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Omidubicel is an advanced cell therapy derived from umbilical cord blood (UCB) for use in allogeneic hematopoietic cell transplantation (HCT). A recent randomized phase 3 clinical trial demonstrated faster engraftment, shorter length of hospital stays, and lower rates of infection with omidubicel compared with standard UCB transplantation in patients with high-risk hematologic malignancies. Despite the proven clinical benefits of omidubicel, its impact on health-related quality of life (HRQL) from the patient's perspective has not been described. This study analyzed patient-reported HRQL measures collected prospectively in the randomized phase 3 trial comparing omidubicel to standard UCB transplantation. A total of 108 patients at 33 international stem cell transplantation centers underwent myeloablative allogeneic HCT with either omidubicel or standard UCB. Patients completed serial HRQL questionnaires at screening and on days 42, 100, 180, and 365 post-transplantation. The HRQL surveys included the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), a 50-item cancer-specific questionnaire assessing physical, functional, emotional, social/family, and HCT-specific well-being, and the EuroQol 5-Dimension 3-Level, a 5-item generic HRQL survey. A mixed model with repeated measures was used to compare changes in HRQL from baseline in the 2 treatment arms. The average change in HRQL scores over time was compared by estimating the difference in the area under the curve (AUC) in each treatment group. Seventy-five patients (omidubicel arm, n = 37; standard UCB arm, n = 38) who completed the FACT-BMT at baseline and on 1 or more follow-up visits were included in this study. Baseline characteristics were similar in the 2 treatment arms. Over the first year post-transplantation, the AUCs of mean changes in physical, functional, and total FACT-BMT scores indicated significantly better HRQL with omidubicel (P < .05), with mean differences across time points ranging from 1.4 to 3.1 points, 1.6 to 3.2 points, and 7.2 to 11.0 points, respectively. The minimal clinically important difference was exceeded at 1 or more time points for each of these measures. The HRQL improvements with omidubicel were observed as early as 42 days post-transplantation and persisted at 1 year, indicating the potential long-term benefits of omidubicel on HRQL. Across all patients, adverse clinical outcomes, such as grade 3 viral infections and lower rates of neutrophil engraftment, were associated with worse HRQL scores. The observed improvements in HRQL measures may reflect the known clinical benefits of omidubicel. Compared with standard UCB, allogeneic HCT with omidubicel resulted in significant and clinically meaningful improvements in patient-reported HRQL measures., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Early detection of pulmonary complications can improve outcomes for patients with hematological malignancy (HM). For detecting lung injuries, lung ultrasound (LUS) images have been found to be of greater sensitivity than radiographic images. Our group performed a pilot study of LUS imaging to enhance early detection of pulmonary complications in HM patients. This prospective single-center feasibility study evaluated LUS for detecting pulmonary complications in 18 HM patients enrolled while hospitalized for a hematopoietic cell transplant (HCT) (concurrent-HCT group) or re-hospitalized for complications (post-HCT group). Serial LUS exams were performed and assigned a score from 0 to 5 based on pleural line, B-line, consolidation and pleural effusion features. Correlations between patients' clinical characteristics and LUS features were analyzed. Comparisons between the LUS and radiographic images were evaluated. In the concurrent-HCT patients (79 LUS exams), non-significant fluctuating findings were commonly identified, but one-third of the patients presented pathologic findings (LUS scores ≥ 3). In the post-HCT patients (29 LUS exams), LUS images revealed severe pathologic findings (LUS score = 5) in every patient and, compared with radiographic images, were more sensitive for detecting pleural effusions (p < 0.05). LUS can be routinely performed on hospitalized HM patients, allowing point-of-care early detection of pulmonary complications., Competing Interests: Conflict of interest disclosure The authors declare they have no conflicts of interest., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Host immune depletion has been recognized as a necessary step for successful adoptive immune cell transfer in both the autologous and allogeneic settings. The chemotherapy agent fludarabine as an immune suppressive agent has a central role in multiple conditioning regimens for both transplantation and immune effector cell therapies. With the recent and sudden recognition of an imminent worldwide fludarabine shortage, novel approaches to overcome supply chain disruption are needed, including exploration of alternative therapies. The fludarabine shortage has highlighted the need to prioritize the development of institutional algorithms for maintaining ongoing clinical trials and standard of care procedures in the setting of critical drug shortages., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor (CAR) T cell therapies approved for the treatment of relapsed/refractory aggressive B cell lymphomas. We present a multicenter retrospective study among centers that prescribe either commercial product to evaluate usage patterns, safety and efficacy outcomes, and resource utilization. Data collection included all patients from 8 US centers who underwent apheresis between May 1, 2018, and July 31, 2019. Patient selection, toxicity management, and disease assessment followed institutional practices. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy consensus criteria, and tumor responses were assessed according to the Lugano 2014 classification scheme. A total of 260 patients underwent apheresis, including 168 (65%) for axi-cel and 92 (35%) for tisa-cel. Among the infused patients, the median age was 59 years for axi-cel recipients and 67 years for tisa-cel recipients (P < .001). The median time from apheresis to infusion was 28 days for axi-cel recipients and 45 days for tisa-cel recipients (P < .001). Sixty-one percent of the axi-cel recipients and 43% of the tisa-cel recipients would have been ineligible for the ZUMA-1 and JULIET trials, respectively. Grade ≥3 CRS occurred in 9% of axi-cel recipients and in 1% of tisa-cel recipients (P = .017), and grade ≥3 ICANS was seen in 38% of axi-cel recipients and 1% of tisa-cel recipients (P < .001). Inpatient cell therapy infusion was common (92% in axi-cel recipients, 37% in tisa-cel recipients). The day 90 overall response rate was 52% in the axi-cel group and 41% in the tisa-cel group (P = .113), with complete response in 44% and 35%, respectively (P = .319). Twelve-month progression-free survival (42% versus 32%; P = .206) and overall survival (62% versus 59%; P = .909) rates were comparable in the axi-cel and tisa-cel groups. Baseline characteristics differed between the 2 groups, although response rates and survival outcomes were comparable, albeit lower than those in the pivotal trials. Safety and resource utilization appear to be key differentiators between axi-cel and tisa-cel., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

This study compared the real-world healthcare resource utilization (HRU), costs, adverse events (AEs), and AE treatments associated with the chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel), for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Adults with DLBCL who received tisa-cel or axi-cel were identified in the Premier Healthcare Database (2017-2020). Non-CAR-T costs, HRU, and AE rates during the infusion and follow-up periods were compared between the tisa-cel and axi-cel cohorts. Of 119 patients, 33 received tisa-cel (86% as inpatient infusion) and 86 received axi-cel (100% inpatient). Tisa-cel was associated with significantly shorter mean inpatient length of stay than axi-cel during infusion (11.3 vs. 18.3 days) and follow-up ([monthly] 3.9 vs. 6.9 days). Non-CAR-T costs were significantly lower for tisa-cel compared with axi-cel during infusion ($27594.8 vs. $51378.3) and follow-up ([monthly] $28777.3 vs. $46575.7; both p < .05). Rates of AEs and AE treatments were similar.

Background: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T., Patients and Methods: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading., Results: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide., Conclusions: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization., Competing Interests: Disclosure MR holds patents related to CD19 CAR T cells, served as a consultant for NanoString, Bristol Myers Squibb (BMS), GlaxoSmithKline, Bayer, and AbClon, receives research funding from AbClon, NanoString, and Beckman Coulter, and is the scientific founder of viTToria Biotherapeutics. JS served as a consultant for Genmab, Adaptive, AstraZeneca, BMS, Imbrium, ADCT, Atara, Pharmacyclics, Seattle Genetics and received research funding from AstraZeneca, BMS, Incyte, Merck, Seattle Genetics, Pharmacyclics, and TG therapeutics. RTM served as an advisor or consultant for AlloVir, Artiva, CRISPR Therapeutics, Incyte, and Novartis, reports honoraria from BMS/Celgene, Incyte, Intellia, and Kite, has received research support from BMS, AlloVir, and Novartis, has participated in data and safety monitoring boards for Athersys, Vor Pharma, and Novartis, and has a patent with Athersys. EAC served as consultant for Novartis, Beigene, KITE, Tessa, Juno/BMS. SKB served as consultant to Acrotech, Kyowa Kirin, Daiichi Sankyo, and Seagen. SDN received research funding from Pharmacyclics, Roche, Rafael, FortySeven/Gilead. UJ served as a consultant to Novartis, received research funding from Novartis and honoraria from Novartis, BMS/Celgene, Gilead, Janssen, and Miltenyi. JDL received research funding from Curis, Takeda, and Triphase, served on Board of Directors or advisory committees or data and safety monitoring board for Incyte, ADCT, Karyopharm, and Morphosis. SJS served as a consultant to AstraZeneca, BeiGene, Celgene, Genentech, Genmab, Fate Therapeutics, Roche, Incyte, Juno Therapeutics, Legend Biotech, Loxo Oncology, MorphoSys, Mustang Biotech, Nordic Nanovector, Novartis, and Regeneron, received research funding from AbbVie, Adaptive Biotechnologies, Celgene, DTRM, Genentech, Roche, Juno Therapeutics, Merck, Novartis, Incyte, Pharmacyclics, and TG Therapeutics, received honoraria from Celgene and Novartis, and holds patents related to CD19 CAR T cells and autologous co-stimulated T cells. JNG: Kite: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy. AG: Amgen: Honoraria; Tmunity Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Novartis: Research Funding. DLP: National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; American Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria: UJ has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 945393. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and from the Medical-Scientific Funds of the City of Vienna, Cancer Research Funds Project—Nr. 21098. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT) are immunosuppressive and increase the risk for reactivation of and infection with double-stranded DNA (dsDNA) viruses, which contribute to morbidity and mortality after allo-HCT. This retrospective observational study evaluated the association of dsDNA viral infections with clinical outcomes, health resource utilization (HRU), and health care reimbursement after allo-HCT. Patients who underwent allo-HCT between 2012 and 2017 were identified from a US open-source claims database (Decision Resource Group Real-World Evidence Data Repository; n = 13,363) and categorized according to the presence or absence of dsDNA viral infection, defined as having ≥1 diagnosis code for cytomegalovirus (CMV), adenovirus (AdV), human herpesvirus 6 (HHV-6), or BK virus (BKV)/Epstein-Barr virus (EBV)/John Cunningham virus (JCV) (grouped together given a lack of specific diagnoses codes) within 1 year after allo-HCT. Only first allo-HCT data were used in patients who underwent multiple procedures. Study outcomes included clinical outcomes (eg, time to all-cause mortality, new diagnosis of renal impairment), HRU (hospital and intensive care unit length of stay [LOS], readmission rates), and health care reimbursement (total, inpatient, and outpatient costs as reported reimbursements from insurance claims). For all outcomes, patients were stratified by the presence/absence of any dsDNA viral infection and number (none, 1, 2, or ≥3) and type(s) of infection. The effect of graft-versus-host disease (GVHD) was assessed as well. Twenty-nine percent of patients were diagnosed with CMV, 13% with BKV/EBV/JCV, 5% with AdV, and 4% with HHV-6 in the year following their first allo-HCT. A single dsDNA viral infection was documented in 30% of individuals, 2 in 8%, and ≥3 in 2%. Patients with no viral infections had an overall hospital LOS (index hospitalization plus readmissions) of 41.3 days and a total health care reimbursement of $266,345. These numbers increased for every additional viral infection, regardless of the presence or absence of GVHD; the overall hospital LOS was 61.4 days and total healthcare reimbursement was $431,614 in patients with 1 viral infection, 77.0 days and $639,097 in patients with 2 viral infections, and 103.3 days and $964,378 in patients with ≥3 viral infections. An increase in the number of dsDNA viral infections was associated with a significantly higher adjusted hazard of all-cause mortality (1 versus 0 dsDNA viral infections: hazard ratio [HR], 1.5; [95% confidence interval (CI), 1.3 to 1.6]; 2 versus 0: HR, 2.0 [95% CI, 1.7 to 2.3]; ≥3 versus 0: HR, 2.4 [95% CI, 1.8 to 3.3]) and a significantly higher incidence of new diagnosis of renal impairment, regardless of the presence of GVHD (35% of patients with ≥3 infections, 31% of patients with 2 infections, 26% of patients with 1 infection, and 19% of patients with no infection). These results indicate that more directed prevention and treatment strategies for dsDNA viral infections could substantially improve clinical outcomes and reduce HRU., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells are novel therapies showing great promise for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Single-arm studies showed significant variations in outcomes across distinct CD19 CAR T-cell products. To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase 1/2 clinical trial (NCT01865617). After adjustment for age, hematopoietic cell transplantation-specific comorbidity index, lactate dehydrogenase (LDH), largest lesion diameter, and absolute lymphocyte count (ALC), CAR T-cell product type remained associated with outcomes in multivariable models. JCAR014 was independently associated with lower cytokine release syndrome (CRS) severity compared with axicel (adjusted odds ratio [aOR], 0.19; 95% confidence interval [CI]; 0.08-0.46), with a trend toward lower CRS severity with tisacel compared with axicel (aOR, 0.47; 95% CI, 0.21-1.06; P = .07). Tisacel (aOR, 0.17; 95% CI, 0.06-0.48) and JCAR014 (aOR, 0.17; 95% CI, 0.06-0.47) were both associated with lower immune effector cell-associated neurotoxicity syndrome severity compared with axicel. Lower odds of complete response (CR) were predicted with tisacel and JCAR014 compared with axicel. Although sensitivity analyses using either positron emission tomography- or computed tomography-based response criteria also suggested higher efficacy of axicel over JCAR014, the impact of tisacel vs axicel became undetermined. Higher preleukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR. We conclude that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients., (© 2022 by The American Society of Hematology.)

No head-to-head trials have compared the efficacy of tisagenlecleucel vs historical treatments for adults with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This study indirectly compared the overall survival (OS) and overall response rate (ORR) associated with tisagenlecleucel, using data from the JULIET study (Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients; #NCT02445248), vs historical treatments assessed in the CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) study follow-up population. To assess treatment effects in the treated (full analysis set [FAS]) and enrolled (intention-to-treat [ITT]) study populations, the JULIET FAS vs the CORAL follow-up FAS and JULIET ITT vs CORAL follow-up ITT populations were separately compared. Propensity score weighting using standardized mortality ratio weight (SMRW) and fine stratification weight (FSW) was used to compare OS and ORR, adjusting for baseline confounders. The results indicated that tisagenlecleucel was associated with a lower hazard of death among the FAS (adjusted hazard ratio [95% confidence interval], both FSW and SMRW, 0.44 [0.32, 0.59]) and ITT populations (FSW, 0.60 [0.44, 0.77]; SMRW, 0.57 [0.44, 0.73]; all, P < .001). Median OS was 12.48 months (JULIET) vs 4.34 to 4.40 months (CORAL) for the FAS, and 8.25 (JULIET) months vs 4.04 to 4.86 (CORAL) months for the ITT populations. Tisagenlecleucel was associated with a significantly higher ORR compared with historical treatments among the FAS (adjusted response rate difference [95% confidence interval], both FSW and SMRW, 36% [22%, 0.48%]; P < .001) and among the ITT populations after SMRW adjustment (11% [0%, 22%]; P = .043). This analysis supports that improved response and OS are achieved in patients with r/r DLBCL treated with tisagenlecleucel compared with those treated with alternative historical treatments., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

This study compared overall survival (OS), progression-free survival (PFS), complete response rate (CRR), and overall response rate (ORR) of tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) in relapsed or refractory large B-cell lymphomas (r/r LBCL). Using matching-adjusted indirect comparison (MAIC), individual patient-level data from JULIET (tisa-cel) were weighted to match the patient population in TRANSCEND (liso-cel). The main analysis compared infused JULIET patients ( N  = 106) with the TRANSCEND efficacy-evaluable set (EES) ( N  = 256 [infused]). After adjustment, OS, PFS, and the CRR were comparable between tisa-cel and liso-cel EES patients. The estimated adjusted 2-year OS, 2-year PFS, ORR, and CRR were 45.6, 38.2, 62.9, and 47.7%, respectively, for tisa-cel vs. 43.8, 42.1, 72.7, and 53.1% for liso-cel. A scenario analysis compared JULIET patients to the TRANSCEND primary analysis set (PAS) ( N  = 133). ORR was significantly higher in the TRANSCEND PAS compared with matched JULIET patients, but no significant differences in CRR were observed.

Background: Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines., Methods: We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety., Results: A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events., Conclusions: Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.)., (Copyright © 2021 Massachusetts Medical Society.)

The effect of chronic graft-versus-host disease (cGVHD) on the risk of nonrelapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research (CIBMTR) analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (age ≥60 years). We included 4429 adults age ≥40 years who underwent a first HLA-matched peripheral blood stem cell alloHCT for acute myelogenous leukemia or myelodysplastic syndrome between 2008 and 2017. We compared outcomes of 4 groups-older adults (≥60 years) and younger adults (40 to 59 years) with cGVHD and older and younger adults without cGVHD-to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse, and overall survival (OS). We treated cGVHD as a time-dependent covariate. The severity of cGVHD was based on the CIBMTR clinical definitions. cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher for older adults versus younger adults. Adults who developed cGVHD as a group had longer OS compared with age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild to moderate cGVHD was associated with longer OS. Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse, and longer OS. Older adults had a higher risk of NRM, but the increased risk of NRM associated with cGVHD did not differ based on age. The development of mild to moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing the risk of relapse. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) is characterized by multiple molecular and cytogenetic abnormalities, with increasing data to support clinical and prognostic implications to guide clinical decision making. One of the most well described mutations involves fms-like tyrosine kinase 3 ( FLT3 ) that results in a constitutively active tyrosine kinase and is generally associated with poor prognosis involving shorter overall survival and higher rates of relapse. Advancements in targeted therapies have greatly influenced available treatment options in a landscape that has remained largely unchanged for the past five decades. Tyrosine kinase inhibitors (TKI), specifically FLT3 -targeted therapies, are now integral treatment options for patients with this targetable mutation. As allogeneic hematopoietic cell transplant (alloHCT) remains the primary curative therapy for most adult AML patients, the goal is for eligible patients to proceed to transplant. However, post-alloHCT relapse remains exceedingly high even in patients achieving deep responses to therapy. Limited evaluation of FLT3 -targeted TKIs as post-alloHCT maintenance therapy in FLT3 -positive patients suggest improved outcomes and tolerable safety profiles, with ongoing studies further investigating second-generation agents. Thus, this commentary aims to review the role of post-alloHCT FLT3 -targeted maintenance therapy and considerations for clinical practice., Competing Interests: Conflict of Interest No current conflict of interest exists related to the content of this review, by the authors.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in recipients of haploidentical and fully matched transplantations is on the increase. Published studies have reported an increased incidence of cytomegalovirus (CMV) infection with the use of PTCy. Limited data exist on the incidence and outcomes of infection with non-CMV herpesviruses (NCHV) in this setting. The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplantation-specific outcomes in recipients of haploidentical transplantation with PTCy (HaploCy), matched sibling donor transplantation with PTCy (SibCy), and matched sibling donor transplantation with calcineurin inhibitor-based prophylaxis (SibCNI). We hypothesized that, like CMV infection, HaploCy recipients of also will have a higher risk of NCHV infections. Using the Center for International Blood and Marrow Transplantation Research database, we analyzed 2765 patients (HaploCy, n = 757; SibCNI, n = 1605; SibCy, n = 403) who had undergone their first hematopoietic stem cell transplantation (HCT) between 2012 and 2017 for acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The cumulative incidence of NCHV at 6 months post-NCT was 13.9% (99% confidence interval], 10.8% to 17.3%) in the HaploCy group, 10.7% (99% CI, 7.1% to 15%) in the SibCy group, and 5.7% (99% CI, 4.3% to 7.3%) in the Sib CNI group (P < .001). This was due primarily to a higher frequency of human herpesvirus 6 viremia reported in patients receiving PTCy. The incidence of Epstein-Barr viremia was low in all groups, and no cases of post-transplantation lymphoproliferative disorder were seen in either PTCy group. The incidence of NCHV organ disease was low in all 3 cohorts. The development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, or disease-free survival. Patients in PTCy cohorts who did not develop NCHV infection had lower rates of cGVHD. This study demonstrates that the use of PTCy is associated with an increased risk of NCHV infection. The development of NCHV infection was associated with increased nonrelapse mortality, especially in the HaploCy group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for a better understanding of the clinical relevance of viral reactivation in different HCT settings., (Copyright © 2021. Published by Elsevier Inc.)

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In 2021 the BMT CTN held the 4th State of the Science Symposium where the deliberations of 11 committees concerning major topics pertinent to a particular disease, modality, or complication of transplant, as well as two committees to consider clinical trial design and inclusion, diversity, and access as cross-cutting themes were reviewed. This article summarizes the individual committee reports and their recommendations on the highest priority questions in hematopoietic stem cell transplant and cell therapy to address in multicenter trials., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Omidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase 3 trial to evaluate the efficacy of omidubicel compared with standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients age 13 to 65 years with hematologic malignancies were randomly assigned to omidubicel vs standard UCBT. Patients received myeloablative conditioning and prophylaxis with a calcineurin inhibitor and mycophenolate mofetil for graft-versus-host disease (GVHD). The primary end point was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% confidence interval [CI], 10-14 days) for the omidubicel arm and 22 days (95% CI, 19-25 days) for the control arm (P < .001). The cumulative incidence of neutrophil engraftment was 96% for patients receiving omidubicel and 89% for patients receiving control transplants. The omidubicel arm had faster platelet recovery (55% vs 35% recovery by 42 days; P = .028), had a lower incidence of first grade 2 to 3 bacterial or invasive fungal infection (37% vs 57%; P = .027), and spent more time out of hospital during the first 100 days after transplant (median, 61 vs 48 days; P = .005) than controls. Differences in GVHD and survival between the 2 arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduces early transplant-related complications compared with standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT. The trial was registered at www.clinicaltrials.gov as #NCT02730299., (© 2021 by The American Society of Hematology.)

Purpose: Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined., Methods: We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration., Results: The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined., Conclusion: We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS., Competing Interests: Ryotaro NakamuraConsulting or Advisory Role: Viracor Eurofins, Magenta Therapeutics, Kadmon, Napajen PharmaResearch Funding: Helocyte, Miyarisan PharmaceuticalTravel, Accommodations, Expenses: Kyowa Hakko Kirin, Alexion Pharmaceuticals Bart ScottHonoraria: Bristol Myers SquibbConsulting or Advisory Role: Celgene, Acceleron Pharma, Astex Pharmaceuticals, NovartisSpeakers' Bureau: Alexion Pharmaceuticals, Celgene, Jazz Pharmaceuticals, NovartisResearch Funding: Celgene Betul OranResearch Funding: AROG Phamarceuticals, Astex Pharmaceuticals Asmita MishraResearch Funding: Novartis Richard T. MaziarzHonoraria: Novartis, Omeros, PACT PharmaceuticalsConsulting or Advisory Role: Novartis, Incyte, Kite, a Gilead company, Bristol Myers Squibb, Intellia Therapeutics, ArtivaPatents, Royalties, Other Intellectual Property: Athersys Inc shared patent re: use of mesenchymal stromal cells for treatment of GVHDTravel, Accommodations, Expenses: Novartis, Incyte, Kite, a Gilead company Joseph McGuirkHonoraria: Kite, a Gilead company, AlloVir, Juno Therapeutics, Magenta TherapeuticsConsulting or Advisory Role: Kite, a Gilead company, Juno Therapeutics, AlloVir, Magenta Therapeutics, EcoR1 CapitalSpeakers' Bureau: Kite/GileadResearch Funding: Novartis, Fresenius Biotech, Astellas Pharma, Bellicum Pharmaceuticals, Gamida Cell, Pluristem Therapeutics, Kite, a Gilead company, AlloVirTravel, Accommodations, Expenses: Kite, a Gilead company Peter WesterveltConsulting or Advisory Role: Pfizer Sumithira VasuConsulting or Advisory Role: Omeros, Johnson & JohnsonPatents, Royalties, Other Intellectual Property: The Ohio State University has entered into an exclusive licensing agreement with Kiadis Inc Mrinal PatnaikHonoraria: Kura OncologyConsulting or Advisory Role: Kura OncologyResearch Funding: Stemline Therapeutics Stephen J. FormanStock and Other Ownership Interests: MustangBio, Lixte BiotechnologyConsulting or Advisory Role: Alimera Sciences, Lixte Biotechnology, MustangBioResearch Funding: MustangBioPatents, Royalties, Other Intellectual Property: MustangBio Mikkael A. SekeresConsulting or Advisory Role: Celgene, Millennium, Pfizer, NovartisResearch Funding: Takeda, Pfizer, Bristol Myers Squibb Frederick AppelbaumStock and Other Ownership Interests: Jasper Therapeutics Brent LoganConsulting or Advisory Role: Daiichi Sankyo, Enlivex Therapeutics Ltd, Gamida Cell Mary HorowitzConsulting or Advisory Role: Magenta Therapeutics, Janssen Research & Development, MedacResearch Funding: Biovitrum, Jazz Pharmaceuticals, Magenta Therapeutics, Novartis, Kite/Gilead, Actinium Pharmaceuticals, Amgen, Amneal Pharmaceuticals, Anthem, Bluebird Bio, Bristol Myers Squibb, Chimerix, CSL Behring, Cyto-Sen Therapeutics, Daiichi Sankyo, Gamida Cell, GlaxoSmithKline, Mesoblast, Miltenyi Biotec, Neovii, Oncoimmune, Pfizer, Pharmacyclics, Regeneron, Sanofi, Seattle Genetics, Shire Corey CutlerStock and Other Ownership Interests: Bluebird Bio, Idera, Verastem, Northwest Biotherapeutics, Actinium PharmaceuticalsHonoraria: Omeros, PfizerConsulting or Advisory Role: Incyte, Jazz Pharmaceuticals, CareDX, Mesoblast, Syndax, MedsenicNo other potential conflicts of interest were reported.

Background and Objective: The objective of this study was to estimate the lifetime costs of patients receiving treatment for follicular lymphoma (FL) in the United States., Methods: A Markov model was programmed in hēRo3 with a 6-month cycle length, 35-year time horizon (lifetime projection), and health states for line of treatment, response, receipt of maintenance therapy among responders, transformation to diffuse large B-cell lymphoma (DLBCL), development of second primary malignancy (SPM), and death. The model was used to estimate the expected lifetime costs of FL (in 2019 USD), including costs of drug acquisition and administration, transplant procedures, radiotherapy, adverse events, follow-up, DLBCL, SPM, end-of-life care, and indirect costs. Model inputs were based on published sources., Results: In the US, patients with FL receiving treatment have a life expectancy of approximately 14.5 years from initiation of treatment and expected lifetime direct and indirect costs of US$515,884. Costs of drugs for induction therapy represent the largest expenditure (US$233,174), followed by maintenance therapy costs (US$88,971) and terminal care costs (US$57,065). Despite the relatively advanced age of these patients, indirect costs (due to patient morbidity and mortality and caregiver lost work time) represent a substantial share of total costs (US$40,280). Treated FL patients spend approximately 6.9 years in the health states associated with first-line therapy. Approximately 66 and 46% continue to second- and third-line therapies, respectively. The mean (95% credible interval) of expected lifetime costs based on the probabilistic sensitivity analyses was US$559,202 (421,997-762,553)., Conclusions: In the US, the expected lifetime costs of care for FL patients who receive treatment is high. The results highlight the potential economic benefits that might be achieved by treatments for FL that prevent or delay disease progression., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort., Methods: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 10 8 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing., Findings: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported., Interpretation: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy)., Funding: Novartis Pharmaceuticals., Competing Interests: Declaration of interests SJS is an adviser or consultant for Acerta, AlloGene, AstraZeneca, BeiGene, Celgene (Juno), Genentech (Roche), LoxoOncology, Novartis, and Tessa Therapeutics; reports honoraria from Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech (Roche), LoxoOncology, Novartis, Nordic Nanovector, Pfizer, and Tessa Therapeutics; reports steering committee participation for AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer; reports research support from AbbVie, Acerta, Celgene (Juno), DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, and TG Therapeutics; and reports a patent with Novartis. CST reports honoraria from AbbVie, BeiGene, Janssen, Novartis, and Roche, and research support from AbbVie and Janssen. NW reports personal fees from Celgene (Bristol Myers Squibb), Kite (Gilead), and Novartis, and travel support from Celgene and Novartis. JPM is a consultant for Juno; reports honoraria from AlloVir, Juno, and Kite; reports research support from AlloVir, Astellas, Bellicum, Fresenius Biotech, Gamida Cell, Juno, Kite, Novartis, and Pluristem; reports participation on a speakers bureau for Kite; and reports assistance with manuscript preparation from ArticulateScience. HH is an adviser or consultant for Gilead, Roche, Nordic Nanovector, Novartis, and Takeda, and reports honoraria from Novartis. EKW is an adviser or consultant for Cambium Medical Technologies, Celldex, Novartis, Partner Therapeutics, cyclics, and Verastem; reports research support from Amgen, Celldex, Juno, Novartis, and Partner Therapeutics; and owns stocks in Cambium Medical Technologies and Cambium Oncology. SJ reports research support from Kite and Novartis, and personal fees from Juno, Kite, and CRISPR Therapeutics. MRB is a consultant for Celgene, CRISPR Therapeutics, Juno, Kite, and Novartis; reports research support from Novartis; and reports participation on speakers bureaus for Celgene and Kite. SRF reports personal fees from Novartis. JRW is an adviser or consultant for Celgene, Curis, Genentech, Janssen, Juno, Kite, MorphoSys, and Novartis, and reports research support from Celgene, Curis, Forty Seven, Genentech, Janssen, Kite, Novartis, and Unum. IF is an adviser or consultant for AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Roche, and Seattle Genetics, and reports honoraria from AbbVie, Gilead, Janssen, Novartis, Roche, and Seattle Genetics. PJH reports travel support from Celgene, Janssen, La Jolla, and Novartis. SM is an adviser or consultant for Merck and Novartis; reports research support from Kiadis Pharma; reports speaker fees from Celgene, Cellex, DNA Prime, Jazz Pharma, Kiadis Pharma, Miltenyi Biotec, and Novartis; reports participation in an expert panel for Bellicum and Kite (Gilead); reports participation in a data and safety monitoring board for Miltenyi Biotec; and reports travel support from Celgene, Cellex, the European Hematology Association and the European Society for Blood and Marrow Transplantation, the German Society of Hematology and Medical Oncology, the International Society for Cellular Therapy, Kiadis Pharma, Kite (Gilead), Merck, and Miltenyi Biotec. TT is an adviser or consultant for Merck, Novartis, and Takeda; reports honoraria from Bristol Myers Squibb, Fuji Pharma, Kyowa Kirin, Merck, Nippon Shinyaku, Pfizer, Takeda, and Teijin Pharma; reports research support from Astellas, Chugai, Kyowa Kirin, Novartis, and Sanofi; reports grants from the Japan Society for the Promotion of Science and the Japan Science and Technology Agency; and reports assistance with manuscript preparation from Janssen and Novartis. GS is an adviser or consultant for AbbVie, Allogene, Autolus, BeiGene, Celgene, Epizyme, Genmab, Janssen, Kite (Gilead), Merck, MorphoSys, Novartis, Roche, and VelosBio, and reports honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Epizyme, Janssen, Kite (Gilead), Merck, MorphoSys, Novartis, and Roche. KI reports grants from Celgene, Daiichi Sankyo, and Novartis, and personal fees from Celgene and Novartis. MJK is an adviser or consultant for, and reports travel support from, Amgen, Bristol Myers Squibb, Celgene, Janssen, Kite (Gilead), Merck, Miltenyi Biotec, Novartis, and Roche, and reports research support from Celgene, Roche, and Takeda. NW-J is an adviser or consultant for ADC Therapeutics, Bayer, Epizyme, Gilead, Grünenthal, Janssen, Karyopharm, and Regeneron, and reports research support from ADC Therapeutics, Astex, Juno, and Regeneron. KK is an adviser or consultant for AbbVie, AstraZeneca, Celgene, Chugai, Eisai, Janssen, and Novartis; reports honoraria from Celgene, Chugai, Janssen, Kyowa Kirin, Merck, Mundi, Novartis, Ono, Sumitomo Dainippon, and Takeda; and reports research support from AbbVie, Celgene, Chugai, Eisai, Janssen, Kyowa Kirin, Ono, Novartis, and Takeda. MM-P, XH, and RT are employees of Novartis. RTM is an adviser or consultant for AlloVir, Artiva, CRISPR Therapeutics, CytoDyn, Incyte, and Novartis; reports honoraria from Bristol Myers Squibb (Celgene), Incyte, Intellia, Kite, Omeros, Orca BioSystems, and PACT Pharma; reports research support from Juno and Novartis; reports participation in a data and safety monitoring board for Athersys and Novartis; and has a patent with Athersys. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Richter syndrome (RS) represents a transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), which is associated with a dismal prognosis. Patients with DLBCL-RS have poor outcomes with DLBCL-directed therapy; thus, consolidation with hematopoietic cell transplantation (HCT) has been used, with durable remissions observed. Studies reporting HCT outcomes in patients with DLBCL-RS have been small, have not evaluated the prognostic impact of cytogenetic risk factors, and were conducted prior to the era of novel targeted therapy of CLL/SLL. We performed a Center for International Blood and Transplant Research registry study evaluating outcomes after autologous HCT (auto-HCT; n = 53) and allogeneic HCT (allo-HCT; n = 118) in patients with DLBCL-RS treated in the modern era. More auto-HCT recipients were in complete response (CR) at HCT relative to allo-HCT recipients (66% vs 34%), whereas a higher proportion of allo-HCT recipients had 17p deletion (33% vs 7%) and had previously received novel agents (39% vs 10%). In the auto-HCT cohort, the 3-year relapse incidence, progression-free survival (PFS), and overall survival (OS) were 37%, 48%, and 57%, respectively. Among allo-HCT recipients, the 3-year relapse incidence, PFS, and OS were 30%, 43%, and 52%, respectively. In the allo-HCT cohort, deeper response at HCT was associated with outcomes (3-year PFS/OS, 66%/77% CR vs 43%/57% partial response vs 5%/15% resistant; P < .0001 for both), whereas cytogenetic abnormalities and prior novel therapy did not impact outcomes. In our study, HCT resulted in durable remissions in therapy-sensitive patients with DLBCL-RS treated in the era of targeted CLL/SLL therapy, including patients with high-risk features., (© 2021 by The American Society of Hematology.)

Cellular therapy has changed the cancer treatment landscape and potential associated toxicities. The traditional short-term toxicities of chemotherapy-induced nausea, vomiting, and diarrhea are replaced by complex immune activation syndromes and immunologic organ-specific toxicities. Understanding the long-term consequences and impact of these therapies on patient quality of life is necessary., Competing Interests: Declaration of interests Jennifer Saultz declares no competing interests. Richard Maziarz, MD, served as an advisor or consultant for AlloVir, Artiva Therapeutics, CRISPR Therapeutics, Incyte, and Novartis; reported honoraria from Bristol-Myers Squibb/Celgene, Incyte, Intellia, and Kite; has received research support from BMS, Allovir, Omeros, and Novartis; served on a data and safety monitoring board for Athersys, Vor Pharma, and Novartis; holds a patent with Athersys; and served as Chair of the ASTCT Value & Health Economics Interest Group., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition defined by the presence of a somatic mutation in a leukemia-associated gene in individuals who otherwise have no evidence of a hematologic malignancy. In the allogeneic hematopoietic cell transplantation (HCT) setting, clonal hematopoiesis (CH) mutations present in donor stem cells can be transferred to recipients at the time of HCT. Given that the consequences of donor-derived CH in HCT recipients are not entirely clear, we sought to investigate clinical outcomes in patients with engrafted donor-derived CH using a matched cohort analysis of both related and unrelated donors. Of 209 patients with next-generation sequencing performed before and after HCT, donor-derived CH mutations were detected in 15 (5.2%). DNMT3A was the most commonly mutated gene (9 of 15; 60%); mutations in SF3B1, CSF3R, STAT3, CBLB, TET2, and ASXL1 were also identified. Donor-derived CH was not associated with delayed neutrophil or platelet engraftment, and there was no impact on conversion to full donor chimerism. No patients with donor-derived CH experienced relapse, in contrast to 15.6% (7 of 45) in the matched control cohort without CH (P = .176). Donor-derived CH was not associated with worse overall survival; however, patients with donor-derived CH were more likely to develop chronic graft-versus-host disease (GVHD) necessitating systemic immunosuppressive therapy (IST) (P = .045) and less likely to discontinue IST (P = .03) compared with controls without donor-derived CH. We conclude that donor-derived CH does not have an adverse impact on relapse, survival, or engraftment outcomes but may potentiate a graft-versus-leukemia effect, as reflected by increased chronic GVHD necessitating IST., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Several prospective randomized trials comparing conditioning intensity before allogeneic hematopoietic cell transplantation (HCT) have been performed, with conflicting results. Although reduced-intensity conditioning (RIC) leads to lower treatment-related mortality (TRM), this is offset by higher rates of relapse. Long-term follow-up of randomized comparative trials are limited. Here we present long-term follow-up of a randomized comparison of myeloablative conditioning (MAC) compared with RIC before HCT for acute myelogenous leukemia (AML) or myelodysplasia (MDS). Long-term comparative analyses of overall survival, relapse, and relapse-free survival were performed. Patients age 18 to 65 years with <5% marrow myeloblasts were randomized to receive MAC (n = 135) or RIC (n = 137), followed by HCT from an HLA-matched donor. The primary endpoint of the trial was an 18-month pointwise comparison of overall survival. The analyses were performed using a proportional hazards model. The median follow-up of the entire cohort was 51 months. At 4 years, the transplant-related mortality (TRM) was 25.1% for MAC, compared with 9.9% for RIC (P < .001). Patients who received RIC had a significantly higher risk of relapse compared to those who received MAC (hazard ratio [HR], 4.06; 95% CI, 2.59 to 6.35; P < 0.001). Among the patients who relapsed after HCT, postrelapse survival was similar at 3 years (24% for MAC and 26% for RIC). Overall survival was superior for patients who received MAC compared to those who received RIC (HR, 1.54; 95% CI, 1.07 to 2.2; P = .03). Our data show that patients who received MAC were at higher risk of late TRM compared with those who received RIC; however, because of the exceedingly high rates of relapse in the RIC arm, overall survival remained significantly better for patients who received MAC. Among patients with MDS or AML eligible for either MAC or RIC regimens, long-term follow up demonstrates a survival advantage for patients who received MAC., (Copyright © 2021. Published by Elsevier Inc.)

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).

Chimeric antigen receptor (CAR) T-cell therapies that specifically target the CD19 antigen have emerged as a highly effective treatment option in patients with refractory B-cell hematological malignancies. Safety and efficacy outcomes from the pivotal prospective clinical trials of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel and the retrospective, postmarketing, real-world analyses have confirmed high response rates and durable remissions in patients who had failed multiple lines of therapy and had no meaningful treatment options. Although initially administered in the inpatient setting, there has been a growing interest in delivering CAR-T cell therapy in the outpatient setting; however, this has not been adopted as standard clinical practice for multiple reasons, including logistic and reimbursement issues. CAR-T cell therapy requires a multidisciplinary approach and coordination, particularly if given in an outpatient setting. The ability to monitor patients closely is necessary and proper protocols must be established to respond to clinical changes to ensure efficient, effective and rapid evaluation either in the clinic or emergency department for management decisions regarding fever, sepsis, cytokine release syndrome and neurological events, specifically immune effector cell-associated neurotoxicity syndrome. This review presents the authors' institutional experience with the preparation and delivery of outpatient CD19-directed CAR-T cell therapy., Competing Interests: Competing interests: GDM serves as a consultant on the study steering committee for Kymriah (tisagenlecleucel) and on the Speaker's Bureau for Kymriah (tisagenlecleucel). MRV reports salary and stock consultancy for Fate Therapeutics and reports salary from and serves on an advisory board for Novartis. AG has received consulting fees and his institution has received research funding from Acerta, Celgene, Constellation, Infinity, Infinity Verastem, Janssen, Karyopharm, Kite Pharma, Pharmacyclics, Genentech-Hoffman La Roche, AstraZeneca, Genentech and Hoffman La Roche. He is a consultant for Acerta, Celgene, Janssen, Kite Pharma, Pharmacyclics, Gilead, Medscape, MJH Associates, Physicians Education Resource and Xcenda. He has served on advisory boards for Janssen, Kite Pharma, Elsevier’s PracticeUpdate Oncology, and Gilead; has served as a moderator for OncLive Peer Exchange; and has served as an Advisor on Video for AstraZeneca. He is a member of steering committees for AstraZeneca and MorphoSys and Incyte. RTM is a member and chair of the Scientific Steering Committee for Tisagenlecleucel for DLBCL and receives honoraria and research funding from Novartis. He is a consultant for and receives honoraria from CRISPR Therapeutics, Incyte, and Juno Therapeutics; receives honoraria from Kite Therapeutics; and has patents and receives royalties from Athersys. RTM is employed by Oregon Health & Science University (OHSU) and has provided consultant services to and received payment from Novartis. This potential conflict of interest has been reviewed and managed by OHSU., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chimeric antigen receptor T-cell therapy (CAR T) is a novel intervention for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) and other hematologic malignancies. However, it is associated with prolonged hematologic toxicity (PHT) that is unpredictable and can significantly impair patients' quality of life. Reported here is a single-center experience with PHT in adult patients with R/R DLBCL who received commercial CAR T-cell therapy between March 1, 2018 and May 30, 2020. Prolonged hematologic toxicity was defined as ≥ grade 3 neutropenia or thrombocytopenia at day +30 after CAR T-cell therapy. Of the 31 patients identified, 18 patients (58%) developed PHT. Patients with PHT had a shorter 1-year overall survival (OS) than patients without PHT (36% vs. 81%, P < .05). There were no differences in the median time to ANC recovery for those with PHT compared to patients without PHT (16 days vs. 15 days). Several risk factors were identified to be associated with PHT including CRS (P = .002), receipt of tocilizumab (P = .002) or steroids (P = .033), peak ferritin >5000 ng/ml (P = .048), peak C-reactive protein (CRP) > 100 mg/L (P = .007), and ferritin greater than the upper limit of normal at day +30. Seven patients with PHT underwent a bone marrow biopsy after CAR T-cell therapy; all showed complete aplasia or were hypocellular with cellularity ranging from <5% to 10%. These findings identify PHT as a significant toxicity associated with CAR T-cell therapy and highlight the critical need for further investigations to describe PHT in larger cohorts and identify standards for management of this condition., (© 2021 Wiley Periodicals LLC.)

Macaques are physiologically relevant animal models of human immunology and infectious disease that have provided key insights and advanced clinical treatment in transplantation, vaccinology, and HIV/AIDS. However, the small size of macaques is a stumbling block for studies requiring large numbers of cells, such as hematopoietic stem cells (HSCs) for transplantation, antigen-specific lymphocytes for in-depth immunological analysis, and latently-infected CD4+ T-cells for HIV cure studies. Here, we provide a detailed protocol for collection of large numbers of HSCs and T-cells from cynomolgus macaques as small as 3 kg using the Terumo Spectra Optia apheresis system, yielding an average of 5.0 × 10 9 total nucleated cells from mobilized animals and 1.2 × 10 9 total nucleated cells from nonmobilized animals per procedure. This report provides sufficient detail to adapt this apheresis technique at other institutions, which will facilitate more efficient and detailed analysis of HSCs and their progeny blood cells., (© 2020 Wiley Periodicals LLC.)

Purpose: Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown., Methods: Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died., Results: Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P = .022) and decreased OS (3-year OS, 55% v 79%, P = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P = .003) and RFS was lower (3-year RFS, 13% v 49%; P = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication., Conclusion: This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/cci/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). No potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1- myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation-based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.

Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC-matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to HSCT-associated human counterparts BK virus, Epstein-Barr virus, and human cytomegalovirus. Viral replication in recipient macaques resulted in characteristic disease manifestations observed in HSCT patients, such as polyomavirus-associated hemorrhagic cystitis and tubulointerstitial nephritis or lymphocryptovirus-associated post-transplant lymphoproliferative disorder. However, in most cases, the reconstituted immune system, alone or in combination with short-term pharmacological intervention, exerted control over viral replication, suggesting engraftment of functional donor-derived immunity. Indeed, the donor-derived reconstituted immune systems of two long-term engrafted HSCT recipient macaques responded to live attenuated yellow fever 17D vaccine (YFV 17D) indistinguishably from untransplanted controls, mounting 17D-targeted neutralizing antibody responses and clearing YFV 17D within 14 days. Together, these data demonstrate that this macaque model of allogeneic HSCT recapitulates clinical situations of opportunistic viral infections in transplant patients and provides a pre-clinical model to test novel prophylactic and therapeutic modalities., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The SARS-CoV-2 coronavirus (COVID-19) pandemic has significantly impacted the delivery of cellular therapeutics, including chimeric antigen receptor (CAR) T cells. This impact has extended beyond patient care to include logistics, administration, and distribution of increasingly limited health care resources. Based on the collective experience of the CAR T-cell Consortium investigators, we review and address several questions and concerns regarding cellular therapy administration in the setting of COVID-19 and make general recommendations to address these issues. Specifically, we address (1) necessary resources for safe administration of cell therapies; (2) determinants of cell therapy utilization; (3) selection among patients with B cell non-Hodgkin lymphomas and B cell acute lymphoblastic leukemia; (4) supportive measures during cell therapy administration; (5) use and prioritization of tocilizumab; and (6) collaborative care with referring physicians. These recommendations were carefully formulated with the understanding that resource allocation is of the utmost importance, and that the decision to proceed with CAR T cell therapy will require extensive discussion of potential risks and benefits. Although these recommendations are fluid, at this time it is our opinion that the COVID-19 pandemic should not serve as reason to defer CAR T cell therapy for patients truly in need of a potentially curative therapy., Competing Interests: Conflict of interest statement V.B. has received research funding from Novartis, Celgene, Incyte, Gamida Cell, and GT Biopharma and serves on advisory boards for Kite Pharma/Gilead and Seattle Genetics. M.R.B. serves as a consultant and/or advisor for Celgene, Kite Pharma/Gilead, CRISPR Therapeutics, and Novartis and on speakers bureaus for Kite Pharma/Gilead, BMS, and Celgene, and has other financial interests/relationships with Novartis as a part of steering committees. P.D. serves on the advisory board for Kite Pharma/Gilead. B.D. serves as a consultant and/or advisor for Celgene and has received institutional research support from Angiocrine Bioscience, Celyad, and Poseida Therapeutics. S.A.G. has served as a consultant for CBMG, Novartis, Roche, GSK, Cure Genetics, Humanigen, and Jazz Pharmaceuticals; has received research funding from Novartis, Kite Pharma/Gilead, and Servier; and serves on study steering committees or scientific advisory boards for Jazz Pharmaceuticals and Adaptimmune. B.H.-L. and M.J. have no conflicts to disclose. R.T.M. has received honoraria/consultant fees from BMS/JUNO, CRISPR Therapeutics, Kite Pharma/Gilead, Incyte, Intellia Therapeutics, Kadmon, Omeros, and PACT Pharma; serves on a scientific board for Artiva Biotherapeutics; has served on data and safety monitoring boards for Novartis and Athersys; served as chair of the scientific steering committee for the phase II tisagenlecleucel study sponsored by Novartis; and has received research support from Novartis. He also holds patents from Athersys. J.P.M. has received research/grant support from Novartis, Fresenius Biotech, Astellas, Bellicum Pharmaceuticals, Gamida Cell, and Pluristem; has served on advisory boards/speakers bureaus for and received travel accommodations and expenses and research funding from Kite Pharma/Gilead and BMS/JUNO; and has received honoraria, travel expenses along with grant/research funding from AlloVir. L.J.N. has received honoraria from Bayer, Celgene, Gamida Cell, Genentech, Kite Pharma/Gilead, Novartis, MEI, and TG Therapeutics along with research support from Celgene, Genentech, Karus Therapeutics, Merck, Novartis, and TG Therapeutics. O.O.O. has served on scientific advisory boards for Pfizer, Spectrum, Bayer, and Kite Pharma/Gilead; has received honoraria from Pfizer; and has received research support from Novartis. M.-A.P. has received honoraria from AbbVie, Bellicum, BMS, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda; serves on data safety and monitoring boards for Servier and Medigene and on scientific advisory boards of MolMed and NexImmune; and has received research support for clinical trials from Incyte, Kite Pharma/Gilead, Miltenyi Biotec, and Novartis. D.L.P. reports spousal employment along with stock and other ownership interests in Genentech and Roche; has served in a consulting/advisory capacity for Novartis, Kite Pharma/Gilead, Incyte, Gerson Lehrman Group, Glenmark, and Janssen; has received travel expenses from Kite Pharma and Novartis; has received research funding from Novartis; is a listed as an inventor on a patent for CTL019; and serves on the Board of Directors of the National Marrow Donor Program and on the Board Examination Writing Committee of the American Board of Internal Medicine. P.A.R. has served on speakers bureaus for Kite Pharma/Gilead and Bayer and on advisory boards for Verastem Oncology, Novartis, Celgene/BMS, and Bayer; has received honoraria from Novartis; and has received research support from Celgene/BMS, Kite Pharma, and Novartis., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We retrospectively analyzed treatment patterns and healthcare costs among patients diagnosed with diffuse large B-cell lymphoma (DLBCL) during each line of therapy (LOT) using data from the IBM ® MarketScan ® Commercial and Medicare Supplemental Databases from January 2011 to May 2017. Patients were included if they had a diagnosis of DLBCL, ≥12 months of disease-free continuous enrollment prediagnosis, and ≥1 month of postdiagnosis follow-up. Of 2066 eligible patients receiving first-line treatment, 17% ( n  = 340) received second-line treatment; of these, 23% ( n  = 77) received third-line treatment. Mean healthcare expenditures (treatment duration) for first, second, and third LOTs were $111,314 (124.5 days), $88,472 (80.8 days), and $103,365 (70.9 days), respectively. When adjusted to 30-day period costs, first, second, and third LOT healthcare expenditures increased to $26,825, $32,857, and $43,854, respectively. Patients with newly diagnosed and relapsed/refractory DLBCL incur a significant cost burden (for payers), and such costs increase as patients proceed through subsequent LOTs.

Purpose: Patients with acute myeloid leukemia (AML) in remission remain at risk for relapse even after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) status before alloHCT has been shown to be prognostic. Whether modulation of the intensity of the alloHCT conditioning regimen in patients with AML who test positive for MRD can prevent relapse and improve survival is unknown., Methods: Ultra-deep, error-corrected sequencing for 13 commonly mutated genes in AML was performed on preconditioning blood from patients treated in a phase III clinical trial that randomly assigned adult patients with myeloid malignancy in morphologic complete remission to myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC)., Results: No mutations were detected in 32% of MAC and 37% of RIC recipients; these groups had similar survival (3-year overall survival [OS], 56% v 63%; P = .96). In patients with a detectable mutation (next-generation sequencing [NGS] positive), relapse (3-year cumulative incidence, 19% v 67%; P < .001) and survival (3-year OS, 61% v 43%; P = .02) was significantly different between the MAC and RIC arms, respectively. In multivariable analysis for NGS-positive patients, adjusting for disease risk and donor group, RIC was significantly associated with increased relapse (hazard ratio [HR], 6.38; 95% CI, 3.37 to 12.10; P < .001), decreased relapse-free survival (HR, 2.94; 95% CI, 1.84 to 4.69; P < .001), and decreased OS (HR, 1.97; 95% CI, 1.17 to 3.30; P = .01) compared with MAC. Models of AML MRD also showed benefit for MAC over RIC for those who tested positive., Conclusion: This study provides evidence that MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival.

Chimeric antigen receptor-T (CAR-T) cell therapy achieves durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), but may be associated with neurological toxicity (NT). We retrospectively assessed differences and concordance among 3 available grading scales (the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CAR-T Related Encephalopathy Syndrome [mCRES], and American Society for Transplantation and Cellular Therapy [ASTCT] scales) applied to the same set of NT data from the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Individual patient-level NT data from the phase 2, single-group, global, pivotal JULIET trial (NCT02445248) were retrospectively and independently graded, using CTCAE, ASTCT, and mCRES, by 4 medical experts with experience managing patients with 3 different CD19-targeted CAR constructs. According to the US Food and Drug Administration definition of NT using CTCAE, 62 of 106 patients infused with tisagenlecleucel had NT as of September 2017. Among 111 patients infused with tisagenlecleucel (as of December 2017), the 4 experts identified 50 patients (45%) who had any-grade NT per CTCAE, 19 (17%) per mCRES, and 19 (17%) per ASTCT. Reevaluation according to the mCRES/ASTCT criteria downgraded 31 events deemed NT by CTCAE to grade 0. This is the first study to retrospectively apply CTCAE, mCRES, and ASTCT criteria to the same patient data set. We conclude that CTCAE v4.03 was not designed for, and is suboptimal for, grading CAR-T cell therapy-associated NT. The CRES and ASTCT scales, which measure immune effector cell-associated neurotoxicity syndrome, offer more accurate assessments of NT after CAR-T cell therapy., (© 2020 by The American Society of Hematology.)

Chimeric antigen receptor T-cell (CAR-T) therapy yields durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Cytokine release syndrome (CRS) is a CAR-T therapy-related adverse event. To date, clinical trials of different CAR-T products have not been aligned on CRS grading scales and management algorithms. We assessed concordance between the Penn, Lee, and American Society for Transplantation and Cellular Therapy (ASTCT) grading systems by retrospectively regrading CRS events in the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Four medical experts with experience treating patients with 3 different CAR-T products independently regraded individual patient-level CRS events from the phase 2, global, pivotal JULIET trial (#NCT02445248). As of 8 December 2017, a total of 111 patients with r/r DLBCL underwent infusion with tisagenlecleucel. Sixty-four patients had CRS events graded per the Penn scale; on retrospective review, 63 and 61 patients had CRS events regraded per the Lee and ASTCT criteria, respectively. The Lee scale yielded concordance for 39, lower grade for 20, and higher grade for 5 events compared with the Penn scale. The ASTCT criteria provided concordance for 37, lower grade for 23, and higher grade for 4 events compared with the Penn scale. Sixteen (14%) of 111 patients in the JULIET trial received tocilizumab, all for severe events (Penn grade 3/4 CRS). This study is the first to assess concordance between 3 CRS grading scales using the same patient data set and to compare tocilizumab use according to the Lee scale in the JULIET trial and the ZUMA-1 (Long-Term Safety and Activity of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma) trial. This analysis describes key differences between grading scales and may inform CRS management practices., (© 2020 by The American Society of Hematology.)

The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the HRQoL assessments at baseline, including 57 patients who eventually achieved CR or partial response (PR). Further, 30 and 21 patients in clinical response who completed assessments at baseline also completed assessments at months 12 and 18, respectively. Patients who achieved CR or PR sustained HRQoL improvement in all FACT scores at all time points. SF-36 instruments showed improvement above the minimal clinically important differences on 5 of 8 subscales. Long-term follow-up in the phase 2 JULIET study demonstrated that patients with r/r DLBCL who respond to tisagenlecleucel therapy had sustained, clinically meaningful improvements in HRQoL. This trial was registered at www.clinicaltrials.gov as #NCT02445248., (© 2020 by The American Society of Hematology.)

The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248., (© 2020 by The American Society of Hematology.)

Relapse of chronic lymphocytic leukemia (CLL) after allogeneic hematopoietic cell transplantation (HCT) remains a clinical challenge. We studied in a phase II trial whether the addition of peri-transplant rituximab would reduce the relapse risk compared with historical controls (n = 157). Patients (n = 55) received fludarabine and low-dose total body irradiation combined with rituximab on days -3, + 10, + 24, + 36. Relapse rate at 3 years was significantly lower among rituximab-treated patients versus controls (17% versus 31%; P = 0.04). Overall survival (OS), progression-free survival (PFS) and nonrelapse mortality (NRM) were statistically similar: (53% versus 50%; P = 0.8), (44% versus 42%; P = 0.63), and (38% versus 28%; P = 0.2), respectively. In multivariate analysis, rituximab treatment was associated with lower relapse rates both in the overall cohort [hazard ratio (HR): 0.34, P = 0.006] and in patients with high-risk cytogenetics (HR: 0.21, P = 0.0003). Patients with no comorbidities who received rituximab conditioning had an OS rate of 100% and 75% at 1 and 3 years, respectively, with no NRM. Peri-transplant rituximab reduced relapse rates regardless of high-risk cytogenetics. HCT is associated with minimal NRM in patients without comorbidities and is a viable option for patients with high-risk CLL. Clinical trial information: NCT00867529.

In acute myeloid leukemia (AML), the assessment of post-treatment minimal residual disease (MRD) may inform a more effective management approach. We investigated the prognostic utility of next-generation sequencing (NGS)-based MRD detection undertaken before hematopoietic stem cell transplantation (HSCT). Forty-two AML subjects underwent serial disease monitoring both by standard methods, and a targeted 42-gene NGS assay, able to detect leukemia-specific mutant alleles (with >0.5% VAF) (mean 5.1 samples per subject). The prognostic relevance of any persisting diagnostic mutation before transplant (≤27 days) was assessed during 22.1 months (median) of post-transplant follow-up. The sensitivity of the NGS assay (27 MRD-positive subjects) exceeded that of the non-molecular methods (morphology, FISH, and flow cytometry) (11 positive subjects). Only one of the 13 subjects who relapsed after HSCT was NGS MRD-negative (92% assay sensitivity). The cumulative incidence of post-transplant leukemic relapse was significantly higher in the pre-transplant NGS MRD-positive (vs MRD-negative) subjects (P = .014). After adjusting for TP53 mutation and transplant conditioning regimen, NGS MRD-positivity retained independent prognostic significance for leukemic relapse (subdistribution hazard ratio = 7.3; P = .05). The pre-transplant NGS MRD-positive subjects also had significantly shortened progression-free survival (P = .038), and marginally shortened overall survival (P = .068). In patients with AML undergoing HSCT, the pre-transplant persistence of NGS-defined MRD imparts a significant, sensitive, strong, and independent increased risk for subsequent leukemic relapse and death. Given that NGS can simultaneously detect multiple leukemia-associated mutations, it can be used in the majority of AML patients to monitor disease burdens and inform treatment decisions., (© 2019 Wiley Periodicals, Inc.)

Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. Most patients (92%) received bridging therapies to control disease after study entry and before tisagenlecleucel infusion. Here, we examine the efficacy and safety of tisagenlecleucel in the subset of 7 patients who achieved complete response (CR) after bridging therapy and before tisagenlecleucel infusion. Tisagenlecleucel rapidly expanded in all 7 patients, and the transgene levels were measurable for up to 2 years after infusion. After infusion, all 7 patients were still in CR at the month 3 evaluation, and 5 of 7 patients remained progression-free >12 months. Adverse events were similar to the overall JULIET population. Cytokine release syndrome (CRS) was reported in 4 of 7 patients (grade 2 = 2 and grade 3 = 2 using the Penn grading scale), and 1 patient experienced grade 1 neurotoxicity. No patient required tocilizumab or steroids for CRS management. These data provide preliminary evidence of tisagenlecleucel efficacy in patients with r/r DLBCL without detectable disease after bridging or salvage therapies and warrant further investigation of tisagenlecleucel as consolidative therapy in future trials. This trial was registered at www.clinicaltrials.gov as #NCT02445248., (© 2019 by The American Society of Hematology.)

High-dose busulfan (BU) followed by high-dose cyclophosphamide (CY) before allogeneic hematopoietic cell transplantation (HCT) has long been used as treatment for hematologic malignancies. Administration of phenytoin or newer alternative antiepileptic medications (AEMs) prevents seizures caused by BU. Phenytoin induces enzymes that increase exposure to active CY metabolites in vivo, whereas alternative AEMs do not have this effect. Lower exposure to active CY metabolites with the use of alternative AEMs could decrease the risk of toxicity but might increase the risk of recurrent malignancy after HCT. Previous studies have not determined whether outcomes with alternative AEMs differ from those with phenytoin in patients treated with BU/CY before allogeneic HCT. We studied a cohort of 2155 patients, including 1460 treated with phenytoin and 695 treated with alternative AEMs, who received BU/CY before allogeneic HCT between 2004 and 2014. We found no differences suggesting decreased overall survival or relapse-free survival or increased risks of relapse, nonrelapse mortality, acute or chronic graft-versus-host disease, or regimen-related toxicity associated with the use of alternative AEMs compared with phenytoin. The risk of dialysis was lower in the alternative AEM group than in the phenytoin group. Alternative AEMs are safe for prevention of seizures after BU administration and can avoid the undesirable toxicities and drug interactions caused by phenytoin., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Guidelines recommend treatment with 4-5 days of granulocyte colony-stimulating factor (G-CSF) for optimal donor peripheral blood progenitor cell (PBPC) mobilization followed by day 5 collection. Given that some autologous transplant recipients achieve adequate collection by day 4 and the possibility that some allogeneic donors may maximally mobilize PBPC before day 5, a feasibility study was performed evaluating day 4 allogeneic PBPC collection., Methods: HLA-matched sibling donors underwent collection on day 4 of G-CSF for peripheral blood (PB) CD34 + counts ≥0.04 × 10 6 /mL, otherwise they underwent collection on day 5. Those with inadequate collected CD34 + cells/kg recipient weight underwent repeat collection over 2 days. Transplant and PBPC characteristics and cost analysis were compared with a historical cohort collected on day 5 per our prior institutional algorithm., Results: Of the 101 patient/donor pairs, 50 (49.5%) had adequate PBPC collection on day 4, with a median PB CD34 + cell count of 0.06 × 10 6 /mL. Day 4 donors were more likely to develop bone pain and require analgesics. Median collected CD34 + count was significantly greater, whereas total nucleated, mononuclear and CD3 + cell counts were significantly lower, at time of transplant infusion for day 4 versus other collection cohorts. There were no significant differences in engraftment or graft-versus-host disease. Cost analysis revealed 6.7% direct cost savings for day 4 versus historical day 5 collection., Discussion: Day 4 PB CD34 + threshold of ≥0.04 × 10 6 /mL identified donors with high likelihood of adequate PBPC collection. Day 4 may be the optimal day of collection for healthy donors, without adverse effect on recipient transplant outcomes and with expected cost savings., (Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (HSCT) is an integral therapy for patients with hematological malignancies, myelodysplasia, and bone marrow failure. Its use has been increasing over the past decade, as understanding of the treatment and its related toxicities has led to changes in patient selection, conditioning regimens, and post-transplant care. Older (age ≥65 years) patients are often considered unfit for transplantation; however, more recent data suggest that older patients, when selected appropriately, tolerate transplantation well. We report our institutional experience with HSCT in patients aged ≥70 years. A cohort of 22 patients underwent HSCT. Median overall survival was 5.16 years [95% confidence interval (CI): 1.5-8.7 years], and median post-transplant survival was 2.2 years (myelodysplastic syndrome: median 1.3 years, 95% CI: 4.7 months-2.2 years; acute myeloid leukemia: median not reached). Thirty-day mortality following HSCT was 9.5% (n = 2). These data provide further support for the use of HSCT in selected older patients, and highlight the impact of HSCT on overall survival among a patient cohort primarily of acute myeloid leukemia and myelodysplasia., (Published by Elsevier Ltd.)