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Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P

This research project explores family caregiving processes during the first 100 days following autologous blood and marrow transplantation (ABMT). In this paper, we (1) explore patterns in caregiving, and ABMT recipient function early recovery from ABMT; (2) examine the relationships among caregiver demographics, relationship quality, preparedness, ABMT recipient function, predictability of caregiving, caregiver role strain and rewards of caregiving; and (3) examine the relative contribution of caregiver age, preparedness, relationship quality, and ABMT recipient function on caregiver role strain, and rewards of caregiving. Fifty-two family caregivers of ABMT recipients completed questionnaires about caregiving at hospital discharge, and again 2, 6, and 12 weeks following discharge. The amount of caregiving activities performed, and caregiver role strain, declined steadily from 2 weeks to 12 weeks of recovery. The caregiving situation was relatively predictable during recovery, and caregivers reported that caregiving was consistently rewarding. The caregiving activities rated as most difficult were those related to supporting recipients' emotional well-being. Strain from caregiving, although low, was explained by disruption in recipients' emotional and physical functioning, while caregiving rewards were explained by caregivers' preparedness for caregiving. Relationship quality, a significant predictor of strain in other samples, did not influence caregiving strain or rewards in this population. Caregiving processes delineated in studies of caregivers of persons with chronic illness are quite different from those described in this study. The acuity of the recipients' illness, the life threatening nature of the treatment, and the younger age of caregivers, and recipients, may underlie these differences. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation has been a cornerstone of therapy for chronic myelogenous leukemia (CML) for more than 15 years and is still a standard treatment option for patients with CML. The advent of imatinib mesylate, an inhibitor of the molecular defect driving CML, the BCR-ABL tyrosine kinase, has rewritten treatment algorithms for this disease and has shifted focus away from allografting. Despite advances in stem cell transplantation, such as broader availability with the use of modified conditioning regimens, use of allografting has diminished. Also, the nearly universal patient exposure to imatinib or other kinase inhibitors before transplantation may affect the biology of the disease that is currently being treated with an allograft and ultimately may affect outcomes. Exceedingly high rates of meaningful and stable response with longer follow-up continue to drive enthusiasm for imatinib use, and understanding of resistance mechanisms has driven rapid investigation of second-generation tyrosine kinase inhibitors to address imatinib failure and suboptimal response. In most patients, imatinib reduces CML to a minimal residual disease state in which options to further deepen remission, such as immunotherapy, are sought; monitoring techniques and interpretation of response advance in parallel to meet demands; and uncertainty remains as a new natural history of CML is defined in an era of kinase inhibitor therapy. This review summarizes the state of transplant and nontransplant therapy for CML and discusses the decision making for patients with an aim to optimize the use of our best therapies for CML in an era of uncertainty. [ABSTRACT FROM AUTHOR]

Immunocompromised individuals are at risk for developing lymphocryptovirus-associated lymphoproliferative diseases, such as Epstein Barr virus (EBV)-associated B cell lymphomas and post-transplant lymphoproliferative disorder (PTLD). We previously reported development of cynomolgus lymphocryptovirus (CyLCV)-associated PTLD in Mauritian cynomolgus macaques (MCMs) undergoing hematopoietic stem cell transplantation (HSCT), which mirrored EBV-PTLD in transplant patients. Here, we sought to develop a MCM model of lymphocryptovirus-associated lymphoproliferative disease in immunosuppressed MCMs without HSCT. Five simian immunodeficiency virus (SIV)-infected, CD8α+ cell-depleted MCMs received an infusion of autologous B-lymphoblastoid cells transformed with CyLCV, followed by varying degrees of immunosuppression. Four of five infused macaques developed masses coincident with increasing CyLCV plasma viremia, and necropsies confirmed the presence of multicentric lymphomas, which most commonly manifested in lymph nodes, gastrointestinal tract, adrenal glands, and pancreas. Affected tissues harbored neoplastic lymphocytes double-positive for CD20 and CyLCV EBNA2 antigen, large frequencies of proliferating B cells, and high levels of cell-associated CyLCV DNA. In addition, longitudinal 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) of one MCM successfully detected lymphoproliferative disease in the adrenal glands prior to clinical signs of disease. These data demonstrate successful induction of lymphocryptovirus-associated PTLD-like disease in 4 of 5 MCMs, and thus support the use of MCMs as a preclinical NHP model of EBV-associated lymphoproliferative disease that could be employed to test novel diagnostic and therapeutic modalities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Abstract: CD19-directed chimeric antigen receptor T-cell (CAR T) therapies, including axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), have transformed the treatment landscape for B-cell non-Hodgkin lymphoma, showcasing significant efficacy but also highlighting toxicity risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The US Food and Drug Administration has mandated patients remain close to the treatment center for 4 weeks as part of a Risk Evaluation and Mitigation Strategy to monitor and manage these toxicities, which, although cautious, may add to cost of care, be burdensome for patients and their families, and present challenges related to patient access and socioeconomic disparities. This retrospective study across 9 centers involving 475 patients infused with axi-cel, tisa-cel, and liso-cel from 2018 to 2023 aimed to assess CRS and ICANS onset and duration, as well as causes of nonrelapse mortality (NRM) in real-world CAR T recipients. Although differences were noted in the incidence and duration of CRS and ICANS between CAR T products, new-onset CRS and ICANS are exceedingly rare after 2 weeks after infusion (0% and 0.7% of patients, respectively). No new cases of CRS occurred after 2 weeks and a single case of new-onset ICANS occurred in the third week after infusion. NRM is driven by ICANS in the early follow-up period (1.1% until day 28) and then by infection through 3 months after infusion (1.2%). This study provides valuable insights into optimizing CAR T therapy monitoring, and our findings may provide a framework to reduce physical and financial constraints for patients., (© 2024 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.)

Background: Chimeric antigen receptor T-cell (CAR-T) therapies are available for patients with Non-Hodgkin Lymphoma (NHL); however, their use has been limited in accessibility due to nondisease factors., Patients & Methods: We conducted a retrospective study evaluating the influence of sociodemographic factors on access and outcomes after CAR-T therapy for adult patients with B-cell NHL in our institution treated between 2016 and 2023., Results: Among 154 patients treated with CAR-T, 43% were older than 65 years, 68% male, and 14% non-White (including Hispanic). Of those under 65, 66% had private insurance, while 82% over 65 had Medicare. Most patients (85%) were from in-state, 29% from areas below the national poverty level and 18% from nonmetropolitan areas. Distance to the treatment center was greater than 30, 60 or 120 miles for 52%, 40% and 29% of patients, respectively. No significant differences were found in the use of commercial versus investigational products among racial/ethnic minorities or those living >60 miles from the center. However, patients from nonmetropolitan areas and those below the national poverty level were less likely to receive commercial products. With a median follow-up of 11 months, the 1-year overall survival (OS) was 63.2% (95 th CI 59.9%-66.8%). Poverty was associated with lower 1-year OS (HR 0.4, 95 th CI 0.17-0.90, P = .031)., Conclusion: Our study shows that CAR-T therapy can be delivered across sociodemographic barriers and underscores the importance of considering social determinants of health to optimize access for all patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL), accounting for nearly one-third of all NHL. The therapeutic landscape for patients with FL has significantly expanded over the past decade, but the disease continues to be considered incurable. Hematopoietic cell transplantation (HCT) is potentially curative in some cases. Recently, the emergence of chimeric antigen receptor T-cell therapy (CAR-T) for patients with relapsed/refractory (R/R) FL has yielded impressive response rates and long-term remissions, but definitive statement on the curative potential of CAR-T is currently not possible due to limited patient numbers and relatively short follow up. A consensus on the contemporary role, optimal timing, and sequencing of HCT (autologous or allogeneic) and cellular therapies in FL is needed. As a result, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines endorsed this effort to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 15 consensus statements/recommendations. These clinical practice recommendations will help guide clinicians managing patients with FL. Of note, the use of bispecific antibodies in R/R FL was not in the scope of this project., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The ability to perform hematopoietic cell transplant across major histocompatibility complex barriers can dramatically increase the availability of donors and allow more patients across the world to pursue curative transplant procedures for underlying hematologic disorders. Early attempts at haploidentical transplantation using broadly reactive T-cell depletion approaches were compromised by graft rejection, graft-versus-host disease and prolonged immune deficiency. The evolution of haploidentical transplantation focused on expanding transplanted hematopoietic progenitors as well as using less broadly reactive T-cell depletion. Significant outcome improvements were identified with technology advances allowing selective depletion of donor allospecific T cells, initially ex-vivo with evolution to its current in-vivo approach with the infusion of the highly immunosuppressive chemotherapy agent, cyclophosphamide after transplantation procedure. Current approaches are facile and portable, allowing expansion of allogeneic hematopoietic cell transplantation for patients across the world, including previously underserved populations.

Abstract: Chimeric antigen receptor T-cell therapy (CAR T) has revolutionized the treatment of hematological cancers. Its production requires a complex logistical process, and the time from leukapheresis to patient infusion (known as the vein-to-vein time [V2VT]) can be long during which a patients clinical condition may deteriorate. This study was designed to estimate the benefits of reduced V2VT for third-line or later (3L+) relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with CAR T. A mathematical model was developed to estimate the lifetime outcomes of a hypothetical cohort of patients who had either a long or short V2VT. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were estimated. Scenario analyses were performed to assess the robustness of results to key assumptions. The results of the model show that reducing V2VT from 54 days (tisa-cel median V2VT; JULIET) to 24 days (axi-cel median V2VT; ZUMA-1) led to a 3.2-year gain in life expectancy (4.2 vs 7.7 LYs), and 2.4 additional QALYs (3.2 vs 5.6) per patient. Furthermore, a shorter V2VT was shown to be cost-effective under conventional willingness-to-pay thresholds in the United States. Results are driven by a higher infusion rate and a better efficacy of CAR T for those infused. Scenario analyses using a smaller difference in V2VT (24 vs 36 days) produced consistent results. Our study is the first to quantify lifetime V2VT-related outcomes for 3L+ R/R LBCL patients treated with CAR T utilizing currently available evidence. Shorter V2VTs led to improved outcomes, demonstrating the importance of timely infusion achievable by faster manufacturing times and optimization of hospital delivery., (© 2024 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.)

Introduction: CMML is a rare neoplasm with overlapping myelodysplastic and myeloproliferative features whose only potential cure is allogeneic hematopoietic cell transplantation (allo-HCT)., Methods: This retrospective study examined 27 CMML patients with high-risk clinical features who underwent first allo-HCT at our institution between 2004 and 2022., Results: Nineteen patients were diagnosed with the proliferative subtype (CMML-MPN) and 8 with the dysplastic subtype (CMML-MDS). Median OS was 15 months post-HCT (95% CI: 5-71); OS at 1, 3, and 5 years was 52%, 35%, and 35%, respectively. Compared to those with CMML-MPN, patients with CMML-MDS had longer OS (median, 8.6 vs. 0.9 years; p = 0.025), RFS (4.4 vs. 0.5 years; p = 0.021), and GVHD-free, relapse-free survival (GRFS, 9.4 vs. 3.4 months; p = 0.033) as well as lower 1-year NRM (13 vs. 47%; p = 0.043), with the statistical significance of this CMML subtype effect maintained in multivariable models. High-risk cytogenetics were associated with shorter GRFS in the univariable (median, 3.1 vs. 6.2 months; p = 0.013) and multivariable (HR = 4.88; p = 0.006) settings., Conclusions: Patients who underwent transplant for CMML-MDS experienced substantially better outcomes than those transplanted for CMML-MPN. Future studies are needed for transplantation optimization in CMML, especially CMML-MPN., (© 2024 S. Karger AG, Basel.)

Background: Administration of anti-CD19 chimeric antigen receptor T-cell (CART19) immunotherapy for large B-cell lymphomas (LBCLs), a subset of non-Hodgkin lymphoma (NHL), involves high costs and access to specialized tertiary care centers. We investigated whether minority health populations (MHPs) have equal access to CART19 and whether their outcomes are similar to those of non-MHPs., Methods: We analyzed the prevalence and clinical outcomes of patients treated with commercial CART19 at two geographically and socioeconomically different institutions: the Abramson Cancer Center (ACC, Philadelphia, Pennsylvania) and the Knight Cancer Institute (KCI, Portland, Oregon)., Results: In the ACC catchment area, 8956 patients were diagnosed with NHL between 2015 and 2019 (latest available data from the state registry), including 17.9% MHPs. In the ACC, between 2018 and 2022 (CART became available in 2018), 1492 patients with LBCL were treated, and 194 received CART19. The proportion of MHPs was 15.7% for the entire LBCL cohort but only 6.7% for the CART19 cohort. During the same time, in the KCI catchment area, 4568 patients were diagnosed with NHL, including 4.2% MHPs. In the KCI, 396 patients with LBCL were treated, and 47 received CART19. The proportion of MHPs was 6.6% for the entire LBCL cohort and 4.2% for the CART19 cohort. The 3-month response, survival, and toxicities after CART19 infusion showed similar results, although the number of patients who were treated was limited., Conclusions: This study shows that the access of MHPs to tertiary centers for LBCL care was preserved but appeared reduced for commercial CART19 immunotherapy. Although clinical outcomes of MHPs seemed similar to those of non-MHPs, the small sample size precludes drawing firm conclusions. Further studies are needed. (Funded by the Laffey McHugh Foundation and others.).

Purpose: BMT CTN 1102 was a phase III trial comparing reduced-intensity allogeneic hematopoietic cell transplantation (RIC alloHCT) to standard of care for persons with intermediate- or high-risk myelodysplastic syndrome (MDS). We report results of a cost-effectiveness analysis conducted alongside the clinical trial., Methods: Three hundred eighty-four patients received HCT (n = 260) or standard of care (n = 124) according to availability of a human leukocyte antigen-matched donor. Cost-effectiveness was calculated from US commercial and Medicare perspectives over a 20-year time horizon. Health care utilization and costs were estimated using propensity score-matched cohorts of HCT recipients in the OptumLabs Data Warehouse (age 50-64 years) and Medicare (age 65 years and older). EuroQol 5 Dimension (EQ-5D) surveys of trial participants were used to derive health state utilities., Results: Extrapolated 20-year overall survival for those age 50-64 years was 29% for HCT (n = 105) versus 13% for usual care (n = 44) and 31% for HCT (n = 155) versus 12% for non-HCT (n = 80) for those age 65 years and older. HCT was more effective (+2.36 quality-adjusted life-years [QALYs] for age 50-64 years and +2.92 QALYs for age 65 years and older) and more costly (+$452,242 in US dollars (USD) for age 50-64 years and +$233,214 USD for age 65 years and older) than usual care, with incremental cost-effectiveness ratios of $191,487 (USD)/QALY and $79,834 (USD)/QALY, respectively. For persons age 50-64 years, there was a 29% chance that HCT was cost-effective using a willingness-to-pay (WTP) threshold of $150K (USD)/QALY and 51% at a $200K (USD)/QALY. For persons age 65 years and older, the probability was 100% at a WTP >$150K (USD)/QALY., Conclusion: Among patients age 65 years and older with high-risk MDS, RIC HCT is a high-value strategy. For those age 50-64 years, HCT is a lower-value strategy but has similar cost-effectiveness to other therapies commonly used in oncology.

Abstract: Patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplant (allo-HCT) require extensive care. Using the Merative MarketScan Commercial Claims and Encounters database (2016 Q1-2020 Q2), we quantified the costs of care and assessed real-world complication rates among commercially insured US patients diagnosed with a hematologic malignancy and aged between 12 and 64 years undergoing inpatient allo-HCT. Health care resource use and costs were assessed from 100 days before HCT to 100 days after HCT. Primary hospitalization was defined as the time from HCT until first discharge date. Incidence of complications was assessed using medical billing codes from HCT date to 100 days after HCT. Among the 1082 patients analyzed, allo-HCT grafts included peripheral blood (79%), bone marrow (11%), and umbilical cord blood (3%). In the 100 days after HCT, 52% of the patients experienced acute graft-versus-host disease; 21% had cytomegalovirus infection. The median primary hospitalization length of stay (LOS) was 28 days; 31% required readmission in first 100 days after HCT. Across the transplant period (14 days pretransplant to 100 days posttransplant), 44% of patients were admitted to the intensive care unit with a median LOS of 29 days. Among those with noncapitated health plans (n = 937), median cost of all-cause health care per patient during the transplant period was $331 827, which was driven by primary hospitalization and readmission. Additionally, the predicted median incremental costs per additional day in an inpatient setting increased with longer LOS (eg, $3381-$4071, 10th-20th day.) Thus, decreasing length of primary hospitalization and avoiding readmissions should significantly reduce the allo-HCT cost of care., (© 2024 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.)

Introduction: The success of an allogeneic hematopoietic stem cell transplantation (alloHCT) is measured by cure from the underlying malignancy, immune reconstitution (IR), and freedom from graft-versus-host disease, without the continued need for immunosuppressive therapy., Areas Covered: Effective IR is critical to the success of alloHCT wherein poor IR can potentially increase the risk of infection and disease relapse. Different stem cell sources give rise to varying patterns of IR. Particularly with umbilical cord blood transplant, delayed IR is commonly seen with associated increased infection rates and non-relapse mortality, attributable to low CD34+ cell doses and predominance of naïve T cells in the graft. Recent FDA approval of omidubicel, an expanded cord blood graft, was granted due to rapid hematologic recovery and a reduced incidence of high-grade infections associated with improved IR. This review focuses on IR and infections seen with omidubicel and compares those to IR after alloHCT with other graft sources., Expert Opinion: Characteristics of omidubicel, such as ready availability, high infused CD34+ cell dose, and rapid hematologic and immune recovery improve upon the shortcomings of standard umbilical cord blood transplantation. We feel that the data support the emergence of omidubicel as an alternative donor product.

Objective: The purpose of this study was to investigate the efficacy and safety of netupitant/palonosetron (NEPA) for the prevention of chemotherapy-induced nausea and vomiting (CINV) for hematopoietic cell transplantation (HCT) patients receiving BEAM therapy. Study Design: This phase II, prospective, intention-to-treat, single-center, single-arm study involved 43 adult patients who received NEPA and dexamethasone for the prevention of CINV due to BEAM conditioning chemotherapy. An interim analysis, performed after 13 patients, determined utility versus futility, and supported continuation to full enrollment. Descriptive statistics were used to report complete response (CR), complete protection, incidence of emesis, and administration of rescue agents. A Kaplan-Meier curve depicted time to first emesis and first rescue medication. Patients self-reported levels of daily nausea descriptively via a CINV Questionnaire. Results: By study end, 13 of 43 patients achieved a CR with an average of 10.6 emesis-free days (SD 0.95) over the 11-day observation period, with no emetic events in any patient during the acute/chemotherapy phase. Nausea was well-controlled throughout the acute therapy phase (Day 1-6) and increased during the delayed phase (Day 7-11) with a peak mean level of 2.79/10 at Day 10. Aside from lower grade (≤2), headaches, constipation, and diarrhea were the most widely reported adverse effects. Conclusion : The combination of NEPA and dexamethasone is safe and effective for the prevention of CINV in patients receiving BEAM conditioning therapy prior to HCT. The regimen demonstrated greater effectiveness in the acute phase versus the delayed phase, with low levels of nausea throughout the study period and complete emesis prevention during chemotherapy., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Helsinn Therapeutics provided research funding and study drug to JB.

Identifying plasma biomarkers early after allo-HCT may become crucial to prevent and treat severe aGvHD. We utilized samples from 203 allo-HCT patients selected from the Blood & Marrow Transplant Clinical Trials Network (BMT CTN) to identify new biomarker models to predict aGvHD and overall mortality. Two new biomarkers (Gal-3 and LAG-3), and previously identified biomarkers (ST2/IL33R, IL6, Reg3A, PD-1, TIM-3, TNFR1) were screened. Increased Gal-3 levels measured at Day +7 post-transplant predicted the development of aGvHD (grade 2-4) in the total population [AUC: 0.602; P = 0.045] while higher Day +14 levels predicted overall mortality due to toxicity among patients receiving reduced intensity conditioning [P = 0.028] but not myeloablative conditioning. Elevated LAG-3 levels (Day +21) were associated with less severe aGvHD [159.1 ng/mL vs 222.0 ng/mL; P = 0.046]. We developed a model utilizing Gal-3, LAG-3, and PD-1 levels at Days +14 and +21 with an improved performance to predict aGvHD and overall non-relapse mortality. We confirmed four informative biomarkers (Reg3A, ST2, TIM-3, and TNFR1) predict severe aGvHD at day +14 and day +21 (grade 3-4). In conclusion, the combination of Gal-3 alone or in combination with LAG-3, and PD-1 is a new informative model to predict aGvHD development and overall non-relapse mortality after allo-HCT., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

A phase 3 trial (ClincialTrials.gov identifier NCT02730299) of omidubicel-onlv, a nicotinamide-modified allogeneic hematopoietic progenitor cell therapy manufactured from a single umbilical cord blood (UCB) unit, showed faster hematopoietic recovery, reduced rate of infections, and shorter hospital stay compared with patients randomized to standard UCB. This prospective secondary analysis of the phase 3 trial characterized resource utilization in the first 100 days post-transplantation with omidubicel-onlv compared with UCB. This analysis examined resource utilization, including hospital length of stay, hospital care setting, visits by provider type, rate of transfusions, and readmissions, among the 108 treated patients (omidubicel-onlv, n = 52; UCB, n = 56) from day 0 to day 100 post-transplantation. Demographics were generally balanced between the 2 arms, except a higher proportion of females (52% versus 37%) and older median age (40 years versus 36 years) were noted in the omidubicel-onlv arm. Compared with patients receiving UCB transplantation, patients receiving omidubicel-onlv had a shorter average total hospital length of stay (mean, 41.2 days versus 50.8 days; P = .027) in the first 100 days post-transplantation and more days alive and out of the hospital (mean, 55.8 days versus 43.7 days; P = .023). Fewer patients died in the omidubicel-onlv arm compared with the UCB arm (12% vs 16%) before day 100 post-transplantation. During primary hospitalization (ie, time from transplantation to discharge), fewer patients receiving omidubicel-onlv required intensive care unit (ICU) admission (10% versus 23%) and spent fewer days in the ICU (mean, .4 day versus 4.7 days; P = .028) and transplant unit (mean, 25.3 days versus 32.9 days; P = .022) compared with those receiving UCB. Patients receiving omidubicel-onlv required fewer outpatient consultant and nonconsultant visits and fewer platelet or other transfusions within 100 days from transplantation. Our findings suggest that faster hematopoietic recovery in omidubicel-onlv patients is associated with significantly shorter hospital stay and reduced healthcare resource use compared with UCB., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study., Methods: We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53 multihit if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity)., Results: The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P = .89), ASXL1 (23% v 29%; P = .37), and SRSF2 (16% v 16%; P = .99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P < .001). Among those with a TP53 mutation, OS was similar between TP53 single versus TP53 multihit (22% ± 8% v 20% ± 6% at 3 years; P = .31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P = .04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P < .001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P = .001)., Conclusion: HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.

Allogeneic hematopoietic cell transplantation (allo-HCT) has the potential for curative outcomes for a variety of hematologic malignancies. Current allo-HCT studies often describe the outcomes and costs in the near term; however, research on the lifetime economic burden post-allo-HCT remains limited. This study was conducted to estimate the average total lifetime direct medical costs of an allo-HCT patient and the potential net monetary savings from an alternative treatment associated with improved graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS). A disease-state model was constructed using a short-term decision tree and a long-term semi-Markov partitioned survival model to estimate the average per-patient lifetime cost and expected quality-adjusted life years (QALYs) for an allo-HCT patient from a US healthcare system perspective. Key clinical inputs included overall survival, GRFS, incidence of both acute and chronic GVHD, relapse of the primary disease, and infections. Cost results were reported as ranges based on varying the percentage of chronic GVHD patients that remained on treatment after 2 years (15% or 39%). Over a lifetime, the average per-patient medical cost of allo-HCT was estimated to range from $942,373 to $1,247,917. The majority of the costs were for chronic GVHD treatment (37% to 53%), followed by the allo-HCT procedure (15% to 19%). The expected lifetime QALYs of an allo-HCT patient were estimated as 4.7. Lifetime per-patient treatment costs often exceed $1,000,000 for allo-HCT patients. Innovative research efforts focused on the reduction or elimination of late complications, particularly chronic GVHD, may provide the greatest value to improved patient outcomes., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Fludarabine is one of the most common agents given for lymphodepletion before CD19 chimeric antigen receptor T cells, but its optimal therapeutic intensity is unknown. Using data from a multicenter consortium, we estimated fludarabine exposure (area under the curve [AUC]) using a population pharmacokinetic (PK) model in 199 adult patients with aggressive B-cell non-Hodgkin lymphomas who received commercial axicabtagene ciloleucel (Axi-cel). We evaluated the association of estimated fludarabine AUC with key outcomes, aiming to find an AUC that optimized efficacy and tolerability. We identified low (<18 mg × hour/L [mgh/L]), optimal (18-20 mgh/L), and high (>20 mgh/L) AUC groups for analyses; the 6-month cumulative incidences of relapse/progression of disease (relapse/POD) by AUC groups were 54% (45%-62%), 28% (15%-44%), and 30% (14%-47%), respectively; and the 1-year progression-free survival (PFS) rates were 39% (31%-48%), 66% (52%-84%), and 46% (30%-70%) and the overall survival (OS) rates were 58% (50%-67%), 77% (64%-92%), and 66% (50%-87%), respectively. In multivariable analyses compared with low AUC, an optimal AUC was associated with the highest PFS (hazard ratio [HR], 0.52; 0.3-0.91; P = .02) and lowest risk of relapse/POD (HR, 0.46; 0.25-0.84; P = .01) without an increased risk of any-grade cytokine release syndrome (HR, 1.1; 0.7-1.6; P = .8) or and immune effector cell-associated neurotoxicity syndrome (ICANS) (HR, 1.36; 0.83-2.3; P = .2). A high AUC was associated with the greatest risk of any-grade ICANS (HR, 1.9; 1.1-3.2; P = .02). Although the main cause of death in all groups was relapse/POD, nonrelapse-related deaths, including 3 deaths from ICANS, were more frequent in the high AUC group. These findings suggest that PK-directed fludarabine dosing to achieve an optimal AUC may result in improved outcomes for patients receiving axi-cel., (© 2023 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.)

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of many patients with aggressive relapsed or refractory large B-cell lymphoma (LBCL). Treatment can be complicated by clinically evident cytokine release syndrome (CRS), which is characterized by the development of fever, hypoxia, and hypotension, and can be life-threatening. Most patients treated with CAR-T cells develop CRS, which is thought to represent an immune phenomenon. It was previously unknown whether patients who did not develop CRS had reduced CAR-T cell activity and were therefore likely to have worse outcomes. We conducted a multicenter retrospective analysis of 352 adult patients treated at 8 academic medical centers in the United States who received axicabtagene ciloleucel or tisagenlecleucel for the treatment of LBCL. The outcomes of interest included progression-free survival, overall survival, complete response rate, and overall response rate. Of the included patients, 262 (74.4%) developed CRS. There was no significant difference in progression-free survival (P = .99) or overall survival (P = .16) between patients who developed CRS and those who did not develop CRS. Peak ferritin levels >5000 ng/mL during treatment and lactate dehydrogenase levels greater than the institutional upper limit of normal before lymphodepleting chemotherapy were associated with significantly worse progression-free and overall survival in the multivariate analysis. There was no significant difference in the complete response or overall response rates between patients who did and did not develop CRS. In this retrospective analysis, we report that patients who develop CRS have clinical outcomes similar to those of patients without CRS treated with commercial anti-CD19 CAR-T cells., (© 2023 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.)

Umbilical cord blood (UCB) transplantation (CBT) has been an important alternative donor option for patients lacking matched related donor (MRD) or unrelated donor (URD) grafts. Only 30% of patients with high-risk hematologic malignancies have a human leukocyte antigen (HLA)-identical sibling; subjects without a MRD option are referred for HLA-matched URD selection, or utilize alternative donor sources such as HLA-mismatched URD, UCB, or haploidentical donor grafts. While CBT demonstrates an excellent graft- versus -leukemia (GVL) effect, use of UCB as a graft source is limited due to a lower cell dose that can result in delayed engraftment and an immature immune system with increased infectious risk as a consequence. Together, increased transplant related mortality (TRM) has been associated with UCB allografts. Omidubicel is an ex vivo expanded single cord blood product that has demonstrated rapid engraftment, improved immune reconstitution, and reduced infectious complications in clinical trials. Omidubicel has now been granted U.S. Food & Drug Administration approval to enhance neutrophil recovery and decrease infectious risk. This review will focus on CBT, benefits and barriers to using this alternative donor source, and finally the potential advancements with incorporation of omidubicel in the transplant setting for malignant and non-malignant diseases., Competing Interests: AG and LN report no COI. RTM reports serving as consultant for AlloVir, Kite and Novartis, research support from Gamida, Orca Therapeutics, AlloVir and Novartis, participating in a DSMB for Athersys, Novartis, and VorPharma and a patent with Athersys, (© The Author(s), 2023.)

CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), inducing sustained remissions in these patients. However, CAR T cells can result in significant toxicities. Preinfusion disease burden is associated with toxicities and outcomes after CAR T-cell therapy. We identified 33 patients with R/R DLBCL treated at 8 academic centers who had no detectable disease at the time of CAR T-cell therapy. The median time from leukapheresis to CAR T-cell infusion was 48 (19-193) days. Nine patients received axicabtagene ciloleucel, and 24 received tisagenlecleucel. There was no severe (grade ≥3) cytokine release syndrome, and only 1 patient developed severe neurotoxicity (grade 4). After a median follow-up of 16 months, 13 patients relapsed (39.4%) and 6 died (18.1%). One-year event-free survival and overall survival were 59.6% and 81.3%, respectively. Our findings suggest that, in patients with R/R DLBCL who have an indication for CAR T-cell therapy, treating patients in complete remission at the time of infusion is feasible, safe, and associated with favorable disease control. Further exploration in a larger clinical trial setting is warranted., (© 2023 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.)

Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5 Δ32/Δ32 ) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV + , anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4 + T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT., Competing Interests: Declaration of interests J.B.S. has a significant financial interest in and serves on the scientific advisory board of CytoDyn, a company that may have a financial interest in the results of this research and technology. This potential individual conflict of interest has been reviewed and managed by OHSU., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Tisagenlecleucel (tisa-cel) is an approved CD19-directed chimeric antigen receptor T cell (CAR-T) therapy for relapsed/refractory B cell malignancies. Given potentially life-threatening toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, inpatient tisa-cel infusion and toxicity monitoring are often considered; however, the toxicity profile of tisa-cel may be conducive to outpatient administration. Here we review the characteristics and outcomes of tisa-cel recipients treated in the outpatient setting. Patients age ≥18 years with B cell non-Hodgkin lymphoma who received tisa-cel between June 25, 2018, and January 22, 2021, at 9 US academic medical centers were included in a retrospective analysis. Six of the 9 representative centers (75%) had an outpatient program in place. A total of 157 patients were evaluable, including 93 (57%) in the outpatient treatment group and 64 (43%) in the inpatient treatment group. Baseline characteristics, toxicity and efficacy, and resource utilization were summarized. The most common lymphodepletion (LD) regimen was bendamustine in the outpatient group (65%) and fludarabine/cyclophosphamide (91%) in the inpatient group. The outpatient group had more patients with a Charlson Comorbidity Index of 0 (51% versus 15%; P < .001), fewer patients with an elevated lactate dehydrogenase (LDH) level above the normal range at the time of LD (32% versus 57%, P = .003) compared to the inpatient group, and a lower Endothelial Activation and Stress Index score (.57 versus 1.4; P < .001). Any-grade CRS and ICANS were lower in the outpatient group (29% versus 56% [P < .001] and 10% versus 16% [P = .051], respectively). Forty-two outpatient tisa-cel recipients (45%) required an unplanned admission, with a median length of stay of 5 days (range, 1 to 27 days), compared to 13 days (range, 4 to 38 days) in the inpatient group. The median number of tocilizumab doses administered was similar in the 2 groups as were the rate of intensive care unit (ICU) transfer (5% versus 8%; P = .5) and median length of ICU stay (6 days versus 5 days; P = .7). There were no toxicity-related deaths in the 30 days post-CAR-T infusion in either group. Progression-free survival and overall survival were similar in the 2 groups. With careful patient selection, outpatient tisa-cel administration is feasible and associated with similar efficacy outcomes as inpatient treatment. Outpatient toxicity monitoring and management may help optimize healthcare resource utilization., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n = 40) and grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n = 3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P = .069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P = .039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P = .02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings., (Published by Elsevier Inc.)

Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection. The 2022 European LeukemiaNet (ELN) recommendations were recently published, with notable updates to risk group assignment. The complexity of risk stratification and comparative outcomes between the 2022 and 2017 ELN guidelines remains unknown. This comparative analysis evaluated outcomes between the 2017 and 2022 ELN criteria in patients enrolled within the multicenter Beat AML cohort. Five hundred thirteen patients were included. Most patients had 1 or 2 ELN risk-defining abnormalities. In patients with ≥2 ELN risk-defining mutations, 44% (n = 132) had mutations spanning multiple ELN risk categories. Compared with ELN 2017 criteria, the updated ELN 2022 guidelines changed the assigned risk group in 15% of patients, including 10%, 26%, and 6% of patients categorized as being at ELN 2017 favorable-, intermediate-, and adverse-risk, respectively. The median overall survival across ELN 2022 favorable-, intermediate-, and adverse-risk groups was not reached, 16.8, and 9.7 months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy compared with ELN 2017 guidelines. The updated ELN 2022 guidelines better stratify survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification., (© 2023 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.)

Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3 + , CD4 + , CD8 + , CD19 + , CD116 + CD56 + , and CD123 + immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background Aims: In a previous pilot study of HLA-matched sibling donor hematopoietic cell transplantation (HCT), the authors determined the feasibility of day 4 versus day 5 granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) collection compared with a historical cohort. Given identified differences in the PBSC product (day 4 cohort with significantly lower infused total nucleated, mononuclear and CD3 cells compared with other collection cohorts), the authors performed a follow-up study to determine long-term post-HCT outcomes, including detailed characterization of chronic graft-versus-host disease (GVHD)., Methods: This was a prospective observational study, and the authors collected data on chronic GVHD, staging, sites of involvement and treatments. Performance status, incidence of relapse, overall survival and duration of immunosuppressive therapy (IST) were also evaluated. Data were examined retrospectively. To account for differences in length of follow-up among cohorts, the authors also determined performance status and chronic GVHD staging, sites and treatment at 2 years post-HCT., Results: At 2 years post-HCT, the overall survival rate was 71.7% in the day 4 cohort compared with 61.5%, 52% and 56% in the day 5, 2-day and historical cohorts, respectively (P = 0.283). The cumulative incidence of chronic GVHD was 65.2% in the day 4 cohort versus 46.4% in the day 5 cohort, 51.1% in the 2-day cohort and 65% in the historical cohort (P = 0.26). There was no significant difference in the maximum overall stage of chronic GVHD (P = 0.513), median number of sites involved (P = 0.401) or cumulative incidence of discontinuation of IST (P = 0.32). Death from chronic GVHD was less common in the day 4 and day 5 cohorts compared with the 2-day and historical cohorts, though this did not reach statistical significance., Conclusions: The authors' preliminary results demonstrated that collection of allogeneic matched sibling donor PBSCs on day 4 of G-CSF was feasible, reduced donor exposure to growth factor and was associated with an initial cost savings. Importantly, the authors now demonstrate that transplantation of day 4 mobilized PBSCs is not associated with any adverse outcomes post-HCT, including late effects such as chronic GVHD. Further investigation of donor G-CSF collection algorithms is merited in other HCT settings, including unrelated and mismatched related donors., Competing Interests: Declaration of Competing Interest RTM reports consultancy for and research funding from Novartis; consultancy and advisory board participation for Incyte; advisory board participation for Kite Pharma/Gilead; research funding from AlloVir; data and safety monitoring board membership with Novartis, Athersys and Vor Pharma; and scientific advisory board participation for Artiva. AG reports advisory board participation for Gamida Cell and Talaris Therapeutics., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)