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The incidence of excessive adiposity is increasing worldwide, and is associated with numerous adverse health outcomes. We compared outcomes by body mass index (BMI) for adult patients with acute myelogenous leukemia (AML) who underwent autologous (auto, n = 373), related donor (RD, n = 2041), or unrelated donor (URD, n = 1801) allogeneic myeloablative hematopoietic cell transplantation (HCT) using bone marrow or peripheral blood stem cells reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2004. Four weight groups by BMI (kg/m2) were defined: underweight <18 kg/m2; normal 18-25 kg/m2; overweight >25-30 kg/m2; and obese >30 kg/m2. Multivariable analysis referenced to the normal weight group showed an increased risk of death for underweight patients in the RD group (relative risk [RR], 1.92; 95% confidence interval [CI], 1.28-2.89; P = .002), but not in the URD group. There were no other differences in outcomes among the other weight groups within the other HCT groups. Overweight and obese patients enjoyed a modest decrease in relapse incidence, although this did not translate into a survival benefit. Small numbers of patients limit the ability to better characterize the adverse outcomes seen in the underweight RD but not the underweight URD allogeneic HCT patients. Obesity alone should not be considered a barrier to HCT. [Copyright &y& Elsevier]

Abstract: High-dose therapy with autologous hematopoietic cell transplantation (auto-HCT) is frequently used to improve outcomes in lymphoma. However, small studies suggest a survival disadvantage among obese patients. Using a retrospective cohort analysis, we studied the outcomes of 4681 patients undergoing auto-HCT for Hodgkin or non-Hodgkin lymphoma between 1990 and 2000 according to body mass index (BMI). Four groups categorized by BMI were compared by using Cox proportional hazards regression to adjust for other prognostic factors. A total of 1909 patients were categorized as normal weight (BMI 18-25 kg/m2), 121 as underweight (BMI <18 kg/m2), 1725 as overweight (BMI >25-30 kg/m2), and 926 as obese (BMI >30 kg/m2) at the time of HCT. Outcomes evaluated included overall survival, relapse, transplantation-related mortality (TRM), and lymphoma-free survival. TRM was similar among the normal, overweight, and obese groups; the underweight group had a higher risk of TRM (relative risk [RR], 2.46; 95% confidence interval [CI], 1.59-3.82; P < 0.0001) compared with the normal-BMI group. No differences in relapse were noted. Overall mortality was higher in the underweight group (RR, 1.48; 95% CI, 1.17-1.88; P = .001) and lower in the overweight (RR, 0.87; 95% CI, 0.79-0.96; P = .004) and obese (RR, 0.76; 95% CI, 0.67-0.86; P < .0001) groups compared with the normal-BMI group. In light of our inability to find differences in survival among overweight, obese, and normal-weight patients, obesity alone should not be viewed as a contraindication to proceeding with auto-HCT for lymphoma when it is otherwise indicated. [Copyright &y& Elsevier]

Survival in Epstein–Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT. In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov , NCT03394365 , and is ongoing. From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23–77) of 14 participants in the HSCT group and 15 (52%, 33–71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7–23·9) and 6·0 months (1·8–18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel. Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options. Atara Biotherapeutics. [ABSTRACT FROM AUTHOR]

Abstract: Outcome disparity associated with race or ethnicity in the United States has been observed in hematopoietic cell transplantation (HCT). The underlying reasons for such disparity are not known. In the United States, an optimal study of health care disparity by race or ethnicity involves consideration of both biologic and psychosocial determinants, which requires an adequately powered, prospective cohort study design. To better characterize the nature and quantify the magnitude of the many impediments relevant to conducting a successful prospective study involving racial or ethnic minorities in HCT, we conducted a feasibility study to help guide planning of a larger scale outcome and disparity study in HCT. The primary questions to be addressed in the study were: (1) can we establish a racially or ethnically diverse patient sample that will respond to a survey focused on sociodemographic, economic, health insurance, cultural, spiritual, and religious well-being, and social support information? (2) What is the retention rate in the study over time? (3) What is the quality of the data collected from the patients over time? The challenges we faced in conducting this multicenter feasibility study are summarized in this report. Despite the difficulty in conducting disparity studies in racial and ethnic minorities, such studies are essential to ensure that people of all ethnic and racial backgrounds have the best chance possible of benefiting from HCT. [Copyright &y& Elsevier]

Abstract: We determined treatment-related mortality, progression-free survival (PFS), and overall survival (OS) after a second autologous HCT (HCT2) for patients with lymphoma relapse after a prior HCT (HCT1). Outcomes for patients with either Hodgkin lymphoma (HL, n = 21) or non-Hodgkin lymphoma (NHL, n = 19) receiving HCT2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were analyzed. The median age at HCT2 was 38 years (range: 16-61) and 22 (58%) patients had a Karnofsky performance score <90. HCT2 was performed >1 year after HCT1 in 82%. The probability of treatment-related mortality at day 100 was 11% (95% confidence interval [CI], 3%-22%). The 1-, 3-, and 5-year probabilities of PFS were 50% (95% CI, 34%-66%), 36% (95% CI, 21%-52%), and 30% (95% CI, 16%-46%), respectively. Corresponding probabilities of survival were 65% (95% CI, 50%-79%), 36% (95% CI, 22%-52%), and 30% (95% CI, 17%-46%), respectively. At a median follow-up of 72 months (range: 12-124 months) after HCT2, 29 patients (73%) have died, 18 (62%) secondary to relapsed lymphoma. The outcomes of patients with HL and NHL were similar. In summary, this series represents the largest reported group of patients with relapsed lymphomas undergoing SCT2 following failed SCT1, and with long-term follow-up. Our series suggests that SCT2 is feasible in patients relapsing after prior HCT1, with a lower treatment-related mortality than that reported for allogeneic transplant in this setting. HCT2 should be considered for patients with relapsed HL or NHL after HCT1 without alternative allogeneic stem cell transplant options. [Copyright &y& Elsevier]

Patients (pts) undergoing a solid organ (SOT) or allogeneic hematopoietic cell transplant (HCT) are at risk for developing Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV+PTLD). There is a need for effective and well-tolerated therapies in pts with EBV+PTLD who have failed rituximab ± chemotherapy (CT). Tabelecleucel (tab-cel) is an investigational, off-the-shelf, allogeneic EBV-specific T-cell immunotherapy generated from healthy donors that is selected for a given pt from an existing library, based on human leukocyte antigen (HLA) restriction and matching. Here, we report long-term outcomes using tab-cel through an ongoing US, multicenter Expanded Access Program (EAP) study (EBV-CTL-201, NCT02822495) in pts with relapsed/refractory (R/R) EBV+PTLD following HCT (n = 14) and SOT (n = 12). Pts received tab-cel matched by ≥2/10 HLA alleles, including ≥1 HLA allele through which tab-cel exerts cytotoxicity (HLA restriction). In each 5-week cycle, pts received tab-cel 1.6–2 × 106 cells/kg intravenously on days 1, 8, and 15, with an imaging-based response assessment around day 28. Pts were treated until maximal response (with up to 4 tab-cel restrictions), unacceptable toxicity, or withdrawal of consent. Results herein reflect a data snapshot from June 3, 2019. All pts had received prior rituximab and 7/12 SOT pts received prior CT. Intermediate/high risk PTLD-prognostic index (PTLD-IPI; Choquet et al, Ann Hematol 2007) was noted in 79% and 42% of HCT and SOT pts, respectively. The results are presented in figure 1. While the median follow-up time in HCT pts was short, 3 pts were followed for over 12 months including 2 who were followed for more than 24 months. In pts responding to tab-cel, 1-year OS was 85.7% in HCT and 100% in SOT, and no deaths were attributable to EBV+PTLD progression. In a subset of study pts (HCT: n = 11; SOT: n = 11) with adequate ECOG, no CNS disease, and no PTLD-related ventilatory support who would have likely been eligible for Atara's ongoing Phase 3 studies, the ORR was 55% (HCT) and 82% (SOT), with a 2-yr OS of 79% (HCT) and 81% (SOT). The safety profile of tab-cel was consistent with previously published data. At the data snapshot for this abstract, no tab-cel-related adverse events led to treatment discontinuation or death. In addition, no cytokine release syndrome, organ rejection or tumor flare adverse events were reported in the EBV+PTLD pts treated with tab-cel in this EAP study. The data demonstrate a high response rate for tab-cel in EBV+PTLD in both HCT and SOT after initial treatment failure. Longer term follow-up shows a favorable 2-year OS in this predominantly high-risk population for whom there are no approved alternative therapies. Similar outcomes were observed in the subset of pts potentially eligible for ongoing Phase 3 studies of tab-cel in R/R EBV+PTLD following SOT or HCT. [ABSTRACT FROM AUTHOR]

Abstract: Racial or ethnic minorities with leukemia who receive HLA-identical sibling hematopoietic stem cell transplants (HSCTs) are reported to have worse survival when compared with whites. Characteristics of US HSCT centers according to the proportion of ethnic minorities who undergo transplantation were compared to explore systematic differences among centers; the association with 100-day mortality was evaluated to determine whether center factors may explain the observed discrepant survival among ethnic minorities. One hundred sixteen US transplantation centers that performed HLA-identical sibling transplantations for leukemia were analyzed. We compared physician and health care provider staffing, transplantation unit procedure and resources, and medical center organization according to the volume procedure ratio of ethnic minorities who underwent transplantation and also according to the ratio of Hispanics who underwent transplantation. Centers that performed transplantation in a higher proportion of ethnic minorities were more likely to perform fewer transplantations per year, to have fewer devoted transplant beds, to be in an urban setting, to have a lower physician to patient volume ratio, and to follow up survivors 1 year after transplantation. Centers that performed transplantation in a higher proportion of Hispanics were more likely to perform fewer transplantations per year and to have fewer devoted transplantation beds, were less likely to perform outpatient transplantations, were more likely to be in an urban setting, and were less likely to have posttransplantation immunization protocols. Observed differences in center factors were not associated with 100-day mortality after adjustment for disease severity. Our results suggest that the inferior survival reported in ethnic minorities after HSCT may not be readily explained by center effects. [Copyright &y& Elsevier]

In immunocompromised individuals where T-cell function is impaired, EBV-transformed B-cells can proliferate resulting in lymphoproliferative disorders or lymphoma (EBV+LPD). EBV+LPD following solid organ transplant (SOT) is known as EBV+ post-transplant lymphoproliferative disorder (EBV+PTLD). Treatments for EBV+PTLD following SOT include reduction in immunosuppression and off-label rituximab ± multi-agent chemotherapy (CT). Limitations of current EBV+PTLD treatments include lack of response, relapse, potential for graft rejection, short- and long-term toxicity and high mortality, highlighting a clear unmet medical. Tabelecleucel (tab-cel) is an off-the-shelf allogeneic EBV-specific T cell immunotherapy generated from healthy donors that is selected for each patient (pt) from a library of T cells using the most appropriate human leukocyte antigen (HLA) restriction to address the patient's disease. Tab-cel has been evaluated in several clinical studies; One published interim analysis showed that in ALLELE-eligible patients with EBV+PTLD following SOT, the objective response rate (ORR) was 83% (5/6 patients) (Prockop et al, ASH 2017). Here we describe the design of an ongoing study of tab-cel for SOT subjects with EBV+PTLD after failure of rituximab ± CT. ALLELE is a multicenter, open-label, single arm, phase 3 study evaluating the clinical benefit of tab-cel in pts with EBV+PTLD following SOT (n=33) after failure of (1) rituximab monotherapy or (2) rituximab plus CT (NCT03394365). Key inclusion criteria are a diagnosis of locally assessed, biopsy-proven EBV+PTLD and failure of rituximab or rituximab plus concurrent/sequential CT. Exclusion criteria include untreated or in-progress treatment of central nervous system PTLD and suspected or confirmed grade >2 graft-vs-host disease. Tab-cel is partially matched to each patient from a library that is HLA-characterized using 1 EBV HLA restriction allele and at least 1 other matched HLA allele. Tab-cel is administered in cycles lasting 5 weeks (35 days). During each cycle, subjects receive intravenous (IV) tab-cel at a dose of 2 × 106 cells/kg on days 1, 8, and 15, followed by observation through day 35. Response per clinical and radiographic assessment are evaluated at the end of each cycle by the investigator and independent review using modified Lugano Classification criteria. Up to 2 different HLA restrictions are allowed per protocol. Treatment is continued until maximal response, unacceptable toxicity, initiation of non-protocol therapy, or failure of the maximum allowable HLA restrictions. After treatment is completed or discontinued, subjects are assessed every 3 months, up to 24 months and every 6 months thereafter up to 5 years for survival status. The primary endpoint of the study is overall response rate (ORR) following the administration of tab-cel. [ABSTRACT FROM AUTHOR]