Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

Background The ACCESS trial is a multicenter phase II study that evaluated standard dose post-transplant cyclophosphamide in recipients of HLA mismatched unrelated donor (MMUD) hematopoietic cell transplantation (HCT) for hematologic malignancy. This study examines 1-year post-treatment quality of life (QOL) trajectories among 7/8 HLA matched versus <7/8 HLA matched unrelated donor recipients. Methods This longitudinal study included ACCESS (NCT04904588) trial participants who completed at least one patient reported outcome (PRO) for analysis. Patients completed QOL surveys at baseline, day (D)100, D180, and 1-year post-HCT, using the Lee Symptom Scale (LSS), nine Patient Reported Outcome Measurement Information System (PROMIS) domains, and a measure of financial toxicity (FT, COST-FACIT). Clinically meaningful differences were defined as >5 points, with PROMIS and COST-FACIT cut points and published norms used to interpret symptom burden. Fisher exact or Wilcoxon rank-sum test were applied to compare patient characteristics between <7/8 and 7/8 patients. Results Among the 268 patients enrolled into the ACCESS trial, 232 (87%) submitted at least one survey. Of those patients, 68% (n=158) had a 7/8 MMUD and 31% (n=74) had a <7/8 MMUD. Compared to <7/8 MMUD recipients, patients receiving <7/8 MMUD were younger (median age: 57.6 v. 63.4 years), were more likely to be of racial and/or ethnic minority ancestry (64% v. 42%) and were less likely to be retired (27% v. 43%).At baseline, both cohorts experienced mild FT: 23.9, Grade 1 for <7/8 MMUD recipients and 25.6, Grade 1 for 7/8 MMUD recipients (Fig 1a). At D180 and 1 year, patients receiving <7/8 MMUD continued to report mild financial toxicity while 7/8 MMUD recipients reported no significant financial toxicity at D180 or 1 year.LSS overall scores were similar between groups across all timepoints.PROMIS scores for 7/8 and <7/8 MMUD groups were within the normal limits of symptom burden across all domains except physical and sexual function. At baseline, <7/8 patients had a lower average physical function score (44.1, 95% Confidence interval, CI: 43.3–44.9), indicating mild dysfunction, compared to 7/8 patients (45.7, 95% CI: 44.7–46.7), who were within normal limits (Fig 1b). Both groups showed similar physical function trajectories, with declines at D100 (3.6-point decline for 7/8; 3.9 point decline for <7/8) and recovery to normal ranges by one year (mean 47 for 7/8; mean 46.3 for <7/8). Conclusions There were no clinically meaningful differences between patients with a 7/8 and <7/8 MMUD on overall QOL. Both cohorts demonstrated similar QOL trajectories, returning to baseline scores at 1-year post-HCT. Small differences involving physical function and FT warrant further study. These findings highlight the expansion of access to HCT through HLA mismatch does not come at the cost of QOL, with equal QOL experienced regardless of HLA match.

Safety evaluation is an essential component of clinical trials. To protect study participants, these studies often implement safety stopping rules that will halt the trial if an excessive number of toxicity events occur. Existing safety monitoring methods usually treat these events as binary outcomes. A strategy that instead handles these as time-to-event (TITE) endpoints can offer higher power and a reduced time to signal of excess risk, but must manage additional complexities including censoring and competing risks. We propose the TITE-safety approach for safety monitoring, which incorporates TITE information while handling repeated analyses, censored observations, and competing risks appropriately. This strategy is applied to develop stopping rules using score tests, Bayesian beta-extended binomial models, and sequential probability ratio tests. Operating characteristics of these methods are studied via simulation for common phase 2 and 3 trial scenarios. Across simulation settings, the proposed techniques offer reductions in expected toxicities of 20% or more compared to binary data methods and maintain the type I error rate near the nominal level for various event time distributions. These methods are demonstrated through a redesign of the safety monitoring scheme for Blood and Marrow Transplant Clinical Trials Network 0601, a single arm, phase 2 trial that evaluated bone marrow transplant as treatment for sickle cell disease. Our R package "stoppingrule" offers functions to construct and evaluate these stopping rules, providing valuable tools for trial design to investigators.

Background Access to allogeneic hematopoietic cell transplantation (HCT) remains limited for patients of non-European ancestry due to donor unavailability. While 7/8 mismatched unrelated donors (MMUD) provide acceptable outcomes, HCT with ≥2 allele mismatches (<7/8) have historically yielded poor survival and prohibitive toxicity. Post-transplant cyclophosphamide (PTCy) has significantly improved outcomes after MMUD HCT, but the prognostic effect of increasing HLA disparity in this setting is unclear. Methods The prospective ACCESS trial (NCT04904588) evaluated PTCy-based GVHD prophylaxis in adults receiving 4–7/8 HLA-mismatched peripheral blood stem cells (PBSC) from donors ≤35 years old after myeloablative (MAC) or reduced-intensity/non-myeloablative (RIC/NMA) conditioning. Primary endpoint was 1-year overall survival (OS). Secondary endpoints included graft failure, non-relapse mortality (NRM), relapse, acute and chronic GVHD, and GVHD-free relapse-free survival (GRFS). Results Among 268 adults, 85 received <7/8 and 183 received 7/8 MMUD PBSC grafts. The <7/8 cohort (median age 57, range 24–78; 49% male) was racially diverse, with the majority (61%) identifying as racial/ethnic groups other than non-Hispanic White, and included 6/8 (82%), 5/8 (14%), and 4/8 (4%) matches. Conditioning intensity in this group was MAC (n=23) and RIC/NMA (n=62). Diagnoses included AML (55%), MDS (15%), lymphoma (14%) and ALL (11%). Most received fludarabine/melphalan (44%) or myeloablative busulfan/fludarabine (21%); the median CD34+ cell dose was 5.5 × 10^6/kg, and 75% of grafts were cryopreserved. The 7/8 group (median age 63, range 20–79; 52% male) had similar disease distribution, conditioning intensity [MAC (n=52), RIC/NMA (n=131)], and infused cell dose. In this cohort, 61% of grafts were cryopreserved, and nearly half (45%) identified as racial/ethnic groups other than non-Hispanic White.At 1 year, OS was 86% (95% CI, 76–92) for <7/8 vs 79% (72–84) for 7/8. Relapse was 23% (14–33) vs 17% (12–23); NRM 8% (4–16) vs 14% (9–19); and GRFS 55% (43–65) vs 51% (44–58) in <7/8 and 7/8, respectively. At 6 months, grade II–IV acute GVHD occurred in 34% (24–44) vs 39% (32–46), and grade III–IV in 7% (3–14) vs 8% (5–13) in <7/8 and 7/8, respectively. At 1 year, moderate/severe chronic GVHD was 8% (3–15) vs 11% (7–16). Primary graft failure occurred only after RIC/NMA: 8% (3–18) with <7/8 vs 3% (1–8) with 7/8.In <7/8 recipients, 1-year OS was 91% with MAC and 84% with RIC/NMA; relapse 32% vs 20%; GRFS 53% vs 55%; and NRM 9% vs 8%, respectively. Conclusions PTCy-based GVHD prophylaxis results in excellent outcomes following <7/8 MMUD HCT, with OS >80% and low NRM and GVHD, comparable to 7/8. Extending donor criteria to 4–6/8 mismatches should broaden equitable donor access while permitting optimization of non-HLA factors.

Introduction Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy with event-free survival approaching 80% with human leukocyte antigen (HLA)-matched donors. Objectives In patients without HLA-matched donors, mismatched related or unrelated donors (MMRD or MMUD) have been used, but detailed comparisons of HCT outcomes for these two options are limited. Methods This study investigated 46 patients with CGD who underwent MMRD (n=24) or MMUD (n=22) HCT at 21 Primary Immunodeficiency Treatment Consortium (PIDTC) centers between 1996 and 2023. HLA match was classified based on typing for 8 alleles. Results Most (n=42, 91%) were male, most (n=38, 83%) had X-linked CGD. Patients with MMRD were significantly older at HCT [median 5.6 (range 0.5-23.6) vs. median 2.2 (range 0.7-19) years, p=0.010] and had a higher incidence of pre-HCT inflammatory disease (63% vs. 19%, p=0.009) than patients with MMUD. Because of this, a significantly higher percentage of MMRD patients received systemic corticosteroids in the year prior to HCT (46% vs. 14%, p=0.018). Severe inflammation was the primary indication for MMRD HCT (42%); in contrast, severe infection (45%) or a diagnosis of CGD (45%) were the primary indications for MMUD HCT. MMRD HCTs were more likely to be T cell depleted, 7 (29%) with TCRαβ/CD19+ depletion and 11 (46%) with post-HCT cyclophosphamide (PTCy). Conversely, 11 (50%) MMUD grafts underwent ex vivo T cell depletion, and no patients received PTCy. Most (n=34, 74%) patients received busulfan-based conditioning and most (n=38, 83%) received serotherapy. Graft-versus-host disease (GVHD) prophylaxis regimens were different between the two groups. MMRD patients received primarily PTCy-based regimens (46%) or no prophylaxis with TCRαβ/CD19+ depletion (29%) whereas patients with MMUD received primarily calcineurin inhibitor-based (73%) regimens. Estimated 5-year overall (MMRD 70%, MMUD 77%, p=0.645) and event-free survival (MMRD 58%, MMUD 58%, p=0.88) (Figure 1), cumulative incidence of graft failure (MMRD 21%, MMUD 11%, p=0.242), and rates of Grade II-IV acute (MMRD 31%, MMUD 21%, p=0.314), Grade III-IV acute (MMRD15%, MMUD 11%, p=0.XXX) and chronic (MMRD 29%, MMUD 12%, p=0.576) GVHD (Figure 2) were similar between the two groups. Pre-existing infections and inflammatory disease resolved post-HCT in both groups with no new CGD-related infections or inflammatory disease for up to 10 years of follow up. Conclusion MMRD and MMUD HCT are associated with higher rates of GVHD and lower event-free survival than HLA-matched HCT but are feasible options for CGD patients without an HLA-matched donor, offering long-term survival and resolution of disease. Future efforts should be focused on the reduction of graft failure and GVHD.

Importance:Allogeneic hematopoietic cell transplant (HCT) is curative for hematologic cancers, yet access remains inequitable for racially and ethnically underrepresented and socioeconomically disadvantaged populations, making the goal of having a suitable donor for every patient who needs a transplant challenging. The ACCESS trial broadened access by enrolling patients without matched donors, who instead received an HCT from a mismatched unrelated donor. Objective:To compare baseline characteristics of ACCESS trial participants with participants enrolled in a similar clinical trial and a patient-reported outcome (PRO) protocol cohort. Design, Setting, and Participants:This cross-sectional study included adult participants (aged ≥18 years) from 3 cohorts-the ACCESS trial (2021-2024), BMT CTN 1703 trial (2019-2021), and Center for International Blood and Marrow Transplant Research (CIBMTR) PRO Protocol observational study (2020-2025)-who completed a baseline PRO survey. The ACCESS and PRO Protocol cohorts were stratified by conditioning intensity (myeloablative [MAC] vs reduced-intensity and nonmyeloablative [RIC/NMA]); all BMT CTN 1703 participants received RIC/NMA. Exposure:Hematopoietic cell transplant. Main Outcomes and Measures:Racial and ethnic diversity, insurance type, education, and income were compared among cohorts using counts and percentages, and socioeconomic and structural disadvantage were measured using the Social Vulnerability Index and Comprehensive Score for Financial Toxicity-Functional Assessment of Chronic Illness Therapy. Results:Baseline surveys were completed by 208 participants in the ACCESS trial (median [range] age at transplant, 62.3 [20.4-78.9] years; 108 male [51.9%]), 122 participants in the PRO Protocol study (median [range] age at transplant, 63.9 [21.1-78.0] years; 67 male [54.9%]), and 342 participants in the BMT CTN 1703 trial (median [range] age at transplant, 66.9 [20.7-78.6] years; 218 male [63.7%]). Participants in ACCESS were more racially and ethnically diverse, with 15 (7.2%), 25 (12.1%), 46 (22.2%), 110 (53.1%), and 11 (5.3%) of Asian, Black or African American, Hispanic or Latino, White, and other race and ethnicity, respectively, compared with 4 (3.3%), 2 (1.6%), 8 (6.6%) 104 (85.2%), and 4 (3.3%), respectively, in the PRO Protocol and 10 (3.0%), 0, 16 (4.8%), 302 (91.0%), and 4 (1.2%), respectively, in the BMT CTN 1703 trial. Participants in ACCESS were more likely to have Medicaid (36 [18.1%]) vs PRO Protocol (8 [6.7%]) and BMT CTN 1703 (16 [5.1%]) participants and reported lower education (some college or an associate's degree: 103 [49.5%] vs 73 [59.8%] in the PRO Protocol; postcollege education: 34 [17.3%] vs 35 [29.2%] in the PRO Protocol) and household income (<$40 000 annually: 25 [24.0%] vs 8 [11.6%] in the PRO Protocol and 7 [38.9%] in the BMT CTN 1703 trial). Median Social Vulnerability Index scores were highest among participants in the ACCESS MAC group (median [range], 0.72 [0.01-0.97] vs 0.61 [0.16-0.78] in the PRO Protocol MAC group), and 16 participants [27.6%] in the ACCESS MAC group reported moderate to severe financial toxicity. The ACCESS participants lived closer to transplant centers, especially in the RIC/NMA group (median [IQR], 28 [14-75] miles vs 47 [16-96] miles for BMT CTN 1703 participants and 49 [21-104] miles for PRO Protocol participants). Conclusions and Relevance:This cross-sectional study of clinical trial participants and a clinical cohort found that the ACCESS trial enrolled a more racially and ethnically diverse and socioeconomically disadvantaged population. Trial designs that broaden eligibility could expand access to HCT, highlighting the need for systemic interventions to ensure equity.

Randomized clinical trials in hematologic oncology (HO) are designed to assess the efficacy of experimental therapies for improving clinically relevant outcomes such as overall survival (OS). However, due to the frequent use of subsequent therapies necessitated by a patient's disease condition, appropriately summarizing the treatment effect is challenging. In this paper, we treat the subsequent therapy usage as a mediator and define the treatment efficacy as controlled direct effect using the potential outcome framework. We compared several approaches for the effect estimation by studying their asymptotic theoretical properties and required assumptions. We also compared these approaches via simulation motivated by real trials and illustrated them on real trials.

Composite endpoints, which combine multiple events of interest, are commonly used in medical research. Compared to evaluating a single outcome, a composite endpoint analysis captures the full clinical impact of treatment and leverages a greater number of events, potentially reducing the required sample size for the study. While composite endpoints have gained much attention in clinical trials, studying them in group sequential designs remains challenging due to the correlated nature of event data collected from the same individual, as the sequence of test statistics may not possess an independent increments structure. In this paper, we propose both one-sample and two-sample group sequential designs grounded in the mean frequency function, defined as the cumulative count of all recurrent and terminal events over time. Recognizing the lack of independent increments, our proposed method leverages the asymptotic covariance structure of the test statistics to construct group sequential boundaries that control the Type I error rate. Extensive simulation studies show the proposed design controls Type I error well and achieves the desired power. We illustrate the utility of our method through a reanalysis of BMT CTN 1703, a phase III randomized controlled trial that evaluated an experimental therapy for the prevention of adverse outcomes after allogeneic stem cell transplant.

BMT CTN 1506 ("MORPHO") was a phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib versus placebo for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) in first remission. Subgroup analysis indicated a significant benefit of post-HCT gilteritinib for participants in North America, but no benefit for those in Europe or Asia. We conducted a post-hoc analysis of the data focusing on days from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD measurable residual disease (MRD). Participants transplanted < 120 days from AML diagnosis and/or those treated with FLT3 inhibition pre-HCT were more likely to have improved survival from post-HCT gilteritinib. Pre-HCT MRD levels were higher (P = 0.001) in participants transplanted within 120 days from diagnosis and in those treated with a FLT3 inhibitor pre-HCT and transplanted within 120 days (P = 0.008). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, as participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Time from AML diagnosis to HCT and pre-HCT FLT3 inhibitor use both appeared to impact MRD levels immediately prior to HCT, and geographic differences in these two practice patterns likely accounted for the observed regional differences in benefit from post-HCT gilteritinib. Increasing the number of courses of treatment pre-HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition, but with a presumed risk of some patients experiencing early progression. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

Introduction In 2020, the CIBMTR began collecting patient-reported outcomes (PRO). We assessed patient factors associated with enrollment of HCT recipients to evaluate the representativeness of the PRO data. Methods The CIBMTR Survey Research Group approaches adult patients who agreed to be contacted for future research at the time of their consent to the CIBMTR Research Database and were treated at one of the >40 centers that have opted-in to the CIBMTR PRO protocol. A descriptive analysis was conducted to compare patient characteristics—demographic, clinical, and Social Vulnerability Index (SVI) factors—based on (1) whether patients agree to be contacted for future research (“patient agreement”) and (2) whether patients enroll in the PRO protocol (“patient enrollment”) between August 2020 and August 2025. Differences of ≥5% within groups were considered meaningful. Results The Research Database enrolled 96,662 patients from 08/2020-08/2025, of whom 57,481 agreed to be contacted for research, representing 59% patient agreement. Compared to those who did not agree, those who agreed to be contacted were more likely to be Non-Hispanic White (70% vs. 59%) and less likely to have a high SVI (28% vs. 34%). There were no significant differences in clinical characteristics based on patient agreement. Of the 57,481 patients who agreed, 6,185 (11%) were eligible for recruitment to the PRO protocol.Outreach attempts were made to 4,364 (71%) of those eligible, and 1,389 (32%) of those contacted enrolled (Figure 1). Unenrolled patients included those who declined, or contact attempts were unsuccessful (n=2975, 68%). Patients aged 65–74 were more likely to enroll than not (36% vs. 30%), while those aged 18–44 were less likely to enroll than not (14% vs. 21%). A higher proportion of enrolled patients were Non-Hispanic White (62% vs. 49%) and a lower proportion were Hispanic (14% vs. 20%) or Black/African American (13% vs. 20%). Additionally, enrolled patients tended to have low to medium SVI scores (23% vs. 30%), while unenrolled patients were more likely to have high SVI scores (34% vs. 24%) (Table 1). The proportion of patients with an HCT comorbidity index of 3 or higher was lower among enrolled patients compared to those who were not enrolled (43% vs. 48%). Conclusion We found differences in patient agreement to be contacted and enrollment in PRO data collection by race, ethnicity, and SVI. Additionally, age-related differences were noted for enrollment. Despite these differences, the enrolled population is clinically similar to the broader patient cohort, providing reassurance for the representativeness of CIBMTR PRO data with regards to clinical factors. Future research will explore strategies to make recruitment and participation more accessible to patients with higher SVI.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for many hematological malignancies, but graft-versus-host disease (GVHD) is a common complication. Low gut microbiome diversity is associated with higher GVHD risk and shorter survival in multiple studies. Recently, the BMT CTN 1703 clinical trial demonstrated superiority of a GVHD-prophylaxis regimen including post-transplant cyclophosphamide (PTCy) compared to the standard prophylaxis (tacrolimus and methotrexate, Tac/MTX) in terms of GVHD-free, relapse-free survival at one year among reduced intensity conditioning allo-HCT recipients. However, the effect of PTCy on the gut microbiome and its association with clinical outcome have not been described. Here, we report on a companion randomized clinical controlled trial (BMT CTN 1801), which collected 2575 longitudinal stool samples from 304 study participants. Samples were obtained up to weekly up to day 84 post allo-HCT and at less frequent intervals thereafter, up to 2 years. Microbiome diversity and absolute microbial load were lower in the PTCy group compared to the Tac/MTX group on days 14-28 post-HCT. However, diversity at the timepoint closest to neutrophil engraftment was not significantly associated with non-relapse mortality after one year or other clinical outcomes, contrary to expectations from previous studies. Microbial domination events, when a single species exceeds 30% relative abundance, were comparable across treatment arms and reflected both pathogen blooms as well as less severe disruptions of the microbial community. Clostridium scindens and secondary bile acid metabolism pathways were less prevalent in the PTCy arm than in the Tac/MTX arm post-HCT, yet presence of secondary bile acid metabolism pathways was associated with a lower risk of chronic GVHD. Given that PTCy was associated with a greater disruption of the microbiome as measured by diversity, absolute microbial abundance, and bile acid metabolism capability, but better clinical outcomes overall, these data suggest that the importance of the microbiome in modulating the host immune systems after allo-HCT is specific to different types of GVHD prophylaxis.

BACKGROUNDChronic graft-versus-host disease (cGVHD) is a major contributor to nonrelapse mortality (NRM) following hematopoietic cell transplantation (HCT). Whether machine-learning (ML) models with biomarkers improve the accuracy for predicting future cGVHD/NRM is not established.METHODSWe developed BIOPREVENT (BIOmarkers PREVENTion), a ML algorithm using data from 1,310 HCT recipients, incorporating 7 plasma proteins measured at Day 90/100 post-HCT and 9 clinical variables. Patients were divided into training and validation datasets. ML models - including CoxXGBoost, Group SCAD, Adaptive Group Lasso, Random Survival Forests, and Bayesian Additive Regression Trees (BART) - were used to estimate time-varying Area Under the ROC Curve (AUCt) at Days 180, 270, 360, and 540. Deep learning models were also evaluated.RESULTSML models with biomarkers outperformed clinical-only models for predicting cGVHD, with BART and CoxXGBoost achieving AUCt greater than 0.65 at 1 year. For NRM, models with biomarkers achieved AUCt ranging from 0.75-0.91. Deep learning did not outperform other ML approaches. BART consistently demonstrated high predictive accuracy and was selected for the final BIOPREVENT model. Calibration curves aligned with observed values. Variable importance analysis identified MMP3 and CXCL9 as key for cGVHD prediction and IL1RL1 and sCD163 for NRM. Cumulative incidences of cGVHD and NRM differed significantly based on BIOPREVENT-defined cutpoints.CONCLUSIONBIOPREVENT accurately predicts individual risk of future cGVHD and NRM using biomarkers at 3 months post-HCT. A publicly available R Shiny web application supports its clinical use. Further studies are needed to explore its role in guiding preemptive therapy.TRIAL REGISTRATIONBMTCTN 0201, BMTCTN 1202, and NCT02194439.FUNDINGR01CA264921, U10HL069294, U24HL138660, R01HD074587, and P01HL158505.

ABSTRACT:Acute graft-versus-host disease (aGVHD) contributes to significant morbidity after allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to develop and validate a clinical score to identify patients with significantly different risk for developing aGVHD. Analysis included adults who underwent allo-HCT during 2008-2019. Eligibility criteria were widely inclusive of transplant indications, donor types, graft types, conditioning regimens, and GVHD prophylaxis regimens. The final cohort of 21 796 patients was randomly split into training and validation cohorts, with 15 258 (70%) and 6538 (30%) patients, respectively. The primary outcome was grade 2 to 4 aGVHD, and the secondary outcome was grade 3 to 4 aGVHD, by day 100 posttransplant. Risk scores were developed using the training cohort, tested using the validation cohort, and stratified into 4 percentile groups. The odds of grade 2 to 4 aGVHD by day 100 posttransplant were 1.50 (95% confidence interval [CI], 1.29-1.75; P< .0001) for the 25th to 50th percentile group, 2.0 (95% CI, 1.78-2.40; P< .0001) for the 50th to 75th percentile group, and 3.1 (95% CI, 2.72-3.65; P< .0001) for the >75th percentile group compared with the ≤25th percentile group in the validation cohort. The odds of grade 3 to 4 aGVHD by day 100 posttransplant were 1.4 (95% CI, 1.11-1.74; P = .0043) in the 25th to 50th percentile group, 2.0 (95% CI, 1.61-2.49; P< .0001) in the 50th to 75th percentile group, and 3.2 (95% CI, 2.64-3.98; P< .0001) in the >75th percentile group compared with the ≤25th percentile group in the validation cohort. Here, to our knowledge, we have developed the first validated, widely inclusive clinical risk score for the development of aGVHD after allo-HCT.

Abstract Newer approaches to control alloreactivity may produce similar transplant outcomes using HLA-mismatched donors vs HLA-matched unrelated donors (MUD). However, prospective comparisons are lacking. BMT CTN 1702 used a donor search prognosis score to assign patients to an 8/8 HLA MUD or the center’s preference of haploidentical related donors (HAPLO), mismatched unrelated donors (MMUD), or umbilical cord blood (UCB). Outcomes of MUD were compared to HAPLO, MMUD, and UCB transplantation after adjusting for covariates. Patients (n = 1179 [93% adults]) underwent transplantation with MUD (n = 772), HAPLO (n = 254), MMUD (n = 112), and UCB (n = 41) at a median of 3.7, 3.4, 3.9, and 3.8 months from enrollment. Posttransplant cyclophosphamide (PTCy) was used in 23.9%, 83.9%, 65.2%, and 0% of MUD, HAPLO, MMUD, and UCB. In multivariate analyses, compared to MUD, survival was lower for UCB (hazard ratio [HR], 2.65; P< .001) but not statistically different for HAPLO and MMUD (HRs, 1.08 and 1.18, respectively). Relapse risk was not significantly different by donor, but treatment-related mortality (HR, 3.31; P< .001) and disease-free survival (HR, 1.99; P = .002) were inferior for UCB but not different for HAPLO and MMUD than MUD. In patients who received PTCy, HAPLO and MMUD were associated with increased grade 3 or 4 acute graft-versus-host disease (GVHD; HR, 2.39 [P = .017] and 2.53 [P = .038], respectively) and chronic GVHD (HR, 1.71 for both; P = .028 and .080) than MUD, but other outcomes were not different. HAPLO or MMUD may be used to expedite transplantation when finding MUD is unlikely. This study was registered at www.clinicaltrials.gov as NCT03904134.

Introduction Quality of life (QoL) is a critical indicator of therapeutic benefit and long-term recovery after allogeneic hematopoietic cell transplantation (HCT). BMT CTN 1702 trial (NCT03904134), a multicenter study (2019-2022) evaluating donor search, selection practices and outcomes of HCT using alternative donor sources, incorporated QoL as a secondary endpoint. Objectives The aim of the QoL sub-study was to explore the long-term QoL in a more homogenous subset of patients with AML/ALL in CR1/early stage MDS who provided additional clinical and patient-reported outcomes (PRO) data and compare those receiving MUD or Haplo donors. Methods QoL was assessed using PROMIS measures and Lee Symptom Scale (LSS). PROs were completed at baseline, 1 and 2 years post-HCT. PRO analysis was done using a generalized estimating equation linear regression model with an independent working covariance matrix to model the mean PRO outcome at each time point. Late effects, infection rates, and healthcare utilization were also compared. Statistical significance was defined as p-value ≤ 0.01. Results 304 patients were analyzed (61 Haplo and 243 MUD). Some characteristics differed at baseline (Table 1), but consistent with findings from the parent study. No significant differences were observed in any clinical outcomes including Graft versus Host Disease (GvHD) or GVHD-free survival (GRFS). While PRO submission rates at baseline were similar (MUD 67%, Haplo 64%), retention in the MUD cohort was higher than Haplo (80% and 83% vs. 58% and 60% at year 1, at year 2, respectively). In univariate analysis, there was no significant difference in median PROs score between the two cohorts at any timepoint. Similarly, in multivariable analysis, there were no significant differences in post-HCT trajectory of QoL domains. No significant differences in late effects including pulmonary, cardiac, or renal complications were observed. The use of Haplo donors were associated with significantly more hospital days (median days 27.0 vs. 21.0, p<0.01) and viral infections (49.2% vs. 31.8%, p=0.01) in the first 100 days. Conclusion Despite similar QoL trajectories, the increased hospital days and viral infections in Haplo HCT may reflect differences in post-transplant burden, possible associated with the treatment strategy. These findings suggest that QoL data meaningfully inform donor selection and long-term care strategies.

Posttransplant cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) improves outcomes in recipients of HLA mismatched unrelated donor (MMUD) allogeneic hematopoietic cell transplantation (allo HCT). Outcomes of MMUD HCT using PTCy in patients requiring reduced intensity or non-myeloablative conditioning (RIC/NMA) are not well described. The Phase II, prospective, ACCESS trial sought to evaluate PTCy-based GVHD prophylaxis in adult recipients of MMUD using peripheral blood stem cell allografts. Here, we report combined results of RIC/NMA recipients treated in the initial study (N = 70) and a planned expansion cohort (N = 123). The number of centers participating in the expansion protocol was 33 compared to 13 in the initial study. Median participant age was 65.0 (range: 22.9-78.9) and the HCT comorbidity index was high-risk (≥ 3) in 65 (33.7%). Donor HLA matching was < 7/8 in 62 (32.1%) participants. One-year survival was 79.6% (95% confidence interval: 73.2-84.7) and was similar between HLA 7/8- and HLA < 7/8-matched donor recipients. Survival was similar between participants in the initial study (78.6%) and the expansion cohort (80.3%) indicating generalizability of this strategy. One-year incidence of severe infection (Grade 3-5) was 39% (32%-46.9%). The 1-year incidence of non-relapse mortality and relapse estimates were 12.5% (8.3%-17.6%) and 17.3% (12.3%-23%), respectively. MMUD with PTCy-based GVHD prophylaxis and RIC/NMA conditioning was safe and effective to facilitate HCT. Outcomes were similar in the expansion cohort that enrolled from a greater number of centers. Post-HCT infections were prevalent.

ABSTRACT:Despite concerns about the toxicity of allogeneic hematopoietic cell transplantation (alloHCT) in older patients, prospective data characterizing prevalence or risk stratification for geriatric morbidity such as disability or frailty are limited. We prospectively assessed the prognostic impact of the novel composite health assessment risk model (CHARM), a score established to predict 1-year nonrelapse mortality (NRM), among 1105 patients aged ≥60 years enrolled on the Bone Marrow Transplant Clinical Trials Network Study 1704. Secondary end points were assessed post-alloHCT at day 100 (D100), D180, and D365 in multivariable models adjusted with predetermined clinical variables. Among alloHCT survivors, the prevalence of disability by instrumental activities of daily living (IADL), frailty by the Physical Frailty Phenotype, and physical function impairment by Patient Reported Measurement Information System (PROMIS) was highest at D100 and lower on D180 and D365. Higher CHARM scores were independently associated with greater disability (coefficient, -0.64; 95% confidence interval [CI], -0.85 to -0.43; P< .001), increased frailty (coefficient, 0.19; CI, 0.081-0.31; P< .001), worse PROMIS physical function, greater PROMIS depression, increased serious organ toxicity by D100, more cognitive decline at D100, and higher mortality after acute graft-versus-host disease (GVHD) but not significantly associated with PROMIS anxiety or acute GVHD. Higher CHARM scores predicted worse disability-free survival (odds ratio [OR], 2.03; CI, 1.66-2.48; P< .001) and lower frailty-free survival (OR, 2.00; CI, 1.61-2.49). In summary, CHARM is an independent prognostic scoring system not only for NRM but also for geriatric morbidity and functional limitation-free survival through 1 year after alloHCT. Pre-alloHCT CHARM is a novel tool to aid shared decision-making for older patients. This trial was registered at www.clinicaltrials.gov as #NCT03992352.

ACCESS is a prospective, multicenter phase II trial evaluating peripheral blood stem cell (PBSC) transplantation using 4-7/8 HLA-mismatched unrelated donors (MMUD) with post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate. Adults undergoing first HCT with myeloablative (MAC) or reduced-intensity/nonmyeloablative (RIC/NMA) conditioning were enrolled, with donors aged 18-35 years and matched at 4/8-7/8 HLA loci by high-resolution typing. This expanded analysis includes all enrolled adult PBSC recipients, including the protocol-specified RIC/NMA cohort expansion, to improve precision of outcome estimates and provide descriptive analyses by HLA match level. Among 268 adults, 183 received 7/8 and 85 received <7/8 MMUD grafts; 82.4% of the <7/8 cohort received 6/8 grafts. Median follow-up among survivors was 11.9 months. At 1-year, overall survival was 78.6% (95% CI, 71.9-83.9) in the 7/8 cohort and 85.6% (95% CI, 76.0-91.5) in the <7/8 cohort. One-year relapse, non-relapse mortality, and GVHD-free relapse-free survival were 17.1%, 13.7%, and 51.1% versus 22.8%, 8.4%, and 54.6%, respectively. The cumulative incidence of grade II-IV and grade III-IV acute GVHD by day 100 was 36.6% and 7.7% in the 7/8 cohort versus 28.3% and 5.9% in the <7/8 cohort. Moderate-to-severe chronic GVHD at 1 year was 11.3% versus 7.7%, respectively. Among adult ACCESS recipients treated on a uniform young-donor PBSC/PTCy platform, short-term outcomes with predominantly 6/8 MMUD transplantation were encouraging. Because donor match level was not prospectively assigned and between-group comparisons were exploratory, these findings are descriptive and should not be interpreted as establishing equivalence with 7/8 MMUD transplantation. (Registered as NCT04904588 at CT.gov)

The Primary Immune Deficiency Treatment Consortium performed a retrospective analysis of 133 patients with severe combined immunodeficiency (SCID) receiving matched sibling donor (MSD) hematopoietic cell transplantation (HCT) between 1980 and 2023 at 30 North American institutions. In this largest cohort of MSD outcomes in patients with SCID to date, we examined the impact of conditioning regimen and graft-versus-host disease (GVHD) prophylaxis on survival and immune recovery. Outcomes after MSD HCT for SCID were excellent. Patients without an active infection or failure to thrive (FTT) at the time of HCT had 5-year overall survival superior to those with infection or FTT. Acute and chronic GVHD outcomes were independent of GVHD prophylaxis, conditioning regimen, SCID type, or presence of maternal engraftment. Patients without active infection at the time of HCT had superior chronic GVHD-free event-free survival vs those with infection. T-cell reconstitution at 6 months was less likely achieved with use of GVHD prophylaxis or serotherapy, and in patients with leaky SCID or Omenn syndrome. At 6 months,1 year, and 2-5 years, T-cell reconstitution was less likely with ADA, DCLRE1C, or RAG genotype. B-cell reconstitution at 1 year and 2-5 years was negatively affected by development of grade 2 to 4 or 3 to 4 acute GVHD. Conditioning did not affect T-or B-cell reconstitution. Our data suggest omitting conditioning and GVHD prophylaxis for patients with typical SCID did not negatively affect 5-year outcomes after MSD HCT, but the data are insufficient to recommend this approach for best long-term outcomes. This trial was registered at www. clinicaltrials.gov as #NCT01186913 and #NCT01346150.

Background: More patients with diverse ancestry and lower socioeconomic status (SES) are diagnosed annually with hematopoietic cell transplant (HCT)-eligible diseases than receive HCT, reflecting access barriers resulting in underrepresentation in clinical trials. The NMDP-sponsored, CIBMTR-led ACCESS (NCT04904588) trial studied safety and efficacy of peripheral blood stem cell allografts from mismatched unrelated donors (MMUD) in adults with hematologic malignancies receiving myeloablative (MAC) or reduced intensity/non-myeloablative conditioning (RIC/NMA) combined with post-transplant cyclophosphamide, mycophenolate mofetil, and tacrolimus as graft-versus-host disease prophylaxis. Analysis from the initial RIC/NMA stratum showed that 51% (n=36) of patients were ethnically diverse (ED) and had a 1-year overall survival of 79% (Al Malki et al. ASCO 2024). ED patients were younger and had higher financial toxicity and social vulnerability index (SVI) than non-Hispanic White (NHW) patients (Yusuf et al. 2024 Tandem Meetings). Enrollment of adult patients on both strata was completed in February 2024. Herein we provide key baseline characteristics to further define profiles that might influence social needs and trial participation of ED patients. Methods: To enroll on ACCESS, patients required an unrelated donor (URD) matched at 4-7/8 HLA alleles (HLA-A, B, C, and DRB1) and aged 18-35 years. Recipients without an available 8/8 related or URD and lacking HLA-specific antibody (anti-HLA-Ab) to any mismatched allele/antigen were eligible. Donor ancestry and recipient utilization of NMDP patient support were collected through NMDP operations. Social drivers/determinants of health (SDOH), including COmprehensive Score for financial Toxicity (COST) and SVI, and patient reported outcomes (PRO) were collected on enrolled patients and compared between NHW and ED subjects, defined as patients having any race and ethnicity besides NHW (AFA, non-Hispanic Black/African American; API, Asian Pacific Islander; HIS, Hispanic; NAM, Native American; MLT, multiple; and UNK, unknown). Wilcoxon rank sum and Fisher exact tests were used for continuous and categorical variables, respectively, to measure statistically significant differences between groups (p<0.05). Results: Of 268 adult patients, 51% were males, 69% had acute leukemia, and 51% were ED: 28% (n=75) HIS, 13% (n=34) AFA, 8% (n=22) API, 1% (n=3) NAM, <1% (n=2) MLT, and <1% (n=1) UNK. Most patients received RIC HCT (n=193, 72%) using a 7/8 MMUD (n=183, 68%). No differences in HCT comorbidity indices were noted between NHW and ED patients (p=0.42). Median donor age was 25 years (18-35 years) and more AFA patients received HCT using a donor above the median age. Of 153 patients with anti-HLA Ab, 58% were female with higher incidence of anti-HLA-Ab noted in patients utilizing MMUD with higher degree of HLA mismatch: 7/8 (n=96) 58%; 6/8 (n=45) 67%; 5/8 (n=9) 75%; and 4/8 (n=3) 100%. Compared to NHW patients, ED patients were younger (median age: 56 v. 64 years), had higher overall SVI (high SVI: 27 v. 10%), and lived closer to a transplant center (mean distance: 35 vs. 62 miles)(all p<0.01). Baseline PRO data were available in 211 patients (113 NHW, 97 ED, 1 Unknown). More ED patients than NHW reported lower educational attainment (college degree: 21 v. 36%), lower personal income (<$50,000: 51 v. 28%), and higher financial toxicity (mean COST: 21 vs. 28)(all p<0.05). In contrast to NHW patients, a larger proportion of ED patients acknowledged needing a caregiver (39 v. 22%)(p<0.05). Of 162 (60%) enrolled patients receiving NMDP support services, 121 (44%) received navigation and 84 (31%) received financial assistance. Of these, 90 (56%) were ED and 72 (44%) were NHW. ACCESS trial participants who received navigation or financial assistance lived in an area (ZIP-based) with a lower percentage of the population with a bachelor or graduate degree (33 v. 39%) and median income ($82,000 v. $93,000) than participants who did not receive support (both p<0.05). Conclusions: Half of adult patients enrolled on the ACCESS trial were ED and had higher social vulnerability needs and obtained more support services compared to NHW patients. The ACCESS trial expanded access for underserved patients and highlights the need for additional support strategies to ensure representation of ED patients in HCT clinical trials.