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S1083879120303621 | Allogeneic hematopoietic stem cell transplantation remains an important treatment modality for patients with acute myeloid leukemia . Recent advances have extended donor availability for patients without matched donors . Transplantation is now increasingly offered to older patients including those above 70 years and less fit individuals . Better prognostic models are being developed . Proceeding faster to transplantation with haploidentical donors if an urgent transplant is needed such as in patients with detectable minimal residual disease may allow more patients to get to transplant and it is hoped more will be cured from their disease . With continuous improvements in treatment related toxicity and mortality relapse has become the most important cause of treatment failure and novel approaches are needed to make the next big leap in the treatment of this disease with transplantation . In this review we aim to summarize recent advances and provide future research directions in the transplantation for patients with AML . | Reduced intensity conditioning increased the use of allogeneic hematopoietic stem cell transplantation allo HSCT to older patients with acute myeloid leukemia AML and those with comorbid conditions. Haploidentical donors expanded the availability of allo HSCT for patients with AML. Improved graft versus host disease prophylaxis with post transplantation cyclophosphamide may further reduce nonrelapse mortality for patients with HLA matched donors. Relapse post transplant is the main cause of treatment failure ongoing research will clarify if it can be decreased especially for high risk AML. Integrated comprehensive and more precise prognostic tools can better assess risk prediction for patients with AML. |
S1083879120303633 | Axicabtagene ciloleucel and tisagenlecleucel are autologous anti CD19 chimeric antigen receptor T cell therapies for the treatment of patients with relapsed refractory large B cell lymphoma . Both can induce durable responses however cross trial comparisons are difficult due to differences in study design . In this study the registration trials of axi cel and tisa cel were compared using a matching adjusted indirect comparison . A MAIC was performed to adjust for differences in patient characteristics between trials . The estimates for the ZUMA 1 trial were adjusted using patient level data to match the study population in JULIET for key variables International Prognostic Index Eastern Cooperative Oncology Group score stage refractoriness or relapsed disease double triple hit status cell of origin and number of prior lines of therapy . The endpoints analyzed were response overall survival and adverse events . After adjusting for differences in patient characteristics between trials axi cel was associated with a greater objective response rate 1.61 95 confidence interval 1.29 to 2.01 and complete response than tisa cel among patients who underwent infusion . The OS from infusion onward comparing axi cel to tisa cel had a hazard ratio of 0.51 . The indirect comparison showed a higher rate of grade 1 to 2 cytokine release syndrome in ZUMA 1 compared with JULIET and similar rates of grade 3 CRS and neurologic events . In the absence of a direct head to head study the MAIC statistical technique suggests axi cel may have superior efficacy but a greater risk of grade 1 to 2 CRS . Future real world studies can further inform the relative efficacy and safety of CAR T therapies in RR LBCL . | Direct cross trial comparison of axi cel ZUMA 1 and tisa cel JULIET chimeric antigen receptor T products is not feasible. Matching adjusted indirect comparison successfully adjusted for differences in patient characteristics between ZUMA 1 and JULIET. Axi cel had a higher objective response complete response and overall survival than tisa cel. Axi cel had higher grade 1 to 2 cytokine release syndrome CRS while both products had similar grade 3 CRS and neurologic events. |
S1083879120303657 | Veno occlusive disease sinusoidal obstruction syndrome is a potentially life threatening complication of hematopoietic cell transplantation . Early diagnosis and subsequently earlier intervention have been shown to be beneficial to clinical outcomes . Diagnostic criteria from the European Society for Blood and Marrow Transplantation include recommendations on the use of imaging for diagnosis . This review discusses evidence on the use of imaging in the management of VOD SOS and how imaging biomarkers can contribute to earlier diagnosis treatment . | Early detection and prompt treatment of veno occlusive disease sinusoidal obstruction syndrome VOD SOS are critical to optimal management. Recent criteria have suggested a role for imaging in diagnosing VOD SOS. Evidence supports the use of ultrasound to confirm diagnosis and monitor treatment. Ultrasound elastography is promising in early VOD SOS diagnosis response evaluation. Clinical studies validating use of imaging in management of VOD SOS are needed. |
S1083879120303669 | The Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup has organized an annual workshop focused on minimal residual disease testing and immune profiling in multiple myeloma since 2016 . In 2019 the workshop took place as an American Society of Hematology Friday Scientific Workshop titled Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma . This workshop focused on 4 main topics the molecular and immunologic evolution of plasma cell disorders development of new laboratory and imaging based MRD assessment approaches chimeric antigen receptor T cell therapy research and statistical and regulatory issues associated with novel clinical endpoints . In this report we provide a summary of the workshop and discuss future directions . | A comprehensive summary of the 2019 BMT CTN Myeloma Intergroup Minimal Residual Disease MRD and Immune Profiling IP workshop is provided. MRD is a prognostic biomarker and should be incorporated into trial designs. IP provides insight into disease biology and response to treatment. |
S1083879120303670 | Immune checkpoint inhibitors are approved in relapsed classic Hodgkin lymphoma . The safety and effectiveness of allogeneic blood or marrow transplantation in ICI pretreated patients with cHL remain unclear . The aim of this study is to assess outcomes of patients with cHL receiving ICIs before alloBMT using post transplantation cyclophosphamide graft versus host disease prophylaxis . We performed a retrospective study of relapsed refractory patients with cHL undergoing alloBMT with PTCy at Johns Hopkins between November 2004 and September 2019 . Engraftment GVHD incidence nonrelapse mortality progression free survival and overall survival were compared between patients receiving pre alloBMT ICI or standard salvage chemotherapy . We identified 105 consecutive relapsed refractory patients with cHL of whom 37 received ICIs and 68 received chemotherapy without ICIs before alloBMT . ICI and no ICI patients experienced a 3 year estimated OS of 94 versus 78 0.35 95 confidence interval 0.08 to 1.56 ICIs do not increase acute or chronic GVHD incidence compared with salvage chemotherapy . Patients with cHL receiving ICIs prior to alloBMT experienced outstanding PFS and OS . Thus ICI therapy is safe in patients with cHL when undergoing alloBMT with PTCy and may improve post alloBMT disease progression and survival . | Immune checkpoint inhibition ICI before allogeneic bone marrow transplantation alloBMT does not increase risk of graft versus host disease in patients receiving post transplantation cyclophosphamide PTCy . ICI therapy before alloBMT with PTCy in patients with classic Hodgkin lymphoma may improve disease progression and survival compared with salvage chemotherapy before alloBMT. |
S1083879120303682 | Severe thalassemia syndromes are highly curable by bone marrow transplant but rejection may still occur . We retrospectively analyzed our fully matched related donor transplants to establish if isolated splenomegaly is an independent risk factor for rejection and if this risk can be reduced by modifying the conditioning protocol . In this study we compared rejection rates between patients with and without splenomegaly in 189 consecutive low risk ST transplants across 2 sequential conditioning regimens regimen A busulfan cyclophosphamide and anti thymocyte globulin 4 mg kg or Fresenius 16 mg kg on days 12 to 10 and regimen B same backbone as regimen A except fludarabine total dose of 150 mg was added upfront and ATG dose was increased to 7 mg kg in case of splenomegaly and or sex mismatched transplants . Compared with regimen A in regimen B both overall rejection rates 16 versus 6.5 | Isolated splenomegaly may increase the risk of rejections in low risk thalassemia transplants. The rejection risk due to splenomegaly can be partially overcome by increasing immunosuppression in the conditioning regimen. |
S1083879120303694 | Chronic graft versus host disease remains a significant late effect issue for allogeneic hematopoietic cell transplantation survivors contributing to morbidity and mortality . The etiology of cGVHD is not well elucidated . Owing to a lack of early diagnostic tests and pathophysiology ambiguity targeted treatments remain limited . Biomarkers for prediction control response or prognostication have not yet been identified . Metabolomics the quantification of metabolites is a potential biomarker of cGVHD but has not been evaluated in this population . In this study we examined global metabolites of stored plasma to identify differentially expressed metabolites of individuals discordant for cGVHD following allo HCT . A descriptive comparative cross sectional study design was used to examine differentially expressed metabolites of plasma samples obtained from 40 adult allo HCT recipients from 2 parent studies . Metabolomics profiling was conducted at the University of Florida s Southeast Center for Integrative Metabolomics . Full experimental methods followed a previously published method . All statistical analyses were performed by a PhD prepared trained bioinformatics statistician . There were 10 differentially expressed metabolites between participants with cGVHD and those without cGVHD . Differential metabolites included those related to energy metabolism amino acid metabolism lipid metabolism caffeine metabolism and neurotransmission . Serotonin had the greatest fold change . This study suggests that cGVHD may be associated with expanded cellular energy and potentially mitochondrial dysfunction . The differential metabolic profile between patients with and without cGVHD indicates metabolic perturbations that merit further exploration as potential biomarkers of cGVHD . These findings support the need for further examination using a larger prospective study design to identify metabolomic risk factors that may signal the need for earlier preventive measures and earlier treatment to reduce cGVHD . | Differential metabolite expression was noted in those discordant for chronic graft versus host disease cGVHD . cGVHD may be associated with expanded cellular energy. Metabolic perturbations may be useful to help characterize cGVHD. Serotonin may be a promising candidate biomarker of cGVHD. More research is needed to identify metabolic risk factors of cGVHD. |
S1083879120303712 | The internet can be a valuable tool in delivering survivorship care to hematopoietic cell transplantation cancer survivors . We describe the reach of INSPIRE an Internet and social media based randomized controlled trial to address healthcare and psychosocial needs of HCT survivors . All survivors 2 10 years after HCT for hematologic malignancy or myelodysplasia from 6 transplantation centers in the US were approached by mail and follow up calls . Eligible participants had access to the Internet an email address and did not have active disease in the past 2 years . We used logistic regression to determine characteristics of eligible survivors who were more or less likely to enroll . Of 2578 eligible HCT survivors 1065 enrolled in the study . The mean age of enrollees was 56.3 12.6 years 52 were male and 94 were white . Survivors less likely to enroll included those who were male age 40 years and who received an autologous transplant all | The INSPIRE online intervention was accessible for a diverse group of HCT survivors. Only 7 did not have Internet and email access. A wide age range participated from 19 to 89 years. Higher enrollment rates were age 40 years allogeneic recipients Native American race. African American and male survivors were less likely to enroll. |
S1083879120303736 | Up to 40 of boys with adrenoleukodystrophy develop a severe central nervous system demyelinating form characterized by white matter changes and gadolinium enhancement on magnetic resonance imaging . Hematopoietic cell transplant is the only proven means to attenuate cALD progression . The elimination of active neuroinflammation is indicated radiographically by the resolution of gadolinium enhancement and correlates to speed of donor neutrophil recovery . We analyzed 66 boys with cALD undergoing HCT for biomarkers correlating with early Gd signal resolution . We found that log Gd volume cm | Blood brain barrier disruption in cerebral adrenoleukodystrophy cALD is indicated by gadolinium enhancement. Gadolinium can be quantified on pre hematopoietic cell transplant HCT magnetic resonance imaging. Gadolinium volume pre HCT correlates to timing of gadolinium resolution after HCT. Early gadolinium resolution after HCT is associated with less neurologic progression 1 year post HCT. |
S1083879120303955 | Immune effector cell therapy is emerging as a promising approach in the field of cancer immunotherapy . Clinical IEC trials predominantly using chimeric antigen receptor T cells have shown excellent responses in CD19 | Chimeric antigen receptor T therapy for solid tumors has encountered challenges in early clinical trials. Toxicity antigen targeting trafficking and immune evasion hamper cell activity. Novel techniques are being explored to improve treatment safety and efficacy. |
S1083879120303967 | The use of cyclophosphamide for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft versus host disease and nonrelapse mortality after HLA matched hematopoietic stem cell transplantation . However recurrent disease remains the primary barrier to long term survival . We extended our 2 step approach to HLA matched related HSCT using a radiation based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization . After conditioning patients received their grafts in 2 components a fixed dose of 210 | There was high tolerance of radiation based myeloablative conditioning with cyclophosphamide. With the use of 3 GVHD prophylaxis agents relapse was a major barrier to survival. Doses of T cells not exposed to cyclophosphamide were associated with less relapse. |
S1083879120303979 | Reduced bone mineral density is a well recognized complication of hematopoietic cell transplantation with significant drops in BMD occurring within the first 12 months after HCT . Guidance on identifying and managing this complication is available in several published guidelines . In this study we investigated current practices in the investigation and management of low BMD in centers registered with the European Society for Blood and Marrow Transplantation . A questionnaire about bone health was sent to all registered centers and responses were received from 99 centers in 25 countries currently registered with the EBMT . Our data highlight considerable heterogeneity in practices across European centers in relation to investigations management and use of guidelines . Our data demonstrate the need for better dissemination and implementation of existing guidelines and also for the development of multidisciplinary guidelines with input from all relevant stakeholders . | Low bone mineral density BMD is frequent after hematopoietic cell transplantation HCT . There is inconsistency of practice in relation to guidelines on BMD after HCT. There is a lack of familiarity with BMD guidelines among European HCT centers. |
S1083879120304006 | The aim of this study was to verify the feasibility of rabbit antithymocyte globulin in combination with 600 cGy of fractionated total body irradiation and fludarabine Flu 150 mg m | A regimen of fractionated total body irradiation 600 cGy fludarabine intermediate dose antithymocyte globulin 5 mg kg results in feasible outcomes. Donor type and comorbidities affected graft versus host diseasefree and failure free survival. Upfront application of haploidentical stem cell transplantation in patients with very severe aplastic anemia might be suggested. |
S1083879120304018 | Graft versus host disease can manifest as acute or chronic complications in patients after hematopoietic cell transplantation . Oral chronic GVHD occurs in approximately 70 of HCT recipients and includes lichenoid like mucosal reactions restricted mouth opening and salivary gland dysfunction . However the underlying histopathological presentation remains to be validated in large cohorts . We characterized the histopathological features of oral mucosal cGVHD and devised a scoring model in a large patient cohort . Oral mucosal biopsy sections with and without oral cGVHD were identified from archived and current HCT recipients with additional healthy controls . Histological screening was performed on hematoxylin and eosin stained and periodic acid Schiff stained sections . A points based grading tool was established based on intraepithelial lymphocytes and band like inflammatory infiltrate atrophic epithelium with basal cell liquefaction degeneration including apoptosis as well as separation of epithelium and pseudo rete ridges . Validation involved 62 biopsy specimens including post HCT and healthy specimens . Remaining biopsy specimens were blindly graded by 3 observers . Histological severity was correlated with clinical diagnostic and distinctive features demonstrating a spectrum of individual patient severity including frequent signs of subclinical GVHD in healthy mucosa . However oral cGVHD presented with significantly higher scores compared with HCT controls with moderate to high positive likelihood ratios for inflammatory infiltrate exocytosis and basal membrane alterations . The grade II IV biopsy specimens demonstrated a histopathological diagnosis of active mucosal lichenoid like cGVHD highlighting the importance of correlating clinical presentation with the dynamic histopathological processes for improved patient stratification . In addition this tool could be used for assessing treatments pathological processes and immune cellular content to provide further insight into this debilitating disease . | This is a large cohort analysis defining oral mucosal chronic graft versus host disease cGVHD histology. A formalized histological grading tool is described. Histology is correlated with clinical staging to define oral mucosal cGVHD criteria. Grades II to IV define pathological diagnostics of oral mucosal cGVHD. Patients are stratified into groups for improved diagnostics and tailored treatments. |
S108387912030402X | The timing of immunosuppressive therapy used in combination with post transplantation cyclophosphamide in haploidentical hematopoietic stem cell transplant is not standardized . We evaluated the schedules of immunosuppression therapy after haplo HSCT in 509 patients with acute leukemia receiving PTCY on days 3 and 4 along with tacrolimus with cyclosporine A and mycophenolate mofetil from day 5 or CSA MMF from day 0 or 1 with PTCY on days 3 and 5 . Compared with the other 2 groups patients in group 3 were younger median age 46 years | There is no standard schedule for post transplantation cyclophosphamide PTCY and associated immunosuppressors in recipients of haploidentical transplantation. Early introduction of cyclosporine A and mycophenolate mofetil with PTCY on days 3 and 5 results in better refined graft versus host disease free relapse free survival and leukemia free survival. |
S1083879120304031 | Cytomegalovirus viremia occurs in 40 to 80 of CMV seropositive recipients of allogeneic hematopoietic cell transplantation . The preemptive therapy strategy has reduced the risk of CMV end organ disease and associated mortality but may lead to substantial healthcare resource utilization and costs . Real world data on the economic impact of PET is relevant for the evaluation of alternative strategies for CMV management . We examined the impact of clinically significant CMV treated with PET on inpatient length of stay number of readmissions and associated costs from day 0 through day 180 post HCT . | We evaluated the impact of cytomegalovirus CMV viremia managed with preemptive therapy PET on healthcare resource utilization after hematopoietic cell transplantation at a single center. In multivariable models CMV infection managed by PET was associated with increased readmissions and higher inpatient costs. CMV related readmission was associated with increased length of stay LOS and greater cost compared with non CMV related readmission. |
S1083879120304043 | Various reduced intensity conditioning regimens are in use for allogeneic hematopoietic cell transplant in patients with idiopathic severe aplastic anemia . We describe the use of fludarabine Campath and low dose cyclophosphamide FCC | Fludarabine Campath and low dose cyclophosphamide FCC. and low dose total body irradiation for unrelated donor graft conditioning for allogeneic hematopoietic stem cell transplant HSCT in children with severe aplastic anemia SAA results in excellent cure rates. Use of peripheral blood stem cell source for alemtuzumab based conditioning in children with SAA does not increase the risk of chronic graft versus host disease or severe viral infections. FCC. TBI conditioning regimen is associated with stable mixed T cell and full myeloid donor chimerism post HSCT. |
S1083879120304055 | There have been several efforts to predict mortality after autologous stem cell transplantation such as the hematopoietic cell transplant comorbidity index described for allogeneic stem cell transplantation and validated for ASCT but there is no composite score in the setting of ASCT combining comorbidities with other clinical characteristics . Our aim is to describe a comprehensive score combining comorbidities with other clinical factors and to analyze the impact of this score on nonrelapse mortality overall survival and early morbidity endpoints after ASCT . For the training cohort we retrospectively reviewed data of 2068 adult patients who received an ASCT in Argentina for multiple myeloma or lymphoma . For the validation cohort we analyzed 2168 ASCTs performed in the Medical College of Wisconsin and Spanish stem cell transplant group . We first performed a multivariate analysis for NRM in order to select and assign weight to the risk factors included in the score . The hazard ratio for NRM increased proportionally with the score . Patients were grouped as low risk with a score of 0 to 1 intermediate risk with a score of 2 to 3 high risk with a score of 4 and very high risk with a score of 5 . The score was associated with a progressive increase in all the early morbidity endpoints . Moreover the score was significantly associated with early NRM as well as long term 1 to 3 years 1.8 to 2.3 versus 3.8 to 4.9 versus 11.7 to 14.5 versus 25.0 to 27.4 respectively | Variables other than comorbidities affect nonrelapse mortality NRM after autologous transplant. We developed in a large cohort a novel score combining hematopoietic cell transplant comorbidity index age disease and sex. The new score predicts early morbidity events and long term NRM and overall survival. The score was validated in an independent large cohort. |
S1083879120304067 | Although hematopoietic cell transplantation from an HLA matched unrelated donor is potentially curative for hematologic malignancies survival is lower for African Americans compared with Caucasians . Because only approximately 20 of African Americans will have an HLA matched unrelated donor many of these patients undergo HLA haploidentical relative or umbilical cord blood transplantation . In this study we analyzed outcomes after HLA haploidentical related donor and umbilical cord blood transplantations in African American patients with hematologic malignancy between 2008 and 2016 . The predominant disease was acute myelogenous leukemia for recipients of both types of donor grafts . The incidences of grade II IV and III IV acute graft versus host disease were higher after umbilical cord blood transplantation compared with HLA haploidentical relative transplantation 56 and 29 respectively versus 33 and 11 respectively | The use of HLA haploidentical and umbilical cord blood transplants expands the access to transplantation is regardless of patient race or ethnicity. The risk of grade II IV and III IV acute graft versus host disease is increased after umbilical cord blood transplantation. The risk of transplantation related mortality is increased with umbilical cord blood transplantation. |
S1083879120304079 | Recipients of allogeneic hematopoietic stem cell transplantation from unrelated donors and mismatched related donors typically have a higher incidence of acute and chronic graft versus host disease compared with matched related donors . Anti T cell globulins are often used to reduce GVHD in these recipients . We report the outcomes of 211 adult peripheral blood stem cell transplant recipients with myeloid malignancies who received a standardized transplant protocol in which ATG was administered to recipients of URD and MMRD but not MRD transplant . For all patients incidence of acute GVHD grades 2 to 4 was 21.4 and chronic GVHD was 35.0 . Two year overall survival was 63.2 relapse free survival was 55.3 and GVHD free relapse free survival was 30.7 . There were no differences between recipients of MRDs and other donors in relapse nonrelapse mortality and overall and relapse free survival . However compared with MRD recipients from URDs and MMRDs had reduced moderate to severe chronic GVHD 10.4 versus 30.1 | A standardized protocol was implemented for peripheral blood stem cell allogeneic transplants for myeloid malignancies. Unrelated and mismatched donor recipients were given Thymoglobuline while matched related donors did not receive Thymoglobuline. Recipients from unrelated and mismatched donors had less chronic graft versus host disease GVHD requiring systemic therapy. As a result unrelated and mismatched donor transplants had superior GVHD free relapse free survival. |
S1083879120304122 | Allogeneic hematopoietic stem cell transplantation can cure primary immunodeficiency diseases . When a HLA matched donor is not available a haploidentical family donor may be considered . The use of T cell replete haploidentical HCT with post transplantation cyclophosphamide in children with PID has been reported in few case series . A donor is usually readily available and haplo PTCy can be used in urgent cases . We studied the outcomes of 73 patients with PID who underwent haplo PTCy including 55 patients who did so as a first transplantation and 18 who did so as a salvage transplantation after graft failure of previous HCT . The median patient age was 1.6 years . Most of the children were male and had active infection at the time of transplantation 10 children had severe organ damage . The diagnosis was severe combined immunodeficiency in 34 patients and non SCID in 39 . The median duration of follow up of survivors was 2 years . The cumulative incidence of neutrophil recovery was 88 in the SCID group and 84 in non SCID group and was 81 for first transplantations and 83 after a salvage graft . At 100 days the cumulative incidence of acute GVHD grade II IV and III IV was 33 and 14 respectively . The majority of patients reached 200 L CD4 | We report the outcomes of 73 patients with PID after transplantation with a haploidentical donor graft and receipt of post transplantation cyclophosphamide haplo PTCy . Haplo PTCy can cure two thirds of PID patients and can be used to rescue graft failure after previous transplantation. Nonmyeloablative conditioning regimens are associated with increased incidence of graft failure and mixed chimerism. We describe the development of different conditioning regimens according to each type of disease treated which may be useful for developing specific protocols. |
S1083879120304134 | The pharmacokinetics of low dose busulfan were investigated as a nonmyeloablative conditioning regimen for autologous gene therapy in pediatric subjects with adenosine deaminase deficient severe combined immunodeficiency disease . In 3 successive clinical trials which included either retroviral or lentiviral vectors subjects were conditioned with BU using different dosing nomograms . The first cohort received BU doses based on body surface area the second cohort received doses based on actual body weight and in the third cohort therapeutic drug monitoring was used to target a specific area under the concentration time curve . Neither BSA based nor ABW based dosing achieved a consistent cumulative BU AUC in contrast TDM based dosing led to more consistent AUC . BU clearance increased as subject age increased from birth to 18 months . However weight and age alone were insufficient to accurately predict the dose that would consistently achieve a target AUC . Furthermore various clinical laboratory and genetic factors were analyzed but no single finding predicted subjects with rapid versus slow clearance . Analysis of BU AUC and the postengraftment vector copy number in granulocytes a surrogate marker of the level of engrafted gene modified hematopoietic stem and progenitor cells demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved the target BU AUC . Although many factors determine the ultimate engraftment following GT this work demonstrates that the BU AUC correlated with the eventual level of engrafted gene modified HSPCs within a vector group with significantly higher levels of granulocyte VCN in the recipients of LV modified grafts compared to recipients of RV transduced grafts . Taken together these findings provide insight into low dose BU pharmacokinetics in the unique setting of autologous GT for ADA SCID and these dosing principles may be applied to future GT trials using low dose BU to open the bone marrow niche . | Low dose busulfan can open the bone marrow niche in the setting of gene therapy. Body surface area and weight based dosing resulted in variable busulfan plasma exposure. Therapeutic drug monitoring based dosing resulted in consistent plasma exposure. Busulfan clearance increased as subject age increased from birth to 18 months. |
S1083879120304146 | Chronic graft versus host disease is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation . Ixazomib is an oral second generation proteasome inhibitor that has been shown in preclinical models to prevent GVHD . We conducted a phase I II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT . Oral ixazomib was administered on a weekly basis for a total of 4 doses beginning days 60 through 90 to recipients of matched related donor or matched unrelated donor allogeneic HCT in phase II portion of the study once the recommended phase II dose of 4 mg was identified in phase I . All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate . Ixazomib administration was safe and well tolerated with thrombocytopenia leukopenia gastrointestinal complaints and fatigue the most common adverse events . In phase II the cumulative incidence of cGVHD at 1 year was 36 19 to 54 in the MRD cohort and 39 in the MUD cohort . One year cumulative incidence of nonrelapse mortality and relapse was 0 and 20 in the MRD cohort respectively . In the MUD cohort the respective NRM and relapse rates were 4 and 34 . The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research controls . This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD 0.85 | Administration of an oral proteasome inhibitor ixazomib in combination with tacrolimus and methotrexate for prevention of chronic graft versus host disease GVHD is safe and convenient but failed to show efficacy when compared with contemporaneous matched Center for International Blood and Marrow Transplant Research controls. B cell activating factor critical for B cell survival and maturation was elevated after administration of ixazomib in chronic GVHD free patients indicating B cell depleting effect of ixazomib. |
S1083879120304389 | Long term therapy related reproductive health side effects impact the quality of life of hematopoietic stem cell transplantation survivors . In this study we evaluated the prevalence of gonadal dysfunction pre and post HSCT analyzed factors associated with GD and explored rates of fertility assessment and fertility preservation in a resource limited setting . FA and outcomes of patients age 45 years undergoing HSCT between June 2000 and May 2018 were collected retrospectively . We included 213 patients with a median age of 26 years . Pre HSCT FA was performed in 71.8 with a GD rate of 17 . The rate of GD was not different between the sexes females 19.5 versus males 16.1 | Quality of life in hematopoietic stem cell transplantation HSCT survivors is impaired by reproductive outcomes. Fertility assessment and preservation must be prioritized at time of diagnosis. In both pre and post HSCT settings women are at higher risk of developing gonadal dysfunction. Low and middle income countries face additional reproductive challenges. Strategies favoring fertility assessment and preservation are of utmost importance. |
S1083879120304407 | Whiteboard videos are a popular video format allowing viewers to see drawings of concepts alongside explanatory text and speech . We hypothesized that whiteboard videos could support the education and recruitment of unrelated stem cell donors in Canada . A series of 5 sharable whiteboard videos about stem cell donation was produced and posted online in September 2018 including 1 full length video | A series of whiteboard videos was developed to support stem cell donor education. Eligible donors from most needed donor demographics viewed the whiteboard video. The videos increased viewers objective and self reported knowledge about donation. The videos reduced viewers ambivalence toward donation. Use of the videos was associated with improved donor recruitment outcomes in Canada. |
S1083879120304420 | Certain anaerobic bacteria are important for maintenance of gut barrier integrity and immune tolerance and may influence the risk of graft versus host disease after allogeneic hematopoietic stem cell transplantation . We conducted a single center retrospective cohort study of allogeneic HSCT recipients to evaluate associations between receipt of antibiotics with an anaerobic spectrum of activity and GVHD outcomes . We identified 1214 children and adults who developed febrile neutropenia between 7 days before and 28 days after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics to patients who received only antibiotics with minimal activity against anaerobes . We performed metagenomic sequencing of serial fecal samples from 36 pediatric patients to compare the effects of specific antibiotics on the gut metagenome . Receipt of anaerobic antibiotics was associated with higher hazards of acute gut liver GVHD 1.26 95 confidence interval 1.03 to 1.54 and acute GVHD mortality but not chronic GVHD diagnosis or chronic GVHD mortality . Anaerobic antibiotics resulted in decreased gut bacterial diversity reduced abundances of Bifidobacteriales and Clostridiales and loss of bacterial genes encoding butyrate biosynthesis enzymes from the gut metagenome . Acute gut liver GVHD was preceded by a sharp decline in bacterial butyrate biosynthesis genes with antibiotic treatment . Our findings demonstrate that exposure to anaerobic antibiotics is associated with increased risks of acute gut liver GVHD and acute GVHD mortality after allogeneic HSCT . Use of piperacillin tazobactam or carbapenems should be reserved for febrile neutropenia cases in which anaerobic or multidrug resistant infections are suspected . | Anaerobic antibiotics are associated with an increased risk of acute gut liver graft versus host disease GVHD . Piperacillin tazobactam and carbapenems deplete key gut anaerobes Clostridiales . Loss of butyrate biosynthesis genes from the gut precedes acute gut liver GVHD. |
S1083879120304432 | Allogeneic hematopoietic cell transplantation is the treatment of choice for acute myelogenous leukemia not responding to induction therapy . It is a therapeutic choice for the blast phase of chronic myelogenous leukemia in patients failing to respond to tyrosine kinase inhibitors . Lipid core nanoparticles concentrate severalfold more in blast cells than in corresponding normal cells . Incorporation of anticancer drugs to LDE formulations increases the pharmacologic action and decreases the toxicity . We tested a drug targeting system LDE etoposide plus total body irradiation in 13 patients with AML not responding to the induction therapy and in 2 patients with CML BP refractory to second generation TKIs . The mean patient age was 46.7 years . The LDE etoposide dose was escalated at 20 30 40 50 and 60 mg kg . No patients developed grade 4 or 5 toxicity however mucositis grade 3 occurred in 6 patients 3 patients experienced diarrhea and 1 patient had an elevated total bilirubin level . No deaths were related to conditioning . All patients were successfully engrafted . The median times to neutrophil and platelet engraftment were 20 5 days and 16 4 days respectively . Five patients had acute graft versus host disease including 4 grade I and 1 with grade II and 8 patients had moderate to severe chronic GVHD | A drug targeting vehicle was used for the first time in hematopoietic cell transplantation conditioning. Etoposide into nanoparticles plus total body irradiation showed low toxicity and safety. All patients had engrafted and no deaths occurred related to the conditioning regimen. Myeloablation engraftment and low toxicity were unrelated to drug dose levels. |
S1083879120304444 | We investigated risk factors for the development of mixed chimerism in 131 patients who underwent transplantation for myelofibrosis and determined the impact of lymphoid and myeloid chimerism on transplant outcome . Disease risk included DIPSS plus categories low to high . The median patient age was 58 years . Patients were conditioned with high intensity or low reduced intensity regimens and received a transplant from a related or unrelated donor . Mixed CD3 | Mixed CD3. chimerism is associated with reduced grafter versus host disease and improved relapse free survival. Mixed CD33. chimerism is associated with increased incidence of relapse. Mixed CD3. chimerism is not associated with risk of graft rejection. |
S1083879120304468 | Sickle cell disease is the most common inherited hemoglobinopathy . Hematopoietic stem cell transplantation is the sole curative therapy for SCD but few patients will have a matched sibling donor . Patients with SCD are mostly of African origin and thus are less likely to find a matched unrelated donor in international registries . Using HaploStats we estimated HLA haplotypes for 185 patients with SCD centers and classified the ethnic origin of haplotypes . Then we assessed the probability of finding an HLA matched unrelated adult donor considering loci A B and DRB1 in international registries . Most haplotypes were African but Brazilians showed a greater ethnic admixture than EBMT patients . Nevertheless the chance of finding at least one 6 6 potential allelic donor was 47 for both groups . Most potential allelic donors were from the US National Marrow Donor Program registry and from the Brazilian REDOME donor registry . Although the probability of finding a donor is higher than previously reported strategies are needed to improve ethnic diversity in registries . Moreover predicting the likelihood of having an MUD might influence SCD management . | Patients with sickle cell disease SCD belong to ethnic groups underrepresented in donor registries. We assessed chances of finding a matched unrelated donor by geographical origin. Brazilian patients showed a greater genetic admixture than European Society for Blood and Marrow Transplantation patients. However chances of having a potential allelic matched unrelated donor were equal in the 2 groups 47 . Further strategies to improve donor representativity are warranted in the SCD setting. |
S108387912030447X | Allogeneic hematopoietic cell transplantation for multiple myeloma with its underlying graft versus tumor capacity is a potentially curative approach for high risk patients . Relapse is the main cause of treatment failure but predictors for postrelapse survival are not well characterized . We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival in 60 MM patients who progressed after myeloablative T cell depleted alloHCT . The median patient age was 56 years and 82 had high risk cytogenetics . Patients received a median of 4 lines of therapy pre HCT and 88 achieved at least a partial response before alloHCT . Of the 38 who received preemptive post HCT therapy 13 received donor lymphocyte infusions and 10 received other interventions . Relapse was defined as very early early or late . At relapse 27 presented with extramedullary disease . The median postrelapse overall survival by time to relapse was 4 months for the very early relapse group 17 months for the early relapse group and 72 months for the late relapse group | Time to relapse after T cell depleted hematopoietic cell transplantation defines distinct postrelapse outcomes. Relapse with extramedullary disease is common and associated with dismal prognosis. Donor lymphocyte infusion for relapse prevention improves postrelapse survival. |
S1083879120304493 | The indication for allogeneic stem cell transplantation in patients with lower risk myelodysplastic syndrome is controversial . Here we report 60 patients with a low risk or intermediate risk classification according to the revised International Prognostic Scoring System who underwent allogeneic SCT with a reduced intensity conditioning or myeloablative conditioning regimen from an HLA identical sibling a matched unrelated donor or a mismatched unrelated donor . The rates of grade II IV and grade III IV acute graft versus host disease were 32 and 7 respectively resulting in a transplantation related mortality of 17 at 3 years . The cumulative incidence of relapse at 5 years was only 7 resulting in a 5 year disease free survival of 72 and overall survival of 79 . Transplantation from a fully matched donor resulted in significantly improved OS at 5 years . Allogeneic SCT in lower risk MDS from an HLA matched donor resulted in excellent OS with a low risk of relapse . | Allogeneic stem cell transplantation SCT in patients with lower risk myelodysplastic syndrome MDS resulted in very good outcomes. Transplantation from a matched donor was a significant factor in survival. The risk of relapse risk is 10 in patients with lower risk MDS after allogeneic SCT. |
S108387912030450X | Autologous hematopoietic cell transplantation is a standard initial treatment for multiple myeloma . Consensus guidelines recommend collecting sufficient hematopoietic progenitor cells for 2 autoHCTs in all eligible patients . Despite a lack of published data on the utilization of HPCs stored for future use it is common practice across transplantation programs to collect enough HPCs for 2 autoHCTs in MM patients . In this single center retrospective study we analyzed the utilization of HPCs collected and stored at the time of first autoHCT in patients with MM along with the cost implications of HPC collection targets sufficient for 2 transplantations . In a cohort of 400 patients after a median follow up of 50.4 months 197 patients had relapsed and 36 had received HPC infusion as salvage autoHCT and or HPC boost . In this cohort a median CD34 | In the majority of patients with multiple myeloma hematopoietic progenitor cells HPCs collected at the time of first autologous hematopoietic cell transplantation autoHCT are not used for a future salvage autoHCT or stem cell boost. The evidence supporting continued collection HPCs for later use in patients age 70 years is weak. A small proportion of the cost incurred during upfront HPC collection before first autoHCT and intended for later use is actually utilized for salvage autoHCT and or stem cell boost. |
S1083879120304511 | The use of myeloablative conditioning in the setting of active relapsed refractory acute myeloid leukemia has been hindered by high historical rates of nonrelapse mortality . FLAMSA chemotherapy followed by reduced intensity conditioning has been proposed as an effective and potentially safer alternative in this scenario . As improvements in supportive care have contributed to decreasing NRM rates after MAC a comparative reassessment of these two strategies was performed . This was a registry based analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation . Eligibility criteria included age 18 to 50 years primary refractory first or second relapsed active AML first allogeneic stem cell transplantation from a matched sibling donor or an unrelated donor performed between 2005 and 2018 MAC or FLAMSA RIC . A total of 1018 patients were included . The median patient age was 39 years . Two hundred and fifty eight patients received busulfan cyclophosphamide 314 received Cy total body irradiation 318 received FLAMSA TBI and 128 received FLAMSA CT . The median duration of follow up was 50 months . In univariate analysis the 2 year relapse incidence 50 57 leukemia free survival and refined graft versus host disease free relapse free survival were not significantly different between cohorts . Lower 2 year NRM was observed in the FLAMSA CT group 7 versus 16 in Bu Cy 19 in Cy TBI and 18 in FLAMSA TBI | FLAMSA fludarabine Ara C and amsacrine sequential chemotherapy followed by total body irradiation TBI based reduced intensity conditioning RIC and myeloablative conditioning MAC led to similar transplantation outcomes in relapsed refractory active acute myeloid leukemia. FLAMSA sequential chemotherapy followed by TBI free RIC was associated with lower nonrelapse mortality resulting in increased overall survival. There were no significant differences in relapse incidence between FLAMSA sequential chemotherapy followed by RIC and MAC. |
S1083879120304523 | With post transplantation cyclophosphamide as graft versus host disease prophylaxis nonmyeloablative HLA haploidentical and HLA matched blood or marrow transplantation have comparable outcomes . Previous reports have shown that discontinuation of immunosuppression as early as day 60 after infusion of a bone marrow haplo allograft with PTCy is feasible . There are certain diseases in which peripheral blood may be favored over BM but given the higher rates of GVHD with PB excessive GVHD is of increased concern . We report a completed prospective single center trial of stopping IS at days 90 and 60 after NMA PB stem cell transplantation . Between 12 2015 7 2018 117 consecutive patients with hematologic malignancies associated with higher rates of graft failure after NMA conditioned BMT and PTCy received NMA PB allografts on trial . The primary objective of this study was to evaluate the safety and feasibility of reducedduration IS . Of the 117 patients the most common diagnoses were myelodysplastic syndrome acute myelogenous leukemia myeloproliferative neoplasms myeloma and chronic lymphoblastic leukemia . Shortened IS was feasible in 75 patients overall . Ineligibility for shortened IS resulted most commonly from GVHD followed by early relapse nonrelapse mortality patient physician preference or graft failure . Of the 57 patients in the D90 cohort 33 stopped IS early as planned and among the 60 patients in the D60 cohort 42 stopped IS early as planned . The graft failure rate was 2.6 . After IS cessation the median time to diagnosis of grade II IV acute GVHD was 21 days in the D90 cohort and 32 days in the D60 cohort with almost all cases developing within 40 days . Approximately one third of these patients resumed IS . All outcome measures were similar in the 2 cohorts and our historical outcomes with 180 days of IS . The cumulative incidence of grade III IV acute GVHD was low 2 in the D90 cohort and 7 in the D60 cohort . The incidence of severe chronic GVHD at 2 years was 9 in the D90 cohort and 5 in the D60 cohort . The 2 year overall survival was 67 for both the D90 and D60 cohorts . The 2 year progression free survival was 47 for the D90 cohort and 52 for the D60 cohort and the GVHD free relapse free survival was 35 for both cohorts . These data suggest that reduced duration IS in patients undergoing NMA PBSCT with PTCy is feasible and has an acceptable safety profile . | This safety and feasibility study of haploidentical peripheral blood transplantation and unrelated donors demonstrates that a substantial subset of patients can discontinue immunosuppression as graft versus host disease prophylaxis as early as day 60. Shortened duration immunosuppression may decrease the risk of relapse and enable earlier and or more effective post transplantation therapies to further improve disease related outcomes. The report includes the proportion of patients who required resumption of immunosuppression. |
S1083879120304535 | Infection is a major cause of morbidity and mortality after hematopoietic cell transplantation . Gut microbiota composition and metabolites provide colonization resistance against dominance of potential pathogens and GM dysbiosis following HCT can be deleterious to immune reconstitution . Little is known about the composition diversity and evolution of GM communities in HCT patients and their association with subsequent febrile neutropenia and infection . Identification of markers before HCT that predict subsequent infection could be useful in developing individualized antimicrobial strategies . Fecal samples were collected prospectively from 33 HCT recipients at serial time points baseline post conditioning regimen neutropenia onset FN onset and hematologic recovery . GM was assessed by 16S rRNA sequencing . FN and major infections ie bloodstream infection typhlitis invasive fungal infection pneumonia and | Significant changes in gut microbiota GM diversity were detected over time from baseline to hematopoietic recovery during hematopoietic cell transplantation HCT . GM functional profiles differed between patients who developed febrile neutropenia and those who did not. We identified a baseline protective GM profile that shows promise in predicting the development of major infection after HCT. |
S1083879120304559 | Accurate prognostic tools are crucial to assess the risk benefit ratio of allogeneic hematopoietic cell transplantation in patients with myelofibrosis . We aimed to evaluate the performance of the Myelofibrosis Transplant Scoring System and identify risk factors for survival in a multicenter series of 197 patients with MF undergoing allo HCT . After a median follow up of 3.1 years 47 of patients had died and the estimated 5 year survival rate was 51 . Projected 5 year risk of nonrelapse mortality and relapse incidence was 30 and 20 respectively . Factors independently associated with increased mortality were a hematopoietic cell transplantation specific comorbidity index 3 and receiving a graft from an HLA mismatched unrelated donor or cord blood whereas post transplant cyclophosphamide was associated with improved survival . Donor type was the only parameter included in the MTSS model with independent prognostic value for survival . According to the MTSS 3 year survival was 62 66 37 and 17 for low intermediate high and very high risk groups respectively . By pooling together the low and intermediate risk groups as well as the high and very high risk groups we pinpointed 2 categories standard risk and high risk . Three year survival was 62 in standard risk and 25 in high risk categories | The Myelofibrosis Transplant Scoring System MTSS model failed to clearly delineate 4 risk groups in our series. The MTSS can still be useful to identify a high risk category with poor outcome. Comorbidities donor type and post transplant cyclophosphamide PT Cy predict survival after hematopoietic cell transplantation. PT Cy was able to negate the adverse effect of HLA mismatching in our series. |
S1083879120304572 | Previous studies have reported a beneficial effect from cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation on immune reconstitution . We determined the CMV antigenemia level associated with increased CMV antigen specific T cells at day 100 and decreased CMV reactivation after day 100 . CMV reactivation and CASTs were measured with CMV antigenemia and CMV specific major histocompatibility complex multimers . The analysis consisted of 775 CAST measurements obtained before and 30 100 and 365 days post alloHCT from 327 consecutive patients treated between 2008 and 2016 . Detectable CASTs correlated with recipient | Cytomegalovirus CMV reactivation induces CMV antigen specific T cells which may prevent subsequent CMV reactivation. Low level CMV antigenemia 5 50 000 polymorphonuclear cells positive for pp65 associates with protective anti CMV immunity after day 100 and may be beneficial. Early therapy of low level CMV antigenemia could be delayed until progression to high level CMV antigenemia. |
S1083879120304584 | The use of myeloablative conditioning in umbilical cord blood transplantation has been associated with high nonrelapse mortality in patients aged 40 years especially those having a high HLA disparity thus limiting wider applications . We hypothesized that the NRM advantage of reduced intensity conditioning and higher graft versus leukemia effect associated with greater HLA disparities would expand its use for patients without compromising efficacy and compared outcomes between RIC and MAC regimens . In total 288 patients aged 40 to 60 years with de novo acute myeloid leukemia receiving UCBT with at least 2 HLA mismatches with RIC or MAC regimens were included . As compared to RIC the MAC cohort included relatively younger patients having received more single UCBT with lower total nucleated cell counts and more in vivo T cell depletion . Median time to neutrophil engraftment infections and grade II to IV acute and chronic graft versus host disease were similar in both groups . In the multivariate analysis overall survival 0.98 | In HLA mismatched umbilical cord blood transplantation UCBT reduced intensity conditioning provided comparable results to myeloablative conditioning for patients with acute myeloid leukemia AML aged 40 to 60 years. The main factor associated with poor outcomes after HLA mismatched UCBT was advanced disease status. UCBT remains an alternative graft source for patients 40 to 60 years old with AML. |
S1083879120304596 | Cyclosporine combined with short course methotrexate is considered standard of care graft versus host disease prophylaxis for patients with severe aplastic anemia who undergo transplantation using cyclophosphamide plus anti thymocyte globulin conditioning . However there is no consensus on optimal post transplant GVHD prophylaxis for patients undergoing matched related donor transplantation using fludarabine based conditioning . We conducted a single center retrospective analysis of patients with acquired AA undergoing MRD transplantation from July 2007 through January 2019 . All patients received Flu Cy ATG conditioning and single agent CsA as GVHD prophylaxis . Median age of the study cohort was 20 years and male to female ratio was 3.8 1 . Median time from diagnosis to transplant was 11.5 months . Graft source was bone marrow harvest in 71 combined bone marrow and peripheral blood stem cells in 34 and peripheral blood alone in 1 patient . Cumulative incidence of neutrophil engraftment at day 28 was 93.4 87.3 to 97.1 while that of platelet engraftment at day 100 was 90.5 . Cumulative incidence of primary graft failure at day 28 was 6.6 while secondary graft failure occurred at a median of 190 days at a cumulative incidence of 3.7 . Cumulative incidence of grade II to IV acute GVHD at day 100 was 3.8 while a 1 year probability of chronic GVHD was calculated as 7.5 . Median follow up post transplant was 61 months . Overall survival was 84.9 disease free survival was 80.2 and GVHD free relapse free survival was 76.3 . This study indicates that single agent cyclosporine is a feasible option for GVHD prophylaxis in MRD hematopoietic stem cell transplantation using Flu Cy ATG conditioning and is associated with very low rates of acute and chronic GVHD . | Graft versus host disease GVHD often leads to post transplant morbidity and mortality and can severely compromise quality of life. Cyclosporine combined with short course methotrexate is considered standard of care GVHD prophylaxis for patients with severe aplastic anemia who undergo transplantation using cyclophosphamide Cy plus anti thymocyte globulin ATG conditioning. Single agent cyclosporine is a feasible option for GVHD prophylaxis in matched related donor hematopoietic stem cell transplantation using fludarabine Cy ATG conditioning and is associated with very low rates of acute and chronic GVHD. |
S1083879120304614 | Total body irradiation cyclophosphamide is a standard of care conditioning regimen in allogeneic hematopoietic stem cell transplant for pediatric acute lymphoblastic leukemia . This study sought to identify whether the addition of thiotepa to TBI CY improves HSCT outcomes for pediatric patients with ALL . A retrospective analysis was performed on 347 pediatric ALL patients who underwent HSCT between 1995 and 2015 with 242 receiving TBI CY TT and 105 patients receiving TBI CY . There were no statistical differences in age donor source or complete remission status between the 2 groups . Comparison of the TBI CY TT versus TBI CY groups demonstrated no difference in transplant related mortality at 1 5 or 10 years . There was lower relapse in the TBI CY TT group at 1 5 10 and 15 years | Thiotepa is safe to use with a total body irradiation TBI cyclophosphamide backbone in pediatric patients with acute lymphoblastic leukemia with no increase in transplant related mortality. Addition of thiotepa to TBI cyclophosphamide did not significantly impact relapse or disease free survival in pediatric acute lymphoblastic leukemia hematopoietic stem cell transplant ALL HSCT . Addition of thiotepa to TBI cyclophosphamide did not impact long term overall survival in pediatric ALL HSCT. |
S1083879120304638 | Angiotensin II type 1 receptor activating autoantibodies have gained attention in solid organ transplant as non HLA antibodies associated with rejection vasculopathy and graft dysfunction . These antibodies have also been reported in the context of pre eclampsia scleroderma and isolated hypertension . Here we present 3 post hematopoietic stem cell transplant cases with patients demonstrating elevated levels of AT1R AAs detected within the first year post HSCT . All patients had hypertension and 2 patients exhibited profound diarrhea and hypokalemia . The hypertension in all cases was refractory to multiple classes of antihypertensives . Upon autoantibody identification an angiotensin receptor blocker losartan was promptly initiated and all patients showed blood pressure improvement . The 2 patients with electrolyte disturbances had rapid normalization of these levels and resolution of the diarrhea . These cases demonstrate a previously unreported association of elevated AT1R AA levels in post HSCT patients with a rapid response to angiotensin receptor blockade initiation . | Patients are at risk of developing angiotensin II type 1 receptor activating autoantibodies AT1R AAs in the post hematopoietic stem cell transplant period. AT1R AAs can drive hypertension refractory to non angiotensin receptor blockade ARB therapies. AT1R AAs may play a role in intestinal graft versus host disease pathology. Prompt ARB initiation may mitigate AT1R AA related pathology. |
S108387912030464X | Although allogeneic hematopoietic stem cell transplantation is the key strategy to cure patients with mature T and natural killer cell lymphomas leukemia especially those with relapsed refractory diseases there is no consensus strategy for donor selection . We retrospectively analyzed the outcomes of allo HSCT in 111 patients in 15 Japanese institutions as a multi institutional joint research project . Thirty nine patients received bone marrow or peripheral blood stem cell transplantation from related donors 37 received BMT PBSCT from unrelated donors and 35 received cord blood transplantation . Overall survival and progression free survival at 4 years were 42 and 34 respectively . The cumulative incidences of relapse and nonrelapse mortality were 43 and 25 . In multivariate analysis CBT showed comparable OS with rBMT rPBSCT 1.63 | Allogeneic hematopoietic stem cell transplantation is beneficial for patients with mature T cell and natural killer cell neoplasms. Cord blood transplantation CBT resulted in favorable outcomes with a lower risk of relapse. CBT could be a preferred option especially for patients with uncontrolled diseases. Better control of lymphoma at transplantation is a key to improved outcomes. |
S1083879120304651 | Ruxolitinib a selective Janus kinase 1 2 inhibitor has recently been proposed for steroid refractory chronic graft versus host disease after allogeneic hematopoietic stem cell transplantation particularly in severe skin cGVHD . Lung function impairment is common in severe skin cGVHD through concomitant bronchiolitis obliterans syndrome or restrictive lung disease from skin sclerosis . To date no treatment has shown a benefit on lung function in this context . We retrospectively assessed the effect of ruxolitinib on lung function in a cohort of 70 patients diagnosed with sclerotic type skin cGVHD between March 2015 and April 2018 . Among these patients 36 received ruxolitinib . To handle confounding by indication bias exposure groups were matched on the propensity score to receive ruxolitinib incorporating age myeloablative conditioning total body irradiation BOS forced expiratory volume in 1 second FEV | Ruxolitinib had no effect on respiratory function in patients with severe skin chronic graft versus host disease. Forced expiratory value over 1 second FEV. decreased significantly over time independent of exposure to ruxolitinib. FEV. trajectory was similar in exposed and unexposed patients. |
S1083879120304675 | We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic graft versus host disease after receiving their first allogeneic transplantation from a 10 10 HLA allele matched unrelated donor using calcineurin inhibitors or a T cell replete haploidentical donor and post transplantation cyclophosphamide at our center between 2005 and 2017 . The median duration of follow up for survivors was 52.5 months | Haploidentical transplantation haplo with post transplantation cyclophosphamide PTCY is associated with a lower incidence of chronic graft versus host disease GVHD compared with matched unrelated donor MUD transplantation using calcineurin inhibitor based GVHD prophylaxis. Haplo with PTCY has faster onset of chronic GVHD and better response to treatment compared with MUD with calcineurin inhibitors. Chronic GVHD after haplo with PTCY has different organ distribution with less involvement of the eyes and joints fascia compared with MUD with calcineurin inhibitors. |
S1083879120304699 | The outcomes of 7 8 allele matched unrelated bone marrow transplantation and umbilical cord blood transplantation have been improving . We retrospectively analyzed adults with acute leukemia who underwent their first 7 8 UBMT or UCBT in Japan . Between January 2008 and December 2017 a total of 4150 patients were recorded including 488 who underwent 7 8 UBMT and 3662 who underwent UCBT . Only 32 patients with 7 8 UBMT had graft versus host disease high risk HLA mismatched pairs . Overall survival at 3 years was 54 for 7 8 the UBMT group and 46 for the UCBT group a nonsignificant difference in multivariate analysis 1.01 95 confidence interval .88 to 1.17 | Hematopoietic stem cell transplantation with 7 8 HLA allele matched unrelated bone marrow 7 8 UBMT and umbilical cord blood UCBT make use of alternative donor sources for patients with acute leukemia who lack HLA identical donors. This report provides an updated comparison of 7 8 UBMT and UCBT in a Japanese nationwide cohort. Disease risk and conditioning intensity based stratification was used for donor source selection. A lower incidence of graft versus host disease was seen in UCBT recipients. There was a survival advantage in 7 8 UBMT recipients with standard risk disease who received a myeloablative conditioning regimen. |
S1083879120304705 | Long driving distances to transplantation centers may impede access to care for hematopoietic cell transplantation survivors . As a secondary analysis from the multicenter INSPIRE study we examined baseline data from relapse free HCT adult survivors to investigate the association between driving distances and patient reported outcome measures of distress and physical function . We analyzed predictors of elevated distress and impaired physical function using logistic regression models that operationalized driving distance first as a continuous variable and separately as a dichotomous variable . Of 1136 patients available for analysis from 6 US centers median driving distance was 82 miles and 44 resided 100 miles away from their HCT centers . Elevated distress was reported by 32 of patients impaired physical function by 19 and both by 12 . Driving distance whether operationalized as a continuous or dichotomous variable had no impact on distress or physical function in linear regression modeling . In contrast chronic graft versus host disease lower income and lack of Internet access independently predicted both elevated distress and impaired physical function . In summary we found no impact of driving distance on distress and physical function among HCT survivors . Our results have implications for how long term follow up care is delivered after HCT with regard to the negligible impact of driving distances on PROs and also the risk of a digital divide worsening outcomes among HCT survivors without Internet access . | Distances from hematopoietic cell transplantation HCT centers exceed 100 miles for 44 of survivors. We examined driving distances distress and physical function among HCT survivors. Chronic graft versus host disease and low income predicted worsened distress and function. Interestingly lack of Internet access also predicted worsened distress and function. Surprisingly driving distance had no impact on distress or physical function. |
S1083879120304730 | There is a paucity of information about nutrition in chronic graft versus host disease . The role of nutrition is important because malnutrition is strongly associated with severe chronic GVHD manifestations . There is a high prevalence of metabolic syndrome and osteoporosis in this setting . Here we review the literature describe main aspects of nutrition and discuss macronutrients micronutrients and supplements . A search was carried out in March 2020 using PubMed . Databases were screened for searching terms in titles and abstracts referring to chronic GVHD nutrition intervention protein and body composition . Data were extracted for the following outcomes nutrition nutrition intervention chronic GVHD nutrition deficiencies diet vitamin dry eye probiotic protein and body composition . In this report we summarize interventional nutrition studies reported in oncology and metabolic syndrome settings and describe our nutritional clinical practice in hematopoietic cell transplantation and chronic GVHD . The impact of nutrition evaluation and intervention on muscle mass loss dry eye dysgeusia metabolic syndrome osteoporosis and comorbidities associated with chronic GVHD need to be studied prospectively . | There are few studies on nutrition and chronic graft versus host disease GVHD . Many drugs used to treat chronic GVHD can lead to nutritional problems and metabolic syndrome. Monitoring and early nutritional measures of metabolic syndrome osteoporosis and loss of muscle mass could improve outcome and response to treatment in these patients. Zinc vitamin A vitamin D omega 3 and probiotics could contribute to symptom reduction and nutritional improvement. |
S1083879120304754 | Increasingly adolescent young adult and adult children are relied upon as donors for their parents undergoing blood and marrow stem cell transplant . How family functioning impacts donors decision making and whether haploidentical donor children have unique supportive care needs is unknown . In this qualitative research study we conducted 15 semistructured telephone interviews among individuals who underwent blood or marrow stem cell donation for their parent . Interviews explored donors perspectives of the transplant experience across the trajectory from screening through early post transplant follow up and elicited unmet needs . Major themes included | This is the first study to describe haploidentical child donor perspectives. Despite relational strains family functioning rarely affected decisions to donate. Participants felt satisfied by decision and ability to give back to their parent. Additional educational emotional support is needed to improve donor experiences. |
S1083879120305048 | A paucity of randomized phase III clinical trials in primary central nervous system lymphoma has resulted in no uniform consensus on the optimal strategy for consolidation and conditioning regimens for autologous stem cell transplant . The past 2 decades have witnessed a preference for thiotepa based conditioning regimens due to superior central nervous system penetration . We retrospectively evaluated outcomes of patients with PCNSL who underwent ASCT at Mayo Clinic Rochester over the past 2 decades and the impact of TT based conditioning regimens . Fifty six patients underwent transplant for PCNSL with 25 and 31 patients receiving BEAM and carmustine TT based conditioning respectively . All patients received high dose methotrexate based induction therapy . While the BCNU TT group had higher risk disease features such as high International Extranodal Lymphoma Study Group prognostic score elevated cerebrospinal fluid protein and older patient population there was no significant difference at 2 years post transplant in progression free survival versus BCNU TT 65.5 | Primary central nervous system CNS lymphoma is a rare entity with limited randomized clinical trials. No consensus exists on the optimal consolidation strategy and conditioning regimen in primary CNS lymphoma. Our 20 year experience at the Mayo Clinic Rochester provides additional insights. Disease response before transplant dictates outcome a novel finding. |
S108387912030505X | Granulocyte colony stimulating factor is administered after allogeneic hematopoietic cell transplantation to aid neutrophil recovery . We compared the effect of empiric G CSF administration on the duration of index inpatient hospitalization stay after HCT for patients aged 18 years with a hematologic malignancy . G CSF was considered empiric if administered between day 3 and day 6 in relation to graft infusion . We studied 3562 HCTs between 2007 and 2016 . Three hundred and thirteen recipients of HLA matched sibling donor HCT and 417 recipients of HLA matched unrelated donor HCT received empiric G CSF therapy . The effect of G CSF therapy on the index hospitalization stay was examined in generalized linear models with adjustment for other patient disease and transplantation characteristics and acute graft versus host disease and infection post transplantation . The duration of index hospitalization by treatment group did not differ for HLA matched sibling donor HCT but was shorter with G CSF for HLA matched unrelated donor HCT 15 days versus 19 days | Empiric granulocyte colony stimulating factor G CSF therapy shortens the duration of in patient stay after HLA matched unrelated donor transplantation. Empiric G CSF therapy does not shorten the duration of in patient stay after HLA matched sibling transplantation. Empiric G CSF therapy is not associated with early survival. |
S1083879120305061 | Allogeneic hematopoietic stem cell transplantation is a valid option in patients with refractory lymphomas . HLA haploidentical stem cell transplantation expanded the accessibility to allogeneic hematopoietic cell transplantation . The aims of study were to retrospectively assess the toxicity and efficacy of haplo SCT using nonmyeloablative conditioning in patients with advanced lymphoma . In total 147 patients with advanced lymphoma at 2 partner institutions were included . Patients received a uniform nonmyeloablative conditioning regimen and graft versus host disease prophylaxis . The primary endpoints were progression free survival overall survival GVHD nonrelapse mortality and GVHD relapse free survival . Median follow up was 39 months . The median age was 46 years . Sixty five percent of patients were in complete remission at transplantation . Cumulative incidence of grade II to IV acute GVHD was 30 23 to 38 . Two year cumulative incidence of all grades of chronic GVHD was 13 . Two year cumulative incidence of disease relapse was 19 with a higher incidence in patients not being in CR at allo HCT CR versus not CR 12 versus 33 | Nonmyeloablative haploidentical stem cell transplantation for advanced lymphomas is highly feasible with low incidence of nonrelapse mortality. It provides a strong graft versus lymphoma effect for both Hodgkin and non Hodgkin lymphoma with low incidence of relapse when performed in partial or complete remission. |
S1083879120305073 | Ruxolitinib is an oral JAK1 2 inhibitor that is approved for use in patients with intermediate and high risk myelofibrosis based on its proven spleen and symptom burden reduction . Its impact on hematopoietic stem cell transplantation outcomes is largely unknown however . A significant number of patients proceeding to HSCT have been treated with ruxolitinib and the specifics of its peritransplantation use vary widely in the published literature . Here we review the currently published data and experience to guide management of patients with MF on ruxolitinib proceeding to HSCT . | A tapering strategy should be used to discontinue ruxolitinib in transplant recipients. Ruxolitinib should be continued until conditioning given the risk of cytokine rebound. Ruxolitinib is well tolerated if continued through conditioning therapy and until engraftment. Patients on ruxolitinib must be monitored closely for cytomegalovirus reactivation and cytopenias. |
S1083879120305085 | Multiple investigations have documented the health related quality of life and donation related experiences of unrelated donors but similar investigations of the related donor experience have been less common . The central goal of this study was to longitudinally examine and compare HRQoL of RD and URD hematopoietic stem cell donors from predonation through 1 year postdonation . This prospective investigation included adult HSC donors ages 18 to 60 years who donated bone marrow or peripheral blood stem cells at one of 48 geographically diverse US transplant donor centers and completed HRQoL interviews at predonation and 4 weeks and 1 year postdonation . At predonation related donors were less ambivalent about donation | Related donors were more certain about and satisfied with the decision to donate. Related donors experienced more pain and symptoms related to donation. Related donors were less likely to be fully recovered at 1 year postdonation. |
S1083879120305097 | For patients with relapsed or refractory classical Hodgkin lymphoma salvage chemotherapy followed by consolidation with autologous stem cell transplant remains the standard of care . Even with this aggressive treatment strategy 5 year progression free survival is 50 and there remains interest in maintenance strategies to improve long term disease free survival . Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL and has also been shown to improve both progression free and overall survival as maintenance therapy after ASCT in multiple myeloma . This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL . Patients were enrolled 60 to 90 days post transplant and received oral lenalidomide on days 1 to 28 of 28 day cycles for a maximum of 18 cycles . Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated . The primary objective of this study was to assess the feasibility of this regimen with a goal 30 rate of discontinuation at or before cycle 12 for drug related reasons . Twenty seven patients were enrolled and 26 received at least 1 dose of lenalidomide . With a median follow up of 51.3 months 23 of 26 patients were alive . Median event free survival was 9.4 months and median progression free survival had not been reached with 17 of 26 patients remaining in remission at last follow up . Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance the discontinuation rate at or before cycle 12 was 52 . Treatment was complicated by a high frequency of hematologic adverse events with 15 patients experiencing grade 3 to 4 hematologic toxicity and 5 experiencing grade 4 hematologic toxicity . We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT . An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL . | We performed a pilot clinical trial to determine the feasibility of maintenance lenalidomide after autologous stem cell transplant in relapsed refractory classical Hodgkin lymphoma rel ref cHL . An unexpectedly high frequency of hematologic toxicities resulting in early lenalidomide discontinuation was observed. The lenalidomide maintenance dose and schedule used in this study are not feasible in rel ref cHL. |
S1083879120305115 | Fanconi anemia is the most common inherited bone marrow failure syndrome and hematopoietic stem cell transplantation is the only curative option . Post transplant cyclophosphamide is challenging in this group of children given their increased sensitivity to chemotherapy . We performed a retrospective analysis of the data on children diagnosed with Fanconi anemia who underwent a haploidentical HSCT with PTCy from January 2014 to December 2019 . Nineteen children underwent 21 haplo HSCTs with PTCy . Fludarabine low dose cyclophosphamide and 200 centi gray total body irradiation were included in the conditioning regimen with 25 mg kg PTCy on days 3 and 4 . Haplo graft was from a sibling in 38 and father in 57 of transplants . The source of stem cells was peripheral blood stem cells in 81 and bone marrow in 19 of transplants with a median CD34 dose of 5.010 | Haploidentical stem cell transplantation with post transplant cyclophosphamide can be considered a viable option in children with Fanconi anemia particularly in resource limited settings given the high costs of hematopoietic stem cell transplantations with an overall survival of 68.4 . Peripheral blood stem cells provide early engraftment decreasing the risk of prolonged neutropenia and sepsis with a focus on maintaining CD34 and CD3 dose of a minimum of 510. kg and 1.510. kg recipient body weight respectively in the infused graft. Supportive care measures including. acetyl cysteine infused concomitantly with cyclophosphamide on day 3 and day 4 can help decrease the incidence of severe mucositis and transaminitis and thereby reduce regimen related toxicity. Monitoring ferritin as a surrogate marker for IL 6 levels and cytokine release syndrome with log increases combined with clinical features as the basis for instituting early steroids can decrease the mortality associated with cytokine release syndrome. Ruxolitinib can be a useful second line agent for chronic graft versus host disease GVHD with good responses in those with skin and mouth GVHD. |
S1083879120305395 | To review the updated trends of national practice and outcomes in transplantation to treat myelofibrosis we retrospectively evaluated 142 patients who underwent allogeneic hematopoietic stem cell transplantation for primary or secondary MF at an Australian New Zealand transplantation center between 2006 and 2017 . The median duration of follow up was 51.8 months . The median age at allo HSCT was 56 years . Fifty two percent of the patients had HLA identical sibling donors and 45 had matched unrelated donors . Conditioning regimens were predominantly reduced intensity . Before transplantation 16 of the patients had undergone splenectomy or splenic irradiation and 38 received JAK inhibitor therapy . | We report updated trends in allogeneic stem cell transplantation for myelofibrosis in Australasia. We identify pretransplantation factors influencing post transplantation outcomes. There has been limited uptake of molecular genomic technology in Australasia. Long term outcomes of patients reported in the previous ABMTRR study are examined. |
S1083879120305401 | The pulmonary function test is an important test for risk stratification before allogeneic transplantation . However it might be preferable to avoid PFT as much as possible in the recent era of coronavirus disease 2019 because PFT requires forced expirations and might produce aerosols increasing the risk of COVID 19 transmission . Therefore we tried to predict normal PFT results before allo HCT based on computed tomography findings . This study included 390 allo HCT recipients at our center for whom lung CT images and PFT results before allo HCT were available . Abnormal CT findings were less likely to be observed in the normal PFT group 47.0 versus 67.4 | The pulmonary function test PFT is an important test for risk stratification before allogeneic hematopoietic stem cell transplantation allo HCT although it might be preferable to avoid unnecessary PFT during the COVID 19 pandemic. Our computed tomography CT based model for predicting normal PFT showed relatively high specificity 80 . PFT might be omitted in patients with normal CT findings before allo HCT. |
S1083879120305413 | Recent progress in genetic analysis technology has helped researchers understand the pathogenesis of acute myeloid leukemia . Considering this progress AML karyotype is still one of the most significant prognostic factors that provides risk adapted treatment approaches . Karyotype changes during treatment have been observed at times but their prognostic impact is sparse especially on allogeneic stem cell transplantation . Here we retrospectively investigated the effect of chromosomal changes between diagnosis and pretransplantation on the prognosis of allo SCT by analyzing the outcomes of 212 consecutive patients who underwent allo SCT for the first time at Toranomon Hospital Tokyo Japan between 2008 and 2018 . Cytogenetic abnormalities at diagnosis and pretransplantation were categorized based on the 2017 European Leukemia Net risk stratification . Genetic abnormalities such as | Effect of acute myeloid leukemia karyotype on the outcomes of allogeneic stem cell transplantation was tested. Cytogenetic evolution affects prognosis after allogeneic stem cell transplantation. |
S1083879120305437 | BiCNU etoposide Ara C melphalan and Campath conditioning was developed to reduce the high transplant related mortality in patients with lymphoma while delivering intensive antilymphoma immunotherapy as well as to some extent a platform for allogeneic stem cell engraftment . Significant numbers of patients appeared to have persistent recipient derived hematopoiesis and therefore we retrospectively analyzed patients with lymphoma undergoing BEAM Campath conditioned allogeneic stem cell transplantation at our center to characterize the patterns of chimerism and patient outcomes . Chimerism was analyzed with short tandem repeat PCR . Mixed donor recipient chimerism was defined as 5 to 94.9 donor . Fifty two patients with a median age of 45 years were identified with histologic diagnoses of Hodgkin lymphoma diffuse large B cell lymphoma low grade non Hodgkin lymphoma mantle cell lymphoma and T cell lymphoma . Pretransplant 93 achieved complete response or partial response with a median of 3 prior therapies . Donors were Matched sibling donors matched unrelated donors miss matched unrelated donors and syngeneic . Acute graft versus host disease developed in 52 and chronic GVHD in 12 . MDRC of T cells developed in 62 and 29 developed MDRC of myeloid cells at a median onset of 100 days . Donor lymphocyte infusion was given to 17 patients with a median starting dose of 110 | BEAM Campath allografts for lymphoma achieve long term disease free survival. One third of patients developed myeloid mixed donor recipient chimerism. T cell mixed chimerism occurred in 62 and was associated with reduced nonrelapse mortality. Neither T cell or myeloid mixed chimerism is associated with increased relapse. Half converted from mixed to full donor chimerism after donor lymphocyte infusion. |
S1083879120305747 | High dose melphalan conditioning before autologous hematopoietic cell transplantation is standard of care for patients with transplantation eligible multiple myeloma . The traditional lyophilized Mel formulation has inadequate solubility and stability after reconstitution leading to the use of propylene glycol as a solubilizing agent . A newer PG free Mel preparation uses beta cyclodextrin captisol as a solubilizing agent and was approved by the United States Food and Drug Administration as a conditioning agent based on a single phase IIb study showing bioequivalence . We compared the outcomes of consecutive patients with myeloma undergoing autoHCT using the 2 formulations of Mel for conditioning as our center switched from using the older formulation to the newer one . Of 294 autoHCT recipients 162 received PG Mel conditioning and 132 received PGF Mel conditioning . The PGF Mel group was older and had a lower average Karnofsky Performance Status score . PGF Mel was associated with faster neutrophil recovery median 12 days versus 13 days | Propylene glycol PG free melphalan PGF Mel Evomela is safe and has similar toxicity profile as PG Mel Alkeran when used as a conditioning regimen for autologous hematopoietic cell transplantation autoHCT for myeloma patients. PGF Mel conditioning was associated with a modest improvement in neutrophil recovery median 12 days versus 13 days. .001 as well as lower rates of grade 3 to 4 infections and rehospitalization after discharge from the index hospital admission for autoHCT. |
S1083879120305759 | Transplant associated thrombotic microangiopathy is a systemic vascular illness associated with significant morbidity and mortality resulting from a convergence of risk factors after allogeneic blood or marrow transplantation . The diagnosis of taTMA has been a challenge but most criteria include an elevated lactate dehydrogenase low haptoglobin and schistocytes on peripheral blood smear . We performed a retrospective review of the 678 consecutive adults who received high dose post transplantation cyclophosphamide based graft versus host disease prophylaxis between January 1 2015 and August 31 2018 . In April 2016 we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies . During the entire period the 1 year cumulative incidence of taTMA was 1.4 . Eight patients were taking tacrolimus at the time of diagnosis and 1 was not on any immunosuppression . Eight of 9 patients were hypertensive . Four patients had invasive infections at the time of diagnosis 4 patients required renal replacement therapy and 5 of 9 patients were neurologically impaired . Eculizumab was given to 6 patients of whom 2 died and 4 recovered with resolution of end organ dysfunction . The paucity of events made the determination of risk factors difficult however the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens low incidence of severe GVHD and use of PTCy . PTCy based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA . | Transplant associated thrombotic microangiopathy taTMA is a serious complication of allogeneic bone marrow transplantation. The incidence of taTMA is low at 1.4 using post transplant cyclophosphamide PTCy based graft versus host disease prophylaxis. Recipient donor mismatch is unlikely to be a risk factor when PTCy is used. |
S1083879120305784 | Delirium is common among adults undergoing hematopoietic stem cell transplantation although the clinical and neuroimaging correlates of post HCT delirium have not been adequately delineated . We therefore examined the frequency of delirium and neuroimaging correlates of post transplant delirium in a retrospective cohort of 115 adults undergoing neuroimaging after allogeneic HCT . Delirium was established using previously validated methods for retrospective identification of chart assessed postprocedural delirium . Chart reviews were independently conducted by a multidisciplinary team with expertise in HCT psychiatry and psychology on consecutive allogeneic HCT patients who underwent neuroimaging assessments and transplantation at a single center between January 2009 and December 2016 . Neuroimaging markers of white matter damage and brain volume loss were also recorded . In total 115 patients were included ranging in age from 20 to 74 years age 49 . Fifty three patients developed post HCT delirium . In an adjusted model delirium incidence was associated with older age 1.92 per decade | Delirium is common following hematopoietic stem cell transplantation. In this select sample greater age treatment regimen intensity and greater white matter burden were all associated with greater delirium incidence. |
S1083879120305802 | The use of potentially inappropriate medications using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation recipients is not known . Here the use of any PIMs and their therapeutic classes in reduced intensity conditioning allogeneic HCT recipients were compared between older and younger patients during their initial HCT admission defined as the number of days that a patient received 1 or more PIMs between day 14 and day 28 . Poisson regression was used to determine rate ratios in the 2 groups . In the 65 years group we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events grade 3 4 toxicities within 100 days and on overall mortality within 1 year post HCT . The rate of any PIM use was similar in the older and younger groups .90 to 1.06 | The rate of potentially inappropriate medication PIM use was similar in older and younger recipients of allogeneic hematopoietic cell transplantation HCT . Females high risk Hematopoietic Cell Transplantation Comorbidity Index and umbilical cord blood recipients had higher use of PIMs. In recipients age 65 years PIM use was associated with higher toxicity and mortality. |
S1083879120305851 | Hematopoietic cell transplantation is an effective treatment for many hematologic malignancies and its utilization continues to rise . However due to the difficult logistics and high cost of HCT there are significant barriers to accessing the procedure these barriers are likely greater for older patients . Although numerous factors may influence HCT access no formal analysis has detailed the cumulative barriers that have been studied thus far . We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines to better categorize the barriers to access and referral to HCT with a focus on the subgroup of older patients . We searched for articles published in English from PubMed Embase Cumulative Index for Nursing and Allied Health and Cochrane Central Register of Controlled Trials between the database inception and January 31 2020 . We selected articles that met the following inclusion criteria study design qualitative cross sectional observational cohort or mixed method study designs outcomes barriers related to patient and physician access to HCT and population adults aged 18 years with hematologic malignancies within the United States . Abstracts without full text were excluded . QUALSYST methodology was used to determine article quality . Data on the barriers to access and referral for HCT were extracted along with other study characteristics . We summarized the findings using descriptive statistics . We included 26 of 3859 studies screened for inclusion criteria . Twenty studies were retrospective cohorts and 4 were cross sectional . There was 1 prospective cohort study and 1 mixed method study . Only 1 study was rated as high quality and 16 were rated as fair . Seventeen studies analyzed age as a potential barrier to HCT referral and access with 16 finding older age to be a barrier . Other consistent barriers to HCT referral and access included nonwhite race insurance status comorbidities and lower socioeconomic status . High quality studies are lacking related to HCT barriers . Older age and nonwhite race were consistently linked to reduced access to HCT . To produce a more just health care system strategies to overcome these barriers for vulnerable populations should be prioritized . Examples include patient and physician education as well as geriatric assessment guided care models that can be readily incorporated into clinical practice . | There are significant barriers to accessing hematopoietic cell transplantation HCT . High quality studies are lacking related to HCT barriers. Older age and nonwhite race were consistently linked to reduced access to HCT. Strategies to overcome these barriers for these vulnerable populations should be prioritized. |
S1083879120305942 | In this cross sectional study we retrospectively evaluated the files of 227 patients with myelofibrosis who underwent transplantation between 1994 and 2015 for relapse later than 5 years after allogeneic stem cell transplantation . A total of 94 patients who were alive and in remission at 5 years were identified with follow up of at least 5 years after SCT . Thirteen patients experienced late molecular or hematologic relapse at a median of 7.1 years while 81 patients did not experience relapse . Relapse patients received either donor lymphocyte infusion and or second transplantation . Of those 72.7 achieved again full donor cell chimerism and molecular remission and after a median follow up of 45 months the 3 year overall survival rates for patients with or without relapse were 90.9 77 to 100 and 98.8 respectively | Late relapse after 5 years occurs in about 14 of myelofibrosis patients after allogeneic stem cell transplantation allo SCT . For detection chimerism and minimal residual disease monitoring should be performed even beyond 5 years after allo SCT. Most relapses can be successfully salvaged by donor lymphocyte infusion and or second allo SCT. |
S1083879120305954 | Severe aplastic anemia is a life threatening disease that can be cured with allogeneic cell transplantation . Haploidentical donor transplantation with post transplantation cyclophosphamide is an option for patients lacking an HLA matched donor . We analyzed 87 patients who underwent haplo PTCy between 2010 and 2019 . The median patient age was 14 years most were heavily transfused and all received previous immunosuppression . Almost two thirds received standard fludarabine cyclophosphamide 29 total body irradiation 200 cGy conditioning and the remaining patients received an augmented conditioning Flu Cy29 TBI 300 400 Flu Cy50 TBI 200 or Flu Cy50 TBI 400 . All patients received PTCy based graft versus host disease prophylaxis . Most grafts were bone marrow . The median duration of follow up was 2 years and 2 months . The median time to neutrophil recovery was 17 days . Primary graft failure occurred in 15 of the patients and secondary or poor graft function occurred in 5 . The incidences of grade II IV acute GVHD was 14 and that of chronic GVHD was 9 . Two year overall survival and event free survival were 79 and 70 respectively . EFS was higher for patients who received augmented Flu Cy TBI .28 | Hematopoietic stem cell transplantation from haploidentical donors for relapsed refractory severe aplastic anemia is feasible. Primary graft failure was 15 2 year event free survival EFS was 70 and 2 year overall survival was 79 . An augmented cyclophosphamide fludarabine total body irradiation regimen is associated with improved EFS. A CD34 cell dose 3.210E6 kg is associated with improved EFS. |
S1087184518301804 | MicroRNAs are endogenous noncoding RNAs that can regulate gene expression . However little information is known about milRNAs and their target genes in | For the first time Identied the milRNAs and their targets experimentally in. Identified many miRNA features that may be unique to basidiomycetes. The milRNAs functions are developmental stages dependent. Different mechanism of regulation for miRNA might be present. Conserved miRNA biosynthesis and processing machineries are present in basdiomycetes. |
S1087184519300404 | Cadmium is a heavy metal present in the environment mainly as a result of industrial contamination that can cause toxic effects to life . Some microorganisms as | tolerates well cadmium exposure although the metal impairs its growth. Genes related to transport glutathione and nitrogen metabolism were up regulated. RNA processing was strongly induced especially components of spliceosome. Carbohydrate metabolism genes related to mycoparasitism were repressed. |
S1087184519300878 | Proteinaceous infectious particles causing mammalian transmissible spongiform encephalopathies or prions are being extensively studied . However due to their hazardous nature the initial screening of potential anti prion drugs is often made in a yeast based screening system utilizing a well characterized | A novel. prion in. was created. prion was used to make a new screening system for anti prion drugs. based screening assay is safe cost efficient and easy to use. |
S1087184519301082 | Modern genome analysis and phylogenomic methods have increased the number of fungal species as well as enhanced appreciation of the degree of diversity within the fungal kingdom . In this context we describe a new | A new Hypocreales fungal species. is proposed. is phylogenetically related the opportunistic fungal pathogen. The genome of. was sequenced assembled and annotated. Comparative genomic studies of Hypocreales reveals unique metabolic profile. Molecular tools complement traditional morphologic fungal species discovery. |
S1087184519301094 | Transmembrane proteins as sensors encoded by fungal genes activate specific intracellular signal pathways in response to stress cues to help the fungus survive in a changing environment . To better understand the role of the cell wall integrity pathway in the entomopathogenic fungus | The significance of. in dimorphic transition conidium and microsclerotium formation. The. mediated regulation of target genes involved in microsclerotium development. It provides valuable understanding the molecular mechanism of microsclerotium development. |
S1087184519301288 | Protein O mannosyltransferases have been identified in fungi but not in plants and nematodes which makes PMTs become attractive targets for developing a new strategy against phytopathogens . Three PMTs have been identified in | Protein O mannosylaion is catalysed by three protein O mannosyltransferases PMT1 PMT2 and PMT4 in. Deletion of each. gene induces differential phenotype and attenuated virulence. Comparative glycoproteomics analysis reveals that different PMTs act on different protein substrates. |
S108718451930129X | Ras GTPases are nucleotide hydrolases involved in key cellular processes . In fungi Ras GTPases regulate conidiation development virulence and interactions with other fungi or plants . | TBRG 1 belongs to a new family of Ras GTPases named the Big Ras GTPases family. The lack of. impairs the conidiophore development in. and therefore the conidiation process. TBRG 1 is a negative regulator of antibiosis and mycoparasitism in. TBRG 1 is necessary to provide the biocontrol capability to. against |
S1087184519301483 | Chitinases the enzymes responsible for the biological degradation of chitin participate in numerous physiological processes such as nutrition parasitism morphogenesis and immunity in various organisms . However the genome wide distribution evolution and biological functions of chitinases are rarely reported in oomycetes . This study systematically investigated the glycoside hydrolase 18 family of chitinases from the mosquito pathogenic oomycete | GH18 chitinases were widely distributed in oomycetes. is required for zoospore production. and. regulate oxidative stress response and virulence. GH18 chitinases play diverse roles in |
S1087184519301665 | The presence of commensal fungal species in the human gut indicates that organisms from this kingdom have the potential to benefit the host as well . | Yeasts can form an important part of the human mycobiome as probiotics. is a well characterized probiotic yeast often used to alleviate GI tract disorders. Several pre clinical and clinical trials have demonstrated its efficacy as a probiotic. Several genome engineering tools available for. can be applied. to improve its probiotic attributes. |
S1087184519301793 | is the main causal agent of fusarium head blight of wheat and barley . This filamentous fungus is able to produce hydrolytic enzymes such as xylanases that cause cell wall degradation permitting host colonization . This study investigated the role of the | showed a role on. virulence during host colonization. was important for fungal growth on heads during the first FHB infection stages. Two genes encoding other xylanases did not show an overexpression in the absence of |
S1087184519302038 | The detrimental effect of fungal pathogens on forest trees is an increasingly important problem that has implications for the health of our planet . Despite this the study of molecular plant microbe interactions in forest trees is in its infancy and very little is known about the roles of effector molecules from forest pathogens . | and. share effector genes. In. many of these are pseudogenized or are poorly expressed. All these effectors are polymorphic among global. isolates. DsEcp2 1 triggers cell death in a non host plant and restricts. growth in pine. These results suggest both pathogen and host adaptation at the molecular level. |
S1087184519302142 | has been employed in the industrial production of cephalosporin C . However there are still some impediments to understanding the regulation of CPC biosynthesis and improving strains due to the difficulty of genetic manipulation in | An improved CRISPR Cas9 system based on a chimeric promoter. This system shows a high efficiency for gene disruption in. A large DNA fragment was deleted at a high efficiency by the system. Blocking the sorbicillinoid biosynthesis increases the CPC production. |
S1087184519302439 | Biotrophic basidiomycete plant pathogens cause billions of dollars in losses to cereal crops annually . The model for this group of fungi is the corn smut pathogen | and. ectopic expression did not complementdeletion phenotype. Deletion of. reduces pathogenesis similarly to P. or. deletion. deletion lack of growth on xylose complemented but not pathogenesis phenotype. codes a putative xylitol dehydrogenase not directly regulated by. Altered expression of antisense transcripts may influencepathogenesis by acting |
S1087184519302476 | Regulation of plant cell wall degradation is of utmost importance for understanding the carbon cycle in nature but also to improve industrial processes aimed at enzyme production for next generation biofuels . Thereby the transcription factor networks in different fungi show conservation as well as striking differences particularly between | Functions of CLR1 and CLR2 in plant cell wall degradation are rewired in. Deletion of clr1 or clr2 breaks coregulation of xylanase genes on xylan. CLR1 and CLR2 form a positive regulatory feedback loop on xylan. |
S1087184519302609 | Septins are highly conserved GTP binding proteins that function in cell cytokinesis polarity and morphogenesis . To evaluate the roles of these proteins in inoculum health and disease mutants deleted for each of five septin proteins were characterized in the ascomycete | The first functional study of the four core septin genes in a Dothideomycete plant pathogen Dothideomycetes is the largest group of phytopathogens. Development of sexual reproductive propagules was impacted in. core. mutants. Wild type asci formed but ascospores appeared to be blocked in the meiotic process and never formed. Development of both asexual reproductive propagules was impacted in. core. mutants. Conidia had dramatically reduced numbers of septa and rates of germination. mutants showed 83 reduced conidial germination compared to wild type and virulence to the host maize was reduced. Virulence could be returned to that of wild type by adjusting amount of inoculum to compensate for low germination rate. Since septins are not found in plants this research may be used to develop strategies that target septins for disease control in the field. |
S1087184519302683 | The HOG pathway is critical for the appropriate adaptation to adverse conditions . Here we demonstrated that the deletion of | Cg. null mutants displayed enhanced sensitivity to osmotic stress. The deletion of. resulted in increased resistance to fludioxonil. Compatible solutes contribute to the. dependent osmoadaptation. Vesicle trafficking related genes were highly downregulated in the. strain. |
S1087184519302786 | Trichothecenes are among the mycotoxins of most concern to food and feed safety and are produced by species in two lineages of | Tri21 is a transcription factor that regulates trichothecene biosynthesis. Tri21 regulates expression of late but not early trichothecene pathway genes. cluster acquired. gene after divergence from other. clusters. cluster has diverged into two lineages one with and one without. gene regulation differs in two trichothecene producing lineages of |
S1087184519302890 | The fungal cell wall consists of proteins and polysaccharides formed by the co ordinated activity of enzymes such as chitin or glucan synthases . These enzymes are delivered via secretory vesicles to the hyphal tip . In the ascomycete | Native chitin Chs5 and glucan synthase Gsc1 visualised in the pathogen. Chs5 and Gsc1 are transported along microtubules. Chs5 and Gsc1 do localise to the apical plasma membrane but not the Spitzenkrper. Light and electron microscopy how co travel of Chs5 and Gsc1 in the same secretory vesicle. Enzyme delivery in. is different from. but similar to |
S1087184519303032 | The endoplasmic reticulum is composed of distinct structural domains that perform diverse essential functions including the synthesis of membrane lipids and proteins of the cell endomembrane system . The polarized growth of fungal hyphal cells depends on a polarized secretory system which delivers vesicles to the hyphal apex for localized cell expansion and that involves a polarized distribution of the secretory compartments including the ER . Here we show that additionally the ER of the ascomycete | An ER domain is associated with the polarized growing apical cells of hyphae. The apical ER domain consists of dynamic and pleomorphic ER sub compartments. The apical ER sub compartments undergo fusion and division events. The apical ER sub compartments display acropetal and basipetal displacements. |
S1087184519303287 | The cell wall is a distinctive feature of filamentous fungi providing them with structural integrity and protection from both biotic and abiotic factors . Unlike plant cell walls fungi rely on structurally strong hydrophobic chitin core for mechanical strength together with alpha and beta glucans galactomannans and glycoproteins . Cell wall stress conditions are known to alter the cell wall through the signaling cascade of the cell wall integrity pathway and can result in increased cell wall chitin deposition . A previously isolated set of | cell wall chitin mutant characterized by co segregation analysis. GDP dissociation inhibitor A. was identified as an essential gene. Intronic SNPs in cell wall mutant. cause inefficient splicing. CRISPR Cas9 genome editing was successfully used to reconstitute mutant. SNPs. The. mutant allele is a candidate for GdiA related secretion studies in fungi. |
S1087184519303299 | Histone deacetylases play essential roles in modulating chromatin structure to provide accessibility to gene regulators . Increasing evidence has linked HADCs to pathogenesis control in the filamentous plant fungi . However its function remains unclear in | FpDep1 is a component of the Rpd3L histone deacetylase complex in. is essential for vegetative development and pathogenicity in. The. gene represses reactive oxygen species ROS accumulation. The Fpdep1 mutant is delayed in endocytosis. |
S1087184519303366 | Sexual reproduction is a highly conserved feature of the eukaryotes yet sexual compatibility is determined by a wide variety of mechanisms . In ascomycete fungi sexual development is controlled by genes at the mating type | A genome editing protocol has been developed for use in. species. a novel mating gene is a true mating gene in. strains show delays in protoascomatal development and hyphal growth. is essential for ascomatal maturation. |
S1087184520300086 | Nitric oxide can be biologically synthesized from nitrite or from arginine . Although NO is involved as a signal in many biological processes in bacteria plants and mammals still little is known about the role of NO in fungi . Here we show that NO levels are regulated by light as an environmental signal in | NO levels are regulated by light. Phytochrome A is required for induction by light of flavohemoglobin B and arginase. The blue photoreceptor LreA represses both genes in the presence of arginine. Intracellular arginine levels are regulated during development. Deletion of. results in loss of light regulation of conidiation and NO levels. |
S1087184520300372 | MicroRNAs play important roles in various cellular growth and developmental processes through post transcriptional gene regulation via mRNA cleavage and degradation and the inhibition of protein translation . To explore if miRNAs play a role in appressoria formation and virulence that are also governed by the regulators of G protein signaling proteins in the rice blast fungus | MicroRNA like milR236 targets the sequence encoding MoHat1. milR236 overexpression induces delayed appressorium formation and virulence attenuation. milR236 expression is regulated by the transcription factor MoMsn2. |
S1087184520300438 | Small GTPases of the ADP ribosylation factor family and their activating proteins regulate mycelial development and pathogenicity in yeast and filamentous fungi however little is known about their roles in nematode trapping fungi . In this study an ortholog of Arf GAP Glo3 in | AoGlo3 is the ortholog of yeast Glo3 and a pleiotropic regulator in. AoGlo3 is indispensable for conidiation trap formation and nematode trapping. AoGlo3 contributes to mycelial growth and environmental adaption. AoGlo3 is required for endocytosis and autophagy. |
S1087184520300566 | Green fluorescent protein and its counterparts are modern molecular biology research tools indispensable in many experimental systems . Within fungi researchers studying | Fluorescent proteins are valuable molecular biology research tools however only handful are available in. Eight fluorescent proteins were identified and expressed with five highly visible under the microscope. Heterologous expression of these five bright fluorescent proteins within. does not influence virulence. Developed six fluoroblasters for seamless tagging. |
S108718452030058X | Filamentous fungi are well known for producing secondary metabolites applied in various industrial segments . Among these lovastatin and itaconic acid produced by | Evaluation of 35. strains isolated from Brazil for lovastatin and itaconic acid production. Molecular identification enabled to separate the 35 Aspergillus terreus strains in three monophyletic groups. Lovastatin production stands out in the monophyletic group. B. There is no specific monophyletic group for itaconic acid producing strains. Identification of seven Brazilian strains with different levels of lovastatin and itaconic acid production. Lovastatin genomic data was corroborated by metabolite detection using LC MS. |
S1087184520300591 | Ergosterol is the most important membrane sterol in fungal cells and a component not found in the membranes of human cells . We identified the | Erg6 is required for. high temperature growth. deletion impairs susceptibility to stress and antifungal agents. Sterol membrane composition affects virulence of human fungal pathogen. |
S1087184520300694 | This work presents the identification and proposed biosynthetic pathway for a compound of mixed polyketide nonribosomal peptide origin that we named acurin A . The compound was isolated from an extract of the filamentous fungus | A biosynthetic gene cluster for the hybrid polyketide nonribosomal peptide compound acurin A in. The PKS and NRPS responsible for acurin A production are two individually transcribed entities. Phylogenetics suggest that the separated PKS and NRPS is a result from the fission of an ancestral PKS NRPS hybrid. The biosynthetic capacity of. is facilitated by the use of CRISPR Cas9 gene editing. |
S1087184520300864 | Paracoccidioidomycosis is a life threatening systemic mycosis widely reported in the Gran Chaco ecosystem . The disease is caused by different species from the genus | Paracoccidioidomycosis is a systemic mycosis reported in the Gran Chaco ecosystem. and. were found in Argentina and Paraguay. S1a specimens from Argentina are associated with chronic forms. In Paraguay. S1b was only the genotype observed. The coexistence of these species in a common area suggests reproductive isolation. |
S1087184520300876 | The ubiquitin proteasome system is critical for the regulation of protein turnover which is implicated in the modulation of a wide array of biological processes in eukaryotes ranging from cell senescence to virulence in plant and human hosts . Proteins to be marked for ubiquitination and subsequent degradation are bound by F box proteins which are interchangeable substrate recognising receptors . These F box proteins bind a wide range of substrates and associate with the adaptor protein Skp1 and the scaffold Cul1 to form Skp1 Cul1 F box complexes . SCF complex components are highly conserved in eukaryotes ranging from yeast to humans . However information regarding the composition of these complexes and the biological roles of F box proteins is limited specifically in filamentous fungal species like the genus | Skp1 Cul1 F box SCF complexes regulate protein degradation in eukaryotes. encoding genes have been identified in. and. SkpA interacts with F box proteins to form SCF complexes in. species. SCF complex conformations vary in response to different exogenous stresses. In both species Fbx45 interacts with SkpA in the presence of Amphotericin B. |
S108718452030089X | Evolution favors the emergence of locally adapted optimum phenotypes that are likely to differ across a wide array of environmental conditions . The emergence of favorable adaptive characteristics is accelerated in agricultural pathogens due to the unique properties of agro ecosystems . We performed a Q | QST FST study of 164 strains using image phenotyping and full genome sequences. Natural selection and genetic drift on quantitative traits. Local adaptation against fungicides and high temperatures among populations. Melanization was found to be under stabilizing selection. Trade off between melanization and growth rates at high temperature. |
S1087184520300906 | Subtilases are a large family of serine proteases that occur throughout biology . A small subset contain protease associated domains that are structurally separate from but encoded within the active site . In bacteria subtilase PA domains function to recruit specific protein substrates . Here we demonstrate that a protease secreted by the fungal corn pathogen | We identified a protease secreted by. a fungal corn pathogen. Kilbournase truncates corn ChitA chitinase cleaving the N terminus multiple times. Kilbournase resembles. ScpA which targets human C5a. Kilbournase and ScpA are PA domain subtilases that target specific host proteins. Kilbournase is the first protein implicated in Stenocarpella ear rot of corn. |
S1087184520300918 | Endocytosis plays critical roles in cellular processes including nutrient uptake and signal transduction . Ede1 is an endocytic scaffolding protein that contributes to endocytic site initiation and maturation in yeast . However the functions of Ede1 in phytopathogenic fungi are not known . Here we identified functions of FgEde1 in | deletion causes reduced hyphal growth and conidiation. is essential for full virulence. deletion mutant shows tolerance to various stresses. deletion displays the aggravated autophagy. |
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