO). NS, no significant response and no DR. For a detailed overview of responses at serial time points on vaccination, see Extended Data Fig. 4a. b, IDO- and PD-L1-specific T cell response in PBMCs in all treated patients measured by the IFN-γ ELISPOT assay at baseline and on vaccination. On-vaccination responses were selected from the ‘best’ ELISPOT response at different time points for each patient (series 3, 6, 12, 18 or 24) during vaccination (n = 30). Wilcoxon matched-pairs signed-rank test was used to compare responses to IDO or PD-L1 peptides in the vaccine between baseline and later time points. c, Representative example of ELISPOT wells with response in patient MM23 in serial PBMCs before and on treatment. d, IDO-specific CD4+ and CD8+ T cells were isolated and expanded from PBMCs stimulated in vitro with the IDO peptide and a low dose of IL-2 for 14–15 d before sorting using the Miltenyi Cytokine Secretion Assay—Cell Enrichment and Detection kit. To assess their cytolytic potential, IDO-specific T cells were stimulated with IDO peptide, and expression of CD107a, IFN-γ and TNF-α was assessed by flow cytometry (the example is from patient MM14).
Sustained vaccine-specific responses were observed 3 and 6 months after the last vaccine, indicating induction of memory responses in nine patients with response to clinical treatment who surpassed follow-up at data lock (Extended Data Fig. 3b). Importantly, PD-L1- and IDO-specific responses were observed irrespective of HLA genotype (Supplementary Table 5).
To verify the functionality of vaccine-induced T cells, IDO- or PD-L1-specific T cells were isolated and in vitro expanded from PBMCs of five patients. Phenotypic characterization by flow cytometry revealed that the isolated vaccine-specific T cells consisted of both CD4+ and CD8+ T cells. Also, both IDO- and PD-L1-specific CD4+ and CD8+ T cells showed pro-inflammatory properties, as they expressed the cytolytic marker CD107a and secreted the cytokines IFN-γ and tumor necrosis factor (TNF)-α (Fig. 3d and Extended Data Fig. 6a–d). Interestingly, we were also able to detect vaccine-specific CD4+ and CD8+ T cell responses in peripheral blood ex vivo (Extended Data Figs. 4 and 5). We observed a significant increase in the overall percentage of CD107a, CD137 and TNF-α expression in response to peptide stimulation in on- or post-treatment PBMC samples compared to that at baseline, further confirming the expansion and the diverse signature of vaccine-specific T cells (Extended Data Fig. 5).
Vaccine-specific responses detected in the skin at the vaccination site
To investigate whether vaccine-specific T cells have the potential to migrate to peripheral tissue, delayed-type hypersensitivity (DTH) tests were performed after six cycles of treatment on 15 patients to assess the presence of vaccine-reactive T cells in the skin. Supplementary Table 6 display an overview of skin-infiltrating lymphocyte (SKIL) cultures.
We detected IDO-specific T cells in the skin of six of ten patients and PD-L1-specific T cells in nine of 11 patients (Extended Data Fig. 7a). Intracellular cytokine staining was performed on SKILs from five patients after stimulation with either PD-L1 or IDO peptide. Here, we detected mainly CD4+ peptide-reactive T cells that secreted TNF-α and upregulated CD107a, and a minor fraction also secreted IFN-γ. In one patient, we detected CD8+ PD-L1-reactive T cells (Extended Data Fig. 7b–d).
Vaccine-induced T cells specifically recognize target cells
To confirm the functionality of vaccine-expanded T cells, vaccine-specific T cell clones (clonal purity was confirmed by T cell receptor (TCR) sequencing) were isolated and expanded from patient PBMCs (Extended Data Fig. 8e). We showed that PD-L1-specific T cells were able to recognize PD-L1+ autologous tumor cells in a PD-L1 expression-dependent manner if the cancer cells also expressed HLA-II (Fig. 4a,b). Similarly, an HLA-DR-restricted IDO-specific CD4+ T cell clone was able to recognize an HLA-DR-matched IDO-expressing model cell line, MonoMac1, in an IDO-expression-dependent manner (Fig. 4e–g). As previously described, IDO- and PD-L1-specific T cells’ mode of action is not limited to targeting only cancer cells. We were able to show that vaccine-specific T cell clones also reacted against PD-L1- and IDO-expressing autologous immune cells (Fig. 4c,h). To provide myeloid cells with a tumor-associated phenotype we treated isolated CD14+ myeloid cells with tumor conditioned medium (TCM) derived from an established autologous tumor cell line. We observed that such TCM-treated CD14+ cells had increased expression of PD-L1 and IDO and were effectively recognized by autologous PD-L1- and IDO-specific CD4+ T cell clones (Fig. 4c,d,h,i).Fig. 4 PD-L1- and IDO-specific T cells from vaccinated patients react against PD-L1- and IDO-expressing target cells.
a, Left, PD-L1-specific T cell culture (MM1636.05) reactivity against PD-L1 peptide or autologous tumor cells in the IFN-γ ELISPOT assay. Tumor cells were either not treated or pretreated with 200 U ml−1 IFN-γ for 48 h before the assay. Effector:target (E:T) ratio of 10:1 was used. Right, PD-L1 and HLA-II surface expression on melanoma cells with (green) or without (yellow) pretreatment with IFN-γ compared to an isotype control (gray) as assessed by flow cytometry. b, Left, PD-L1-specific T cell (MM1636.05) reactivity in the IFN-γ ELISPOT assay against autologous tumor cells pretreated with IFN-γ (500 U ml−1) and transfected with mock or PD-L1 small interfering (si)RNA 24 h after transfection. E:T ratio, 10:1. Right, PD-L1 surface expression on melanoma tumor cells (MM1636.05) assessed by flow cytometry 24 h after transfection with mock (blue) or PD-L1 (red) siRNA compared to the isotype control (gray). c, Reactivity of the CD4+ PD-L1-specific T cell clone (MM1636.14) against PD-L1 peptide or autologous CD14+ cells; E:T ratio, 10:1. CD14+ cells were isolated using magnetic bead sorting and used as targets in an ELISPOT assay directly or after pretreatment for 2 d with TCM derived from the autologous tumor cell line. d, Quantitative PCR with reverse transcription (RT–qPCR) analysis of PD-L1 (CD274) expression in sorted CD14+ cells before and after treatment with autologous TCM for 48 h. e, Reactivity of the IDO-specific CD4+ T cell clone (MM1636.23) against IDO peptide combined with HLA-DR (L243)-, HLA-DQ (SPV-L3)- or HLA-DP (B7/21)-blocking antibodies (aHLA-DR, aHLA-DQ and aHLA-DP) in an intracellular staining assay (ICS) for IFN-γ and TNF-α production. T cells were incubated with individual blocking antibodies (2 μg ml−1) for 30 min before adding IDO peptide. f, Reactivity of the IDO-specific CD4+ T cell clone (MM1636.23) against the HLA-DR-matched IDO-expressing cell line MonoMac1 transfected with mock or IDO siRNA in an ICS assay, E.T ratio, 4:1. siRNA transfection was performed 48 h before the experiment. g, RT–qPCR analysis of IDO1 expression in MonoMac1 cells 48 h after siRNA transfection. h, Reactivity of the CD4+ IDO-specific T cell clone (MM1636.14) against IDO peptide or autologous CD14+ cells; E:T ratio, 20:1. CD14+ cells were isolated using magnetic bead sorting and used as targets in an ELISPOT assay directly or after pretreatment with TCM derived from the autologous tumor cell line. i, RT–qPCR analysis of IDO1 expression in sorted CD14+ cells before and after treatment with autologous TCM for 48 h. Bars in RT–qPCR data (d,g,i) represent the mean of three (d,i) or six (g) technical replicates ±s.d.; P values were determined by two-tailed parametric t-tests. ELISPOT counts (a,b,c,h) represent the mean value of three technical replicates ±s.e.m.; response P values were determined using the distribution-free resampling (DFR) method. TNTC, too numerous to count.
T cell clones in blood and tumors
To track the role of treatment-induced T cell responses, TCR sequencing of the complementarity-determining region 3 (CDR3) was performed on five patients in peripheral blood (baseline and cycles 3, 6 and 12) and paired biopsies. These five patients (MM01, MM02, MM08, MM09 and MM13) were selected due to the availability of material and to investigate a balanced patient group with both responders and non-responders. Due to a limited number of available paired biopsies (either as a consequence of patient refusal or unexpectedly rapid and substantial clinical responses), statistical analysis could not be applied. Details on clinical response are shown in Fig. 2a. Additionally, PBMCs (on treatment) or SKILs were stimulated with the IDO/PD-L1 peptides, and then cytokine-producing T cells were sorted to track vaccine-induced T cells both in the periphery and at the tumor site.
To identify enriched IDO/PD-L1-specific T cell clones, TCR rearrangements in sorted IDO/PD-L1-specific clones and TCR rearrangements in sorted IDO/PD-L1-specific T cell samples were compared to sequences from baseline PBMC samples for each patient. Clonal expansion of vaccine-specific TCR rearrangements from samples on vaccination were then tracked using a differential abundance framework. Cumulative IDO/PD-L1-specific T cell frequencies were tracked in post-treatment samples.
We found no relation between clinical response and the enrichment of vaccine-specific clones, but an increase in IDO/PD-L1-specific T cell clones was observed at different time points in the periphery in all five patients (Extended Data Fig. 3c).
We next investigated overall changes in the T cell repertoire in the blood. A modest increase in the peripheral T cell fraction was observed in the three responding patients at cycle 3, while the two non-responding patients had a clear decrease in T cell fraction (Extended Data Fig. 8a). We thereafter investigated TCR clonality and TCR repertoire richness, exploring the proportion of abundant clones and the number of unique rearrangements, respectively. A decreasing peripheral Simpson clonality and increasing TCR repertoire richness was observed in responding patients at cycle 3, which might indicate tumor trafficking upon treatment. The opposite pattern was observed in non-responding patients (Extended Data Fig. 8b,c).
Peripherally expanded clones were associated with tumors and persisted until cycle 12 (latest time point analyzed). The largest peripheral expansion was observed at cycle 3, with the most significant increase observed in patient MM01 (CR). Responding patients had a larger fraction of peripherally expanded clones that were also found in tumors compared to that of non-responders. By tracking peripherally expanded clones detected at the tumor site, we observed that patient MM01 had a substantial increase after treatment, indicating tumor trafficking of peripheral expanded clones (Extended Data Fig. 8d).
Influx at the tumor site of vaccine-enriched T cell clones
Given the observation of increased T cell fraction and enrichment of IDO- and PD-L1-specific clones in the blood after treatment, we investigated whether the same trend was observed at the tumor site.
Both TCR sequencing and immunohistochemistry (IHC) of paired biopsies from the five patients described above showed an increase in the T cell fraction with an influx of CD3+ and CD8+ T cells after treatment in the three responding patients (Fig. 5a–c). IHC was not possible for patient MM09 due to tissue loss.Fig. 5 Changes in the TME after treatment. Number of CD3+ and CD8+ T cells, TCR fraction, TCR clonality, TCR repertoire, biopsy expanded TCR clones and enrichment of IDO- and PD-L1-specific T cells at the tumor site.
a, Number of CD3+ and CD8+ T cells per mm2 (sum in the validated area) at the tumor site detected by IHC of paired biopsies from four patients. b, Example of IHC of CD3+ and CD8+ T cells at the tumor site before and after treatment (cells per mm2) in one patient (MM01). c, T cell fraction at the tumor site at baseline and cycle 6 by TCR sequencing. The T cell fraction was calculated by taking the total number of T cell templates and dividing by the total number of nucleated cells. d, Tracking of vaccine-associated clones at baseline and cycle 6 in tumor biopsies. Cumulative frequencies of IDO and PD-L1 vaccine-specific TCR rearrangements are represented. e,f, TCR clonality and TCR repertoire richness in five patients at the tumor site at baseline and cycle 6. Simpson clonality measures how evenly TCR sequences are distributed among a set of T cells, where 0 indicates an even distribution of frequencies and 1 indicates an asymmetric distribution in which a few clones dominate. TCR repertoire richness reports the mean number of unique rearrangements. g, Bar chart representing baseline expanded biopsy clones from five patients (colored bars) and the detection of biopsy expanded clones also found in the blood at baseline and series 3, 6 and 12 (white and gray bars) by TCR sequencing.
We thereafter investigated whether some of the IDO/PD-L1 vaccine-linked T cells were present at the tumor site. Vaccine-associated clones were tracked as the combined frequency of IDO- and PD-L1-specific T cell rearrangements. In biopsies, the frequencies at cycle 6 were compared to those at baseline and showed an increase in vaccine-specific T cells in four of five patients, irrespective of clinical response (Fig. 5d). TCR sequencing of PD-L1-specific SKILs (a more specific culture than IDO/PD-L1-specific isolations derived from PBMCs on vaccination) and paired biopsies showed that two of the top five PD-L1-specific SKIL clones were present at the tumor site both before and after treatment (Extended Data Fig. 7e,f).
With a focus on the more abundant T cell clones, we investigated overall TCR clonality at the tumor site before and after treatment. In addition, we explored the number of unique TCR rearrangements, dissecting the lower-frequency clones. Patient MM01 had a significant increase in TCR clonality and a decrease in repertoire richness at the tumor site after therapy, indicating a focused tumor repertoire response of selected clones. All three responding patients had a decrease in TCR repertoire richness, which again might indicate a focused tumor response (Fig. 5e,f).
Deeper analyses showed that the T cell clones that expanded at the tumor site after therapy were also present in the blood at baseline and increased significantly after treatment in four of five patients. The highest proportion was detected early at cycle 3. These data again support trafficking of peripherally expanded clones to the tumor site and could indicate that the T cell response to treatment is derived from pre-existing peripherally tumor-associated T cells (Fig. 5g).
Signs of treatment-induced inflammation in the TME
To dissect changes in the TME induced by T cell influx upon treatment in responding patients, RNA gene expression analyses using the nCounter PanCancer Immune Profiling Panel from NanoString were performed on paired biopsies from two responding patients (MM01 and MM13). Expression of genes related to adaptive immunity such as T cell activation, effector functions (genes encoding IFN-γ, TNF-α, IL-15 and IL-18) and cytotoxicity was increased in post-treatment biopsies (Extended Data Fig. 9a,b). Also, expression of genes related to checkpoint inhibitors such as those encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3), IDO, PD-L1, PD-L2, PD-1 and CTLA-4 increased after treatment, indicating activation of immune cells in the TME (Extended Data Fig. 9c).
Additionally, IHC of paired biopsies from four patients (MM01, MM02, MM05 and MM13) showed an upregulation of PD-L1, IDO, MHC-I and MHC-II on tumor cells, indicating a treatment-induced pro-inflammatory response in the three responding patients, except for a decrease in MHC-II expression in patient MM13. By contrast, the non-responding patient MM02 had a reduction in T cell numbers present in the tumor after treatment and no expression of PD-L1, IDO or MHC-II and, interestingly, total loss of MHC-I, demonstrating tumor immune escape (Extended Data Fig. 10a).
CD8+ T cells and their distance (µm) to PD-L1-expressing cells in baseline biopsies from five patients was investigated by IHC. Except for patient MM13 (PR), distance and clinical responses were associated: the two responders had reduced distance (<20 µm) between cells expressing these markers compared to non-responding patients (>80 µm). This observation indicates that responding patients not only have a higher intratumoral infiltration of CD8+ T cells, but that these cells can surround and attack PD-L1-expressing immune cells and tumor cells (Extended Data Fig. 10b).
Discussion
In this clinical trial, MM1636, 30 patients with metastatic melanoma were treated with a first-in-class immunomodulatory IDO/PD-L1-targeting peptide vaccine combined with nivolumab. The treatment led to an unprecedented high ORR of 80%, with 43% of patients reaching a CR, and a striking mPFS of 26 months (95% CI, 15.4–69 months) was reached. The vaccine represents a new treatment strategy to activate specific T cells that target cells contributing to immune suppression (including tumor cells), positively modulating the TME by inducing local inflammation. Indeed, we show that vaccine-specific T cells isolated and expanded from vaccinated patients recognize not only tumor cells in a target- and HLA-restricted manner but also myeloid cells polarized toward a tumor-associated phenotype. Hence, myeloid cells become targets for vaccine-activated T cells when they have a tumor-associated phenotype in the TME. These phenomena may further induce checkpoint molecules and rewire the TME toward an increasingly aPD1-permissive state.
A drawback of our study is the single-center nonrandomized setup. Comparison between trials or between patients in trials and real-world patients is problematic due to multiple factors, such as period of conduction and other therapies available at the different periods of time. Nevertheless, the rate of investigator-assessed ORR in the phase 3 trial CheckMate 067 was 43.7% in the nivolumab monotherapy group and 57% in the nivolumab and ipilimumab group. CRs occurred in 8.9% and 11.5% of patients, respectively18. The mPFS of 26 months (95% CI, 15.4–69 months) in this trial is more than twice as long as that for patients treated with nivolumab and ipilimumab in CheckMate 067, for which an mPFS of 11.5 months (95% CI, 8.7–19.3 months) was reached.
Patient baseline characteristics were in general comparable to those of patients with MM who have been treated in CheckMate 067, although patients in MM1636 were older (mean age, 70 years) and a larger fraction were positive for PD-L1 (57%)3,18,22. Among patients with PD-L1-negative tumors in MM1636, an ORR of 61.5% was still reached, which would be expected to be around 33% for first-line nivolumab monotherapy23. Some studies suggest that older patients might have a tendency to respond better to aPD1 therapy; however, this is still debated24–27.
To address potential trial bias and the nonrandomized setup, patients in MM1636 were matched for age, performance status, sex, M stage, LDH level, PD-L1 status and BRAF status with a historical control group from the DAMMED, who were treated contemporarily (2015–2019) with aPD1 monotherapy as standard of care17. We found a significantly higher ORR and CRR in MM1636 compared to those of matched patients, who had an ORR of 43% and a CRR of 13%, comparable to patients treated in CheckMate 067. Restrictions of the synthetic control group are of course that it is partially historic and patient selection outside matching criteria cannot be ruled out28.
Numerous contemporary clinical trials are exploring the combination of aPD1 therapy with other immunomodulating agents for advanced melanoma.
Talimogene laherparepvec, an oncolytic virus, is approved by the Food and Drug Administration and the European Medicines Agency to treat advanced melanoma. A small phase 1b trial with 21 patients (MASTERKEY-265) combined talimogene laherparepvec and pembrolizumab to treat patients with advanced unresectable melanoma and reached an ORR of 62% and a CR of 33%29,30. Seventy-one percent of the patients in this trial had an M stage below M1c; this number was 40% in our trial. Furthermore, mainly patients with an M stage below M1c responded to treatment, which was not the case in MM1636. Results from a large randomized phase 3 trial are awaited (KEYNOTE-034).
Epacadostat, an IDO inhibitor, was tested in combination with pembrolizumab in a nonrandomized phase 2 trial in 40 aPD1 treatment-naive patients with MM with promising results, reaching an ORR of 62%. Unfortunately, the phase 3 trial showed no indication that epacadostat provided improvement in PFS and OS31. Limitations of the phase 3 trial were the sparse information on pharmacodynamics as well as biomarker evaluation to improve the design. The IDO/PD-L1 vaccine is different from epacadostat, as it is not an IDO inhibitor but targets IDO- and PD-L1-expressing cells. Similar vaccines administered as monotherapy induced objective responses in lung cancer and basal cell carcinoma, while epacadostat as monotherapy in 52 patients resulted in no responses32,33.
Sahin et al. recently published encouraging data from a first-in-human trial, in which a vaccine containing liposomal RNA targeting four unmutated tumor-associated antigens (NY-ESO-1, MAGE-A3, tyrosinase and TPTE) was administered alone or in combination with nivolumab in patients with advanced melanoma. Responses were observed in both the monotherapy group as well as the combination group in checkpoint inhibitor-experienced patients, suggesting the efficacy of non-mutant shared tumor antigen vaccines34.
The overall safety and tolerability findings are comparable to those of aPD1 monotherapy. Injection site reactions were exclusive to the vaccine. However, these side effects were transient and mild in most patients and most likely due to the adjuvant Montanide. IDO- and PD-L1-specific CD8+ and CD4+ T cells exist among peripheral blood lymphocytes in healthy donors35–38 and expand in response to pro-inflammatory stimuli35,39. Furthermore, both IDO and PD-L1 are induced in cells as a counter response to the inflammatory response. This provides a mechanism that ensures immune homeostasis, which keeps IDO/PD-L1-specific T cells in check; therefore, the risk of triggering autoimmune-related adverse events by vaccination appears to be minimal. This was confirmed in the first clinical trials of IDO and PD-L1 vaccination (NCT01543464 (refs. 33,40) and NCT03042793 (ref. 41)).
The spontaneous (baseline) immune response to the vaccines observed in the current study is in agreement with our previous observation in various patients with cancer35–38. Numerous vaccine-induced changes in the blood and at the tumor site were observed. Peripheral IDO- and/or PD-L1-specific T cells were detected in vitro in a modified ELISPOT in over 93% of patients on vaccination, unrelated to patient HLA type. Immune responses were persistent in patients who surpassed follow-up at data cutoff and were still detectable up to 6 months after the last vaccine, suggesting induction of memory T cells. We did not observe a correlation between vaccine-induced responses in blood and clinical responses. However, the detection of a highly significant increase in vaccine-specific T cell numbers after vaccination in almost all patients together with the very low number of patients with PD makes it difficult to expect such a correlation, especially because other aspects should be taken into account (for example, the loss of class I expression on tumors cells in patient MM02 with PD after vaccination). Frequencies of peripheral T cells induced against PD-L1 were overall higher than those against IDO. Importantly, however, we also observed that it was not the same patients who responded strongly to both IDO and PD-L1, nor did patients react with a similar response pattern to the two antigens; that is, different time points of response were observed. This suggests that each component of the vaccine plays different roles in the ongoing immune response in patients. The goal of IDO/PD-L1 vaccination was to modulate the TME to increase responsiveness to aPD1 therapy, as we have observed in animal models, in which immune conversion is demonstrated in the TME with an increased influx of T cells. Targeting both IDO and PD-L1 together enables synergy, as the TME is known to use different immune escape mechanisms and IDO and PD-L1 are often overexpressed by different cellular compartments. Ex vivo ELISPOT and flow cytometry assays confirmed the induction of immune response toward both epitopes and the higher immunogenicity of the PD-L1 epitope, although because of lower sensitivity failed to detect some of the responses. TCR sequencing of five patients confirmed enrichment of IDO/PD-L1-specific T cell clones in the blood at different time points after treatment. Furthermore, an increase in enriched IDO/PD-L1-specific clones was observed in four of five patients at the tumor site after treatment, irrespective of clinical response.
Phenotypic characterization showed that vaccine-specific T cells, which were expanded in vitro with interleukin (IL)-2 from the blood of vaccinated individuals, were both CD4+ T cells and CD8+ T cells. This was confirmed by ex vivo phenotype description of vaccine-activated T cells. Vaccine-specific T cells expressed CD107a and CD137 and produced IFN-γ and TNF-α upon stimulation with the cognate target, indicating their cytolytic capacity.
Overall, the data from immune monitoring supports the importance of both antigens in the generation of the frequent clinical responses in the study.
Despite a limited number of paired biopsies (due to either patient refusal or the fact that a large fraction of responding patients had no assessable tumors after six cycles), we observed trends indicating treatment-induced general T cell influx in responding patients. It was shown that proliferation of CD8+ T cells in the tumor after aPD1 treatment is associated with radiographic reduction in tumor size42. Additionally, we showed that a large proportion of expanded peripheral TCR clones were associated with tumors and the most considerable amount of clonal expansion was observed early, at cycle 3. For the patient with a CR included in the TCR sequencing analyses (MM01), the number of peripheral expanded clones present at the tumor site increased after treatment compared to that at baseline, indicating tumor trafficking of peripheral expanded clones.
Gene expression analyses (two paired biopsies) and IHC (five paired biopsies) further demonstrated that the combination treatment induced a pro-inflammatory TME in responding patients with signs of T cell activation and cytotoxicity and increased cytokine activity. This may lead to further upregulation of IDO, PD-L1, MHC-I and MHC-II on tumor cells, leading to more treatment targets. It was shown that, following vaccination with a cancer vaccine, PD-L1 expression is increased on tumor cells due to recruitment of tumor-specific T cells and upregulation of adaptive immune resistance pathways in the TME43. Treatment with nivolumab monotherapy enhances PD-L1 expression, and it is therefore problematic to discriminate the effect of the vaccine as compared to that of nivolumab44.
IDO- and PD-L1-specific pro-inflammatory effector T cells were hypothesized to counteract the functions of IDO- and PD-L1-expressing immune-suppressive cells as a means to keep the immune balance between immune activation and inhibition45. However, because the expression of these molecules is induced as a counter-regulatory response to inflammatory mediators such as IFNs, they can also be expressed by, for example, activated myeloid cells or T cells. Thus, activation of PD-L1-specific T cells may result in depletion of activated T cells in the tumor and other sites. Importantly, it was recently described that PD-L1+ T cells mainly have tolerogenic effects on tumor immunity and exert tumor-promoting properties, suggesting that targeting this immune population is indeed also beneficial46. We have previously investigated the effect of activating PD-L1-specific T cells in vitro and in vivo and found that, overall, they supported the effector phase of an immune response by removing PD-L1-expressing regulatory immune cells that inhibit PD-1+ effector T cells47,48. The major role of the PD-1 pathway is believed to be the regulation of effector T cell responses. Thus, this protective pathway is more important after activation, rather than at the initial T cell-activation stage49. Accordingly, the presence of PD-L1-specific T cells during the activation phase of an immune response may not increase or support a pro-inflammatory immune response due to the expression of PD-L1 on potent antigen-presenting cells or on the T cells themselves14. Thus, the overall effects of PD-L1-specific T cells may vary depending on the expression of both PD-1 and PD-L1, that is, due to the microenvironment and the state of the immune response.
In conclusion, here we report an impressive response rate, CR rate and mPFS for a first-in-class immune-modulating vaccine combined with nivolumab. This may be a first step toward a new treatment strategy for patients with MM. Limitations are the low number of patients treated at a single institution and the lack of a randomized design with aPD1 monotherapy as comparator. Studies in aPD1 therapy-resistant or -refractory melanoma are ongoing as well as biomarker analysis for selecting patients at a higher likelihood to benefit from the combination versus aPD1 monotherapy. A larger randomized trial will be essential to validate these findings and determine the specific contribution of the vaccine to clinical responses and changes in the TME. In December 2020, the Food and Drug Administration granted breakthrough therapy designation for the IO102/IO103 vaccine combined with aPD1 therapy in metastatic melanoma based on data from the MM1636 trial.
Methods
Trial design and treatment plan
MM1636 is an investigator-initiated, nonrandomized, open-label, single-center phase 1/2 study. All patients were treated at the Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark. The study was conducted according to the Declaration of Helsinki and Good Clinical Practice (GCP) and monitored by the GCP unit in Copenhagen, Denmark. The protocol was approved by the ethical committee of the Capital region of Denmark (H-17000988), the Danish Medical Agencies (2017011073) and the Capital Region of Denmark Data Unit (P-2019-172). The study was registered at https://clinicaltrials.gov/ under the identifier NCT03047928 and at the EudraCT (no. 2016-0004527-23).
This study initially aimed to include 30 aPD1 treatment-naive patients with MM. An amendment with the addition of two other cohorts with ten patients in each cohort was made to evaluate immune responses and clinical efficacy in aPD1 therapy-resistant patients (cohort B, de novo resistance and cohort C, acquired resistance) for a total of 50 patients. The amendment with cohorts B and C was approved at the inclusion of 18 patients in cohort A. The trial is still including patients in cohorts B and C. This article reports results from cohort A.
The first six patients were treated as for phase 1, evaluating for safety and tolerability before the remaining 24 patients were included in phase 2.
The IDO/PD-L1 vaccine was administered subcutaneously biweekly for the first 10 weeks and thereafter every 4 weeks for approximately 9 months. A maximum of 15 vaccines were administered. Nivolumab was administered according to the approved label (3 mg per kg biweekly) for 24 cycles. The 15th vaccine was administered together with the 24th nivolumab cycle of 3 mg per kg, and responding patients thereafter continued nivolumab monotherapy every 4th week (6 mg per kg) as a standard of care after investigator assessment. Treatment with nivolumab was discontinued at the maximum benefit (assessed by the investigator), after a maximum of 2 years of therapy, at progression or due to severe adverse events (Extended Data Fig. 1b, treatment plan).
Vaccine composition
Each vaccine was composed of 100 µg IO102, a 21-amino-acid peptide (DTLLKALLEIASCLEKALQVF) from IDO, and 100 µg IO103, a 19-amino-acid peptide (FMTYWHLLNAFTVTVPKDL) from the signal peptide of PD-L1 (PolyPeptide Laboratories). Peptides were dissolved separately in 50 µl DMSO, filtered for sterility and frozen at −20 °C (NUNC CyroTubes CryoLine System Internal Thread, Sigma-Aldrich). At <24 h before administration, peptides were thawed. The PD-L1 peptide was diluted in 400 µl sterile water and, immediately before injection, mixed with the IDO peptide solution and 500 µl Montanide ISA-51 (SEPPIC) to achieve a total volume of 1 ml.
Patients
Patients above 18 years of age with locally advanced or stage 4 melanoma according to the AJCC (seventh edition), at least one measurable lesion according to RECIST 1.1 and an ECOG PS of 0–1 were eligible. The main exclusion criteria were prior treatment with aPD1 therapy, CNS metastases >1 cm, severe comorbidities and active autoimmune disease. Enrollment was not restricted to PD-L1 status, but it was known before inclusion. Patients were included after informed consent.
Patients MM42 and MM20 have confirmed their approval of PET–CT images and clinical images that have been included in the article.
Key study assessments
Safety and tolerability were evaluated based on changes in clinical laboratory analyses and reported adverse events. Adverse events were assessed according to Common Terminology Criteria for Adverse Events (version 5.0) and were graded from 1 to 5 for all treated patients up to 6 months after the last dose of the IDO/PD-L1 vaccine.
Clinical efficacy was assessed using FDG PET–CT scans before treatment and every 3rd month until progression. Objective responses were categorized into CR, PR, stable disease or PD according to RECIST version 1.1.
Clinical data were collected at CCIT-DK in the eCRF program OpenClinica version 1.0 and in Microsoft Excel version 2002 on a secure server.
Blood samples for immunologic analyses were collected before treatment, before the third cycle, after the sixth, 12th, 18th and 24th cycles (on vaccination) and 3 and 6 months after the last vaccine.
Two to three tumor needle biopsies (1.2 mm) were collected at baseline and after six cycles from the same tumor site, when accessible, to evaluate immune responses at the tumor site.
DTH skin tests were performed and punch biopsies were taken from the DTH area after cycle 6 for the evaluation of SKILs reactive to PD-L1 and IDO (Supplementary Fig. 1, treatment plan).
Statistical analysis of clinical outcome
Survival curves were computed in GraphPad Prism software version 9.0.0 according to Kaplan–Meier method. Median follow-up time of enrollment was calculated using the reverse Kaplan–Meier method, also in GraphPad Prism software version 9.0.0.
For binary outcomes, 95% two-sided CIs were constructed using the Clopper–Pearson method, also in GraphPad version 9.0.0.
An independent board of certified and experienced oncoradiologists performed an external review to evaluate clinical response to address the potential bias of investigator site review. The external review took place at Rigshospitalet, Copenhagen University Hospital. This hospital did not participate in the MM1636 trial, and the external reviewer had no prior knowledge about the clinical trial or the trial therapy. Only PET–CT images were accessed, and arrows indicating target or non-target lesions appeared on baseline images as the only additional information.
To address potential trial bias regarding treatment effect, we matched patients in MM1636 with patients from the DAMMED, a population-based database that retrospectively collects data on patients with metastatic melanoma in Denmark. Here, data from 938 patients treated with aPD1 monotherapy contemporaneously (January 2015–October 2019) were extracted. Two hundred and eighteen of these patients were eligible for comparison and matching (all parameters available) (Supplementary Table 1), and 74 patients from the DAMMED were found to match. Patients were matched for age (≤70 years, >70 years), sex, LDH levels (normal, elevated), M stage (M1a, M1b, M1c), BRAF status (wild type, mutated) and PD-L1 status (<1%, ≥1%). An exact matching algorithm was used in which patients in MM1636 were matched with patients from the DAMMED with the same combination of variables. Twenty-nine patients from MM1636 were matched with exact combinations of the six variables. One patient could not be matched. To secure balance of the calculations, control patients were weighted according to the number of patients for each MM1636 patient. Estimates for treatment effects were calculated by weighted logistic regression analyses and weighted Cox proportional hazard model. The R package ‘Matchlt’ was used for matching patients.
As the method chosen for matching control patients to protocol patients, a weighted binary logistic regression model was used for comparing response rates in the two matched cohorts. Odds ratios and response rates, including their corresponding 95% CIs, were extracted from the regression models. All P values were two sided, and P values below 0.05 were considered statistically significant. SAS version 9.4M5 was used for the weighted logistic regression models.
Processing of peripheral blood mononuclear cells
Peripheral blood was collected from all patients in heparinized tubes and was processed within 4 h. In brief, PBMCs were isolated using Lymphoprep (Medinor) separation. PBMCs were counted on a Sysmex XP-300 analyzer and frozen in Human AB Serum (Sigma-Aldrich, H4522-100ML) with 10% DMSO using controlled-rate freezing (CoolCell, BioCision) in a −80 °C freezer and were moved the next day to a freezer at −140 °C until further processing.
Needle biopsies at baseline and after the sixth vaccine
Two to three needle biopsies (1.2 mm) were taken at baseline and after the sixth cycle of treatment when assessable from the same tumor lesion.
One fragment was fixed with formalin and embedded in paraffin (FFPE); one to two fragments were used for expanding tumor-infiltrating T cells and establishing autologous tumor cell lines.
Delayed-type hypersensitivity and generation of skin-infiltrating lymphocytes
After six cycles of treatment, we performed intradermal injections of vaccine components without adjuvant and one control injection containing DMSO without peptide. Patients were injected with either a mixture of both IDO and PD-L1 peptides at all three injection sites or PD-L1 peptide, IDO peptide or a mixture of the two at the injection sites, respectively (Supplementary Table 6). Eight hours after injection, punch biopsies were resected from the three sites where the peptide was injected and transported immediately to the laboratory and cut into fragments of 1–2 mm3.
SKILs were expanded to establish ‘young SKILs’ in CM medium consisting of RPMI 1640 with GlutaMAX, 25 mM HEPES, pH 7.2 (Gibco, 72400-021), IL-2 (100 or 6,000 IU ml−1) (Proleukin Novartis, 004184), 10% heat-inactivated Human AB Serum (Sigma-Aldrich, H4522-100ML), 100 U ml−1 penicillin, 1.25 µg ml−1 Fungizone (Bristol Myers Squibb, 49182) and 100 µg ml−1 streptomycin (Gibco, 15140-122). Half of the medium was replaced three times per week.
Young SKILs from samples derived from IDO peptide, PD-L1 peptide and the mixture injection sites were further expanded in a small-scale version of the 14-d rapid expansion protocol as previously described51.
Quantification of specific T cells in blood by ELISPOT
For enumeration of vaccine-specific T cells in the peripheral blood, PBMCs from patients were stimulated with IDO or PD-L1 peptide in the presence of a low dose of IL-2 (120 U ml−1) for 7–13 d before being used in IFN-γ ELISPOT assays with 2.5–3.2 × 105 cells per well.
Briefly, cells were placed in a 96-well PVDF membrane-bottomed ELISPOT plate (MultiScreen MSIPN4W50, Millipore) precoated with IFN-γ-capture antibody (clone 1-D1K, Mabtech). Diluted IDO or PD-L1 peptide stocks in DMSO were added at 5 µM; an equivalent amount of DMSO was added to control wells. PBMCs from each patient were set up in duplicate or triplicate for peptide and control stimulations. Cells were incubated in ELISPOT plates in the presence of the peptide for 16–18 h, after which they were washed off, and biotinylated secondary antibody (anti-human IFN-γ mAB, clone 7-B6-1, Mabtech) was added. After 2 h of incubation, unbound secondary antibody was washed off, and streptavidin-conjugated alkaline phosphatase (Mabtech) was added for 1 h. Next, unbound streptavidin-conjugated enzyme was washed off, and the assay was developed by adding BCIP/NBT substrate (Mabtech). ELISPOT plates were analyzed on the CTL ImmunoSpot S6 Ultimate V analyzer using ImmunoSpot software version 5.1. Responses were calculated as the difference between the average numbers of spots in wells stimulated with IDO or PD-L1 peptide and those from corresponding control wells.
For detection of IDO and PD-L1 peptide responses ex vivo, PBMCs were thawed and rested overnight in medium containing DNase I (1 μg ml−1, Sigma-Aldrich, 11284932001) before being used in IFN-γ ELISPOT assays as described above. A total of 6–9 × 105 PBMCs per well were seeded. Statistical analysis of all ELISPOT responses was performed using the DFR method as described by Moodie et al. using RStudio software (RStudio Team, 2016, http://www.rstudio.com/)50.
Vaccine-specific ELISPOT responses were defined as true if the difference between the spot count in control and peptide-stimulated wells was statistically significant according to DFR statistical analysis or, for samples performed in duplicate, if the spot count in peptide-stimulated wells was at least 2× the spot count in control wells50.
Cancer cell lines and tumor conditioned medium
Autologous melanoma cell lines were established from needle biopsies. Briefly, biopsies were chopped into small fragments and seeded in 24-well cultures in RPMI 1640 with GlutaMAX, 25 mM HEPES, pH 7.2 (Gibco, 72400-021), 10% heat-inactivated FBS (Life Technologies, 10500064), 100 U ml−1 penicillin, 1.25 µg ml−1 Fungizone (Bristol Myers Squibb, 49182) and 100 µg ml−1 streptomycin (Gibco, 15140-122). Established adherent melanoma tumor cell lines were cryopreserved at −140 °C in freezing medium containing FBS with 10% DMSO. PD-L1 and HLA-II expression on established tumor cell lines was assessed by flow cytometry staining with anti-PD-L1–PE-Cy7 (1:23 dilution, clone M1h1 (RUO), BD, 558017) and anti-HLA-II–FITC (1:23 dilution, clone Tu39 (RUO), BD, 555558) antibodies.
To obtain TCM, established tumor cell lines were cultured in 175-cm2 Nunc cell culture flasks until 80–90% confluency was reached. The culture medium was then replaced with 20 ml fresh X-VIVO 15 with Gentamicin and Phenol Red (Lonza, BE02-060Q), medium with 5% heat-inactivated Human AB Serum (Sigma-Aldrich, H4522-100ML). After 24 h of incubation, TCM was collected and centrifuged to remove any resuspended cells, after which TCM was aliquoted, frozen and stored at −80 °C.
The acute monocytic leukemia cell line MonoMac1 was obtained from the DSMZ—German Collection of Microorganisms and Cell Cultures (ACC 252) and cultured in RPMI 1640 with GlutaMAX, 25 mM HEPES, pH 7.2 (Gibco, 72400-021) and 10% heat-inactivated FBS.
Isolation of autologous myeloid cells
Autologous CD14+ cells were sorted from freshly thawed PBMCs using a magnetic bead-separation kit (Miltenyi Biotec, 130-050-201) according to the manufacturer’s instructions. Isolated CD14+ cells were used as targets in the IFN-γ ELISPOT assay directly after sorting or differentiated in vitro into tumor-associated macrophages by culturing with 1 ml fresh X-VIVO 15 medium with Gentamicin and Phenol Red (Lonza, BE02-060Q) and 5% heat-inactivated Human AB Serum, supplemented with 1 ml autologous TCM in 24-well plates for 2 d.
Quantification of vaccine-specific T cells from DTH biopsy sites by ELISPOT
SKILs expanded in vitro were rested in medium without IL-2 overnight before being used in the IFN-γ ELISPOT assay as described above to evaluate reactivity of skin-infiltrating T cells.
Generation of IDO- and PD-L1-specific T cell cultures from PBMCs or SKILs
IDO- or PD-L1-specific T cells were isolated from peptide-stimulated in vitro PBMC cultures on days 14–15 after stimulation or from SKIL cultures expanded in vitro. For specific T cell isolation, PBMCs or SKILs were stimulated with IDO or PD-L1 peptide, and cytokine-producing T cells were sorted using the IFN-γ or TNF-α Secretion Assay—Cell Enrichment and Detection kit (Miltenyi Biotec).
Cytokine-production profile of PD-L1- and IDO-specific T cells by intracellular staining
To assess the T cell cytokine-production profile, isolated and expanded IDO- and PD-L1-specific T cell cultures were stimulated for 5 h with peptide at 5 μM in a 96-well plate. One hour after the start of the incubation, anti-CD107a–PE (1:133 dilution, clone H4A3, BD Biosciences, 555801) antibody and BD GolgiPlug (1:1,000 dilution, BD Biosciences) were added. After a 5-h incubation, cells were stained using fluorescently labeled surface marker antibodies: anti-CD4–PerCP (1:5 dilution, clone SK3, 345770), anti-CD8–FITC (1:5 dilution, clone SK1, 345772) and anti-CD3–APC-H7 (1:20 dilution, clone SK7, 560275) (all from BD Biosciences). Dead cells were stained using FVS510 (1:250 dilution, BD Biosciences, 564406), followed by overnight fixation and permeabilization using eBioscience Fixation/Permeabilization buffers (00-5123-43, 00-5223-56) according to the manufacturer’s instructions. Cells were then stained intracellularly in eBioscience permeabilization buffer (00-8333-56) with anti-IFN-γ–APC (1:20 dilution, clone 25723.11, BD Biosciences, 341117) and anti-TNF-α–BV421 (1:100 dilution, clone Mab11, BD Biosciences, 562783) antibodies. Samples were analyzed on the FACSCanto II (BD Biosciences) using BD FACSDiva software version 8.0.2. The gating strategy is shown in Supplementary Fig. 3a. For assessing the reactivity against IDO expressing MonoMac1 cells, the appropriate amount of cancer cells was added to the IDO-specific T cells to obtain an effector:target ratio of 4:1 in the 96-well plate and T cell cytokine production was tested after 5 h of co-culture as described above. For HLA-blocking experiments, HLA-blocking antibodies (2 μg ml−1) were added directly into wells 30 min before the addition of peptide. Blocking antibodies used were HLA-DR (1:500 dilution, clone L243, Abcam, ab136320), HLA-DQ (1:500 dilution, clone SPV-L3, Abcam, ab23632) and HLA-DP (1:500 dilution, clone B7/21, Abcam, ab20897).
To assess ex vivo T cell reactivity to IDO and PD-L1 peptides in patient PBMCs, cells were thawed and rested for 1–2 d in medium containing DNase I (1 μg ml−1, Sigma-Aldrich, 11284932001). PBMCs were then stimulated with peptide at 5 μM in a 96-well plate for 8 h. An hour after the addition of peptide, anti-CD107a–BV421 (3:50 dilution, clone H4A3, BD Biosciences, 328626) antibody and BD GolgiPlug (1:1,000 dilution, BD Biosciences) were added. Surface and intracellular staining was performed as described above. Antibodies used for surface staining were anti-CD3–PE-CF594 (0.8:30 dilution, clone UCHT1, BD Biosciences, 562280), anti-CD4–BV711 (1:30 dilution, clone SK3, BD Biosciences, 563028) and anti-CD8–Qdot605 (1:150 dilution, clone 3B5, Thermo Fisher, Q10009). Antibodies used for intracellular staining were anti-CD137–PE (1:20 dilution, clone 4B4-1 (RUO), BD Biosciences, 555956), anti-IFN-γ–PE-Cy7 (1.5:20 dilution, clone B27, BD Biosciences, 557643) and anti-TNF-α–APC (1:20 dilution, clone Mab11, BD Biosciences, 554514). Samples were acquired on the NovoCyte Quanteon (ACEA Biosciences) and analyzed using NovoExpress software version 1.4.1. To assess vaccine-specific T cell responses, background values observed in unstimulated PBMC samples were subtracted from values observed in peptide-stimulated conditions. Positive response value threshold was set at a difference of 0.2% from the background values. Based on this response cutoff, only TNF-α, CD107a and CD137 responses were detected in this assay. Statistical analysis comparing baseline with on-treatment or post-treatment cytokine profiles was performed using two-sided Wilcoxon matched-pairs signed-rank test. The gating strategy is shown in Supplementary Fig. 3b.
siRNA-mediated PD-L1 and IDO1 silencing
A stealth siRNA duplex for targeted silencing of PD-L1 (Invitrogen)52, a custom silencer select siRNA for targeted silencing of IDO1 (Ambion) and the recommended silencer select negative control (Ambion) siRNA for mock transfection were used.
The stealth PD-L1 siRNA duplex consisted of the sense sequence 5′-CCUACUGGCAUU-UGCUGAACGCAUU-3′ and the antisense sequence 5′-AAUGCGUUCAGCAAAUGCCAGUAGG-3′. The three silencer IDO siRNA duplexes used were siRNA1 (sense sequence, 5′-ACAUCUGCCUGAUCUCAUATT-3′; antisense sequence, 5′-UAUGAGAUCAGGCAGAUGUTT-3′), siRNA2 (sense sequence, 5′-CCACGAUCAUGUGAACCCATT-3′; antisense sequence, 5′-UGGGUUCACAUGAUCG-UGGAT-3′) and siRNA3 (sense sequence, 5′-CGAUCAUGUGAACCCAAAATT-3′; antisense sequence, 5′-UUUUGGGUUCACAUGAUCGTG-3′). For PD-L1 or IDO1 silencing, cancer cells were electroporated with 0.025 nmol of each siRNA duplex as previously described53. For PD-L1-silencing experiments, cancer cells were treated with IFN-γ (500 U ml−1, PeproTech) 1 h after electroporation. Electroporated cells were used as target cells in ELISPOT and ICS assays 24 h or 48 h after siRNA electroporation.
RT–qPCR
Total RNA was extracted using the RNeasy Plus Mini kit (Qiagen, 74134) following the manufacturer’s instructions. RNA concentration was quantified using a NanoDrop 2000 (Thermo Fisher Scientific), and a total of 1,000 ng RNA was reverse transcribed with the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, 4368814) using 1,000 ng input RNA for transcription. Real-time qPCR analyses were performed using the TaqMan Gene Expression Assay on a Roche LightCycler 480 instrument. RT–qPCR assays were performed with a minimum of three technical replicates and analyzed using the ΔCt method as described in Bookout et al.54 with normalization of IDO1 expression (primer ID, Hs00984148_m1) or PD-L1 expression (primer ID, Hs001125296_m1) to the expression level of the housekeeping gene POLR2A (primer ID, Hs00172187_m1) and the control sample (mock). For low-concentration samples with no amplification, Ct was set to 40. Controls without reverse transcriptase were used as controls for specific amplifications. P values were determined using two-tailed parametric t-tests.
BRAF-mutational status and PD-L1 status at baseline in all patients
A library of historical FFPE biopsies were assessable for all patients and analyzed locally at Herlev and Gentofte University Hospital by experienced pathologists for BRAF status and PD-L1 expression on tumor cells.
The BRAF analysis was carried out with real-time PCR using the EntroGen BRAF Mutation Analysis Kit II (BRAFX-RT64, CE-IVD) to specifically detect mutations corresponding to V600D, V600E and V600K in the BRAF protein.
PD-L1 status was assessed using the monoclonal rabbit anti-PD-L1 antibody (clone 28.8, PD-L1 IHC 28-8 pharmDx) in FFPE biopsies following the manufacturer’s instructions. Patients were considered positive for PD-L1 with expression levels ≥1% and negative for PD-L1 with expression levels <1%.
Human leukocyte antigen type
Blood samples from all 30 patients were genotyped for class I (HLA-A, HLA-B, HLA-C) and three class II types (HLA-DRB1, HLA-DQA1, HLA-DQB1) using LinkSēq HLA Typing Kits (Thermo Fisher, 1580C). These test kits are based on real-time PCR using allele-specific exponential amplification (sequence-specific primers) followed by melting curve analyses.
Immunohistochemistry simplex: Immunoscore CR
IHC staining was performed using a qualified Ventana Benchmark XT with four different steps: (1) antigen retrieval; (2) staining with the following primary antibodies: anti-CD3 antibody (clone HDX2; provider, HalioDx; HD-FG-000013; 10931065/10636667; concentration, 0.25 µg ml−1), anti-CD8 antibody (clone HDX3; provider, HalioDx; HD-FG-000019; 10931069/10337710/10639301; concentration, 0.5 µg ml−1), anti-IDO monoclonal antibody (clone VINC3IDO; provider, Thermo Fisher Scientific; 14-9750-82; E25003-101; concentration, 0.05 µg ml−1), anti-HLA class 1 ABC antibody (clone, EMR8-5; provider, Abcam; ab70328; GR3248333/GR3186494; concentration, 0.5 µg ml−1), anti-HLA-DR/DP/DQ/DX antibody (clone CR3/43; provider, Santa Cruz; sc-53302; L1714; concentration, 1 µg ml−1) and anti-PD-L1 antibody (clone HDX3; provider, HalioDx; HD-FG-000035; 106312810/106312816; concentration, 3.3 µg ml−1); (3) detection with a secondary antibody using the ultraView Universal DAB Detection kit; and (4) counterstaining using Hematoxylin & Bluing Reagent (staining of cellular nuclei). Control slides were systematically included in each staining run to permit quality control of the obtained measurements. Following coverslipping, slides were scanned with the NanoZoomer-XR to generate digital images (20×).
Two consecutive slides were specifically used to perform Immunoscore CR TL staining of CD3+ and CD8+ cells.
Digital pathology of T lymphocytes
The digital pathology for Immunoscore CR TL allowed the quantification of positive cells (in cells per mm2) into the core tumor and invasive margin if present. Each sample was analyzed using the HalioDx Digital Pathology Platform.
Digital pathology and pathologist analysis of IDO
Digital pathology for IDO allowed the quantification of stained area (in mm2) into the whole tumor. Each sample was analyzed using the HalioDx Digital Pathology Platform.
Analysis of IDO+ cells was performed by a pathologist. Results were expressed as an H score from 0 to 300. The score is obtained by the formula 3 × percentage of cells with strong staining + 2 × percentage of cells with moderate staining + percentage of cells with weak staining.
Digital pathologist analysis of MHC-I and MHC-II
Analysis of MHC-I+ and MHC-II+ cells was performed by a pathologist. Results are expressed as a percentage of positive tumor cells and a percentage of positive cells in the stroma.
Digital pathology Immunoscore immune checkpoint (CD8+ and PD-L1+)
The Immunoscore CR IC test allowed the quantification of CD8++ cell density in the whole tumor and a CD8+-centered proximity index (which corresponds to the percentage of CD8++ cells that have at least one PD-L1+ cell in the neighborhood) at different cutoff distances (20 µm, 40 µm, 60 µm and 80 µm).
Pathologist analysis of PD-L1
A pathologist performed analysis of PD-L1+ cells. Positivity of a viable tumor cell was considered when partial or complete cell membrane staining was observed (more than 10% of the tumor cell membrane). Results were expressed as a percentage.
NanoString RNA profiling and Immunosign
RNA was extracted from FFPE tissues using Qiagen RNeasy FFPE extraction kits (Qiagen). Annotations from the pathologist performing H&E staining were used to guide removal of normal tissue from the slides by macrodissection before nucleic acid extraction, which occurred after tissue deparaffinization and lysis. Each extracted RNA sample was independently quantified using a NanoDrop spectrophotometer (NanoDrop Technologies) and qualified (Agilent Bioanalyzer). Degradation was quantified as the percentage of RNA fragments smaller than 300 bp using the RNA 6000 Nano kit (Agilent Bioanalyzer). Good sample quality was defined as less than 50% of RNA fragments being 50–300 bp in size.
RNA expression profiling was performed using the nCounter PanCancer Immune Profiling Panel from NanoString (NanoString Technologies). The PanCancer Immune Profiling Panel contains 776 probes and is supplemented with six genes to complete HalioDx Immunosign targets.
Hybridization was performed according to the manufacturer’s instructions. Hybridized probes were then purified and immobilized on a streptavidin-coated cartridge using the nCounter Prep Station (NanoString Technologies). Data collection was carried out on the nCounter Digital Analyzer (NanoString Technologies) following the manufacturer’s instructions to count individual fluorescent barcodes and quantify target RNA molecules present in each sample. For each assay, a scan of 490 fields of view was performed.
Raw data from the NanoString nCounter were processed using NanoString recommendations.
Quality control enables to retain data of good quality with a binding density that ranges between 0.05 and 2.25. The linearity of positive controls was checked using the R2 value of regression between the counts and the concentrations of positive controls. Samples that showed R2 < 0.75 were flagged and removed from the analysis. The background was removed using a thresholding method at the mean + 2 s.d. of negative controls. Raw counts were normalized using a positive normalization factor. Samples showing positive normalization factors outside the range of 0.3–3 were removed from the analysis. A second normalization was performed using the housekeeping gene normalization factor. Only the most stable housekeeping genes were selected for this normalization step using the variance-versus-mean relationship. All samples showing a normalization factor outside the range of 0.1–10 were removed from the analysis. All statistical analyses were performed on normalized counts using R software (version 2.6.2, 2019-12-12).
T cell receptor variable β chain sequencing
To track longitudinal immune responses to therapy, genomic DNA was extracted from longitudinal pre- and post-treatment PBMCs (five patients), pre- and post-treatment biopsies (five patients) (both FFPE and treated with RNAlater) and IDO- and PD-L1-specific T cell cultures from PBMCs (five patients) or SKILs (one patient). Three clonal (two IDO- and one PD-L1-) specific cultures were also sequenced to confirm clonal purity of cultures.
DNA from PBMCs or RNAlater-treated biopsies was extracted with the DNeasy Blood and Tissue kit (Qiagen, 69504), DNA from sorted IDO and PD-L1-specific T cells from either PBMCs or SKILs was extracted using the QIAamp DNA Micro kit (Qiagen, 565304), and DNA from PFFE biopsies was extracted using the Maxwell RSC DNA FFPE kit (Promega, AS1450).
Immunosequencing of the CDR3 regions of human TCRβ chains was performed using the immunoSEQÒ Assay (Adaptive Biotechnologies). Extracted genomic DNA was amplified in a bias-controlled multiplex PCR, followed by high-throughput sequencing. Sequences were collapsed and filtered to identify and quantitate the absolute abundance of each unique TCRβ CDR3 region for further analysis as previously described55–57.
Statistical analyses of TCRβ sequencing results
Two quantitative components of diversity were compared across samples in this study. First, Simpson clonality was calculated on productive rearrangements by ∑i=1Rpi2, where R is the total number of rearrangements and pi is the productive frequency of rearrangement i. Values of Simpson clonality range from 0 to 1 and measure how evenly receptor sequences (rearrangements) are distributed among a set of T cells. Clonality values approaching 0 indicate a very even distribution of frequencies, whereas values approaching 1 indicate an increasingly asymmetric distribution in which a few clones are present at high frequencies.
Second, sample richness was calculated as the number of unique productive rearrangements in a sample after computationally downsampling to a common number of T cells to control for variation in sample depth or T cell fraction. Repertoires were randomly sampled without replacement five times, and we report the mean number of unique rearrangements.
The T cell fraction was calculated by taking the total number of T cell templates and dividing by the total number of nucleated cells. The total number of nucleated cells was derived from reference genes using the immunoSEQ Analyzer version 3.
To identify enriched vaccine clones in each patient, rearrangement frequencies in their baseline PBMCs and each IDO/PD-L1-sorted T cell sample were compared using a binomial distribution framework as previously described58. In brief, for each clone, we performed a two-sided test to determine whether frequencies were the same in the patient’s periphery and a PD-L1- or IDO-specific T cell sample. The Benjamini–Hochberg procedure was used to control the false discovery rate at 0.01 (ref. 59). Clonal expansion in post-treatment samples was similarly assessed using this differential abundance framework, but an IDO/PD-L1-specific T cell sample was replaced with a post-treatment series sample. In biopsies, the six series frequencies were compared to those of baseline tissue. Lastly, vaccine-associated clones were tracked in each PBMC and tissue sample by summing the frequency of each rearrangement enriched in either PD-L1- or IDO-specific T cells. All statistical analyses were performed in R version 3.6.1.
Reporting Summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Online content
Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-021-01544-x.
Supplementary information
Supplementary Information Supplementary Figs. 1–3 and Tables 1–6
Reporting Summary
Extended data
Extended Data Fig. 1 Mode of Action and treatment plan.
a) Anticipated mechanism of action of the combination therapy of an IDO/PD-L1 derived peptide vaccine and nivolumab (anti-PD1). 1) The IDO/PD-L1 peptide vaccine is administered subcutaneously (s.c) and nivolumab is administered intravenous (IV). 2) The vaccines peptides are phagocytosed by an antigen presenting cell and presented to IDO and PD-L1 specific T cells, which are activated. 3) The activated T cells migrates to the tumor site where they attack both immune-suppressive cells and tumour cells expressing IDO and/or PD-L1 leading to cytokine production and a pro-inflammatory tumour microenvironment. 4/5) Enhanced tumour killing by both IDO/PD-L1 specific T cells and tumor specific cytotoxic T cells due to PD-1 blockade. Created with BioRender.com b) Treatment plan. After written informed content patients were screened. Before treatment start a baseline PET/CT scan was performed, baseline blood sample for research use and if assessable a baseline needle biopsy. Patients were treated with the IDO/PD-L1 peptide vaccine subcutaneously biweekly for the first 6 injections and thereafter every fourth week for a maximum of 15 vaccines. Nivolumab was administered in parallel biweekly (3mg/kg) up to 24 series. If patients needed subsequent nivolumab after ended vaccination regiment they were treated with 6 mg/kg every fourth week up to two years. Needle biopsy and delayed type hypersensitivity (DTH) was performed after 6 series of treatment if assessable. PET/CT scans was performed every third month.
Extended Data Fig. 2 Progression free survival and overall survival in matched historical control group and vaccine injection site reaction.
a) Kaplan-Meier curve of progression free survival with corresponding 95% confidence intervals in the matched historical control group (n=74). Patients were matched on BRAF-status, PD-L1-status, age, gender, M-stage and LDH level). b) Kaplan-Meier curve of overall survival with corresponding 95% confidence intervals in the matched historical control group (n=74). c) Images of injection site reaction in patient MM20 (CR) after 11 vaccination show redness, rash and granuloma at injection site.
Extended Data Fig. 3 Vaccine specific responses in blood.
a) Heatmap of specific (background has been subtracted) IDO and PD-L1 responses in PBMCs at baseline, series 3, 6, 12, 18 and 24 measured by in vitro IFN-γ Elispot assay show fluctuations in the blood during treatment (n=30). b) Heatmap of specific (background has been subtracted) IDO and PD-L1 responses in PBMCs at baseline and 3 and 6 months after last vaccine measured by in vitro IFN- γ Elispot assay (n=30). 2.5–3.2x105 cells per well were used. c) Vaccine associated clones were tracked in the blood by summing the frequency of each rearrangement enriched in either IDO or PD-L1 T cells.
Extended Data Fig. 4 Ex vivo vaccine specific responses in blood.
Heatmaps of detected specific (background has been subtracted) IDO (a) and PD-L1 (b) responses in PBMCs at baseline and on/after treatment as measured by IFNγ ELISPOT (n=25). C) Example of well images of ex vivo ELISPOT wells for three different patients (n=3). 6-9x105 cells per well were used.
Extended Data Fig. 5 CD4 and CD8 vaccine specific T cell responses in blood.
Top: heatmaps of IDO specific CD4 (left) and CD8 (right) T cell responses in PBMCs at baseline and on/post treatment. Bottom: heatmaps of PD-L1 specific CD4 (left) and CD8 (right) T cell responses. Responses quantified by flow cytometry by an increased expression of CD107α, CD137 and TNFα after 8h peptide stimulation. Values represent specific responses after background values have been subtracted (n=21). Statistical analysis were performed using two-sided Wilcoxon matched-paired rank test.
Extended Data Fig. 6 Pro-inflammatory profiles of sorted CD4 and CD8 T cells from blood.
a/b/c/d) Percentage of in vitro stimulated and sorted PD-L1 and IDO specific CD4 and CD8 T cells secreting cytokines.
Extended Data Fig. 7 Vaccine specific responses in skin.
a) IDO and PD-L1 specific T cell responses in SKILs after 6 series of treatment measured by IFN-γ Elispot assay (n=13). SKILs were grown from DTH injection with either IDO peptide, PD-L1 peptide or a mix as presented by different blue colours. * Responses were calculated as the difference between average numbers of spots in wells stimulated with IDO or PD-L1 peptide (triplicates) and corresponding control (DMSO) and statistical analyses of Elispot responses were performed using distribution-free resampling method (Moodie et al.). DR: Not statistically confirmed response due to replicate number but number of spots in peptide wells are two times higher than control wells (DMSO). NS: No significant response and no DR. b/c/d) Percentage of cytokine secreting/CD107a+ CD4+ and CD8+ IDO and PD-L1 specific T cells in response to in vitro peptide stimulation by flow cytometry. e) Skin infiltrating PD-L1 specific T cell clones also found in biopsy in patient MM01. TCR sequencing was performed on a PD-L1 specific T cell culture generated from DTH area on the lower back injected with PD-L1 peptide on patient MM01. Bars show the frequency of top 25 clones in the culture with which indicates a high Simpson clonality of 0.43. f) Tracking the frequency of the top five skin infiltrating PD-L1 specific clones in tumour before and after treatment.
Extended Data Fig. 8 T cell changes in blood after treatment. T cell fraction, TCR clonality and repertoire richness in blood and peripherally expanded TCR clones in both responding and non-responding patients.
a) T cell fraction in peripheral blood of five patients at baseline, series 3, 6 and 12 by TCR sequencing. T cell fraction was calculated by taking the total number of T cell templates and dividing by the total number of nucleated cells (n=5.) b) TCR clonality in peripheral blood of five patients at baseline, series 3, 6 and 12 by TCR sequencing (n=5). Simpson clonality measures how evenly TCR sequences are distributed amongst a set of T cells where 0 indicate even distribution of frequencies and 1 indicate an asymmetric distribution where a few clones dominate. c) TCR repertoire richness in peripheral blood of five patients at baseline, series 3, 6 and 12 by TCR sequencing (n=5). TCR repertoire richness report the mean number of unique rearrangements. d) Bar-chart chart representing dynamics of the expanded T cell clones. Coloured bars represent peripherally expanded clones in five patients at series 3, series 6 and series 12 as compared to the baseline PBMC samples (n=5). Light gray bar represents peripherally expanded clones that are present in baseline biopsy samples while dark gray bar represents peripherally expanded clones that are present in the post-treatment biopsy (after 6 series). e) Frequency of the dominant TCR β chain in clonal PD-L1 and IDO specific cultures as determined by CDR3 sequencing.
Extended Data Fig. 9 Profiling of genes relevant to T cell activation, cytokines and exhaustion markers on pre- and post-treatment biopsies in two patients.
a) RNA expression profiling of genes related to T cell activation was performed using NanoString nCounter (n=2). b) RNA expression profiling of genes related to cytokine activity was performed using NanoString nCounter (n=2). c) RNA expression profiling of genes related to checkpoint inhibitors was performed using NanoString nCounter (n=2).
Extended Data Fig. 10 Treatment induced upregulation of PD-L1, IDO, MHC I and MHC II and distance between CD8 T cells and PD-L1 expressing cells.
a) IHC on 4 paired biopsies stained for CD3 and CD8 T cells, PD-L1, MHC I and MHC II on tumor cells/mm2 (sum in the validated area) and IDO H-score (from 0 to 300). H-score is the expression of IDO on both immune and tumor cells: The score is obtained by the formula: 3 x percentage of cells with a strong staining + 2 x percentage of cells with a moderate staining + percentage of cells with a weak staining (n=4). b) Distance in µm between CD8+ T cells and PD-L1+ stained cells on five baseline biopsies detected by IHC (n=5).
Extended data
is available for this paper at 10.1038/s41591-021-01544-x.
Supplementary information
The online version contains supplementary material available at 10.1038/s41591-021-01544-x.
Acknowledgements
We thank all patients and their relatives for being a part of the trial. We thank Ö. Met, M. Jonassen, S. Ullitz Færch, B. Saxild, S. Wendt and C. Grønhøj for technical support. We thank M. Cumberbatch for input with translational analysis. We thank the nurses at clinic 5 and the head of the Oncology Department at Herlev and Gentofte Hospital, L. Sengeløv. The study was funded through a research funding agreement between IO Biotech and the CCIT-DK, Herlev Hospital and the Oncology Department at Herlev Hospital.
Author contributions
I.M.S. and M.H.A. conceived the study. J.W.K. wrote the protocol with input from I.M.S., M.H.A. and M.-B.Z. J.W.K. and C.L.L. were responsible for patient treatment and patient care with help from R.B.H. and consulting from I.M.S., E. Ellebaek and M.D. I.M.S., E. Ellebaek and M.D. were responsible for patient recruitment. J.W.K. and C.L.L. were responsible for coordinating trial procedures and collecting data and samples. J.W.K. and C.L.L. were clinical investigators, and I.M.S. was a sponsor. J.W.K. and C.L.L. analyzed and interpreted clinical data with support from I.M.S. and E. Ehrnrooth. T.W.K. performed statistical analyses. H.W.H. helped with clinical imaging. J.W.K., E.M., C.O.M., S.M.A., S.E.W.-B., M.O.H. and A.W.P. analyzed and interpreted translational data with support from M.H.A. and I.M.S. Funding was acquired by I.M.S., M.H.A. and M.-B.Z. J.W.K. wrote the manuscript with input from I.M.S., M.H.A., E.M. and A.W.P. All authors reviewed the manuscript, interpreted data and approved the final version.
Data availability
This clinical trial was registered at https://www.clinicaltrials.gov/ before patient enrollment (clinical trial identifier NCT03047928). Each vaccine was composed of 100 µg IO102, a 21-amino-acid peptide (DTLLKALLEIASCLEKALQVF) from the IDO peptide, and 100 µg IO103, a 19-amino-acid peptide (FMTYWHLLNAFTVTVPKDL) from the signal peptide of PD-L1. TCR sequencing data are available from Adaptive Biotechnologies. Upon request, the CCIT-DK office will provide a username and a password to access the designated data within approximately 2–4 weeks (https://www.herlevhospital.dk/ccit-denmark/find-us/Sider/Contact-information.aspx). All requests for the remaining data including raw data and analyzed data and materials will, within a reasonable time frame, be reviewed by the CCIT-DK office (https://www.herlevhospital.dk/ccit-denmark/find-us/Sider/Contact-information.aspx) to verify whether the request is subject to any intellectual property or obligations. Patient-related data not included in the paper were generated as part of clinical trials and may be subject to patient confidentiality. Any data and materials that can be shared will be released via a material-transfer agreement. The following database was used in the study: https://research.regionh.dk/da/publications/the-danish-metastatic-melanoma-database-dammed(32749d99-095f-4cae-b5de-769bae27f01e).html.
Competing interests
M.H.A. is named as an inventor on various patent applications relating to therapeutic uses of IDO and PD-L1 peptides. These patent applications are assigned to the company IO Biotech, which is developing immune-modulating cancer treatments. M.H.A. is a founder, shareholder and advisor for IO Biotech. I.M.S. is a cofounder, shareholder and advisor for IO Biotech. I.M.S. has an advisory board relationship with or lectured for Roche, Novartis, MSD, Celgene, Incyte, TILT Bio, Pfizer and BMS AstraZeneca and has received limited grants for translational research from BMS, Roche and Novartis. M.-B.Z. is the CEO, founder and shareholder at IO Biotech. E.M., A.W.P. and E. Ehrnrooth are employees at IO Biotech. E. Ellebaek has received honoraria from BMS, Pierre Fabre, Roche and Kyowa Kirin and travel support from MSD. M.D. has received honoraria from Genzyme, MSD, BMS, Roche and Novartis and travel support from Novartis, MSD, BMS, Roche and Pfizer. The remaining authors declare that they have no conflict of interest.
Peer review information Nature Medicine thanks George Coukos, Michael Schell and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Javier Carmona was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Julie Westerlin Kjeldsen, Cathrine Lund Lorentzen.
Change history
3/8/2022
A Correction to this paper has been published: 10.1038/s41591-022-01771-w | NIVOLUMAB | DrugsGivenReaction | CC BY | 34887574 | 20,234,459 | 2021-12-09 |
Subsets and Splits