Brent R. Logan

Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T cell–mediated complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for posttransplant cyclophosphamide (PT-Cy)–based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but the T cell biology underpinning these outcomes remains unknown. To determine this, 324 patients were coenrolled onto BMT CTN 1801 to investigate the distinct T cell immune reconstitution pathways of these regimens, including extensive evaluation of T cell receptor (TCR) repertoire, via sequencing of 2359 longitudinal samples and 180,432,350 T cells. Multimodal T cell analysis revealed that PT-Cy was associated with pan–T cell deletion followed by delayed T cell expansion from a smaller founder population compared with Tac/MTX. This created a T cell diversity bottleneck, leading to reduced TCR repertoire diversity for 2 years posttransplant. Reduced TCR diversity, more common in patients receiving PT-Cy, was linked to protection against chronic GVHD when patients were analyzed without regard to study arm. Leveraging donor- and host-specific TCR clonal analysis, we determined that PT-Cy–mediated T cell depletion also depleted pathogen-specific TCRs, rendering PT-Cy patients more likely to lack detectable graft-derived pathogen-specific TCRs early after transplant, which was associated with an increased risk of severe infection. This study reveals how distinct immunosuppression strategies uniquely remodel T cell immunity and shape divergent transplant outcomes.

Winestone et al. demonstrate that in 796 children with SCID transplanted with nonsibling donors between 1982 and 2020, survival was 18.8% lower among Black patients, 14.4% lower among Asian/Pacific Islander patients, and 6.9% lower among Hispanic patients compared with non-Hispanic White patients (P < 0.01). Newborn screening for SCID mitigates wide disparities between Black and non-Hispanic White patients.

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.

PURPOSE: Public reporting of health care outcomes can have unintended effects such as inappropriate risk aversion in patient selection. METHODS: The center-specific survival analysis annually assigns all hematopoietic cell transplantation (HCT) centers in the United States a +1, −1, or 0 score for observed outcomes that are above, below, or within a center-specific predicted range of outcome. For each index year (2012-2016), centers receiving a −1 score after 0 scores in the preceding 2 years were compared with contemporaneous centers with as-predicted outcomes (0 score). Changes in the patient population characteristics in the 3 years before versus the 3 years after the index years were compared between the newly below-expected centers (NBCs) and the controls. A multivariate model adjusted for baseline patient population characteristics and center volume. RESULTS: No differences in patient selection behavior were identified when comparing the NBCs with the controls across eight key patient population characteristics. For the statistically modeled (predicted) 1-year overall survival (OS), reflecting a holistic measure of centers' patient population risk, we observed no statistically significant difference in change (−0.23% [95% CI, −1.4 to 0.9]; P = .70). The observed OS increased in both NBCs and controls by 0.9% and 4.5%, respectively, without statistically significant difference in change. CONCLUSION: Centers receiving a −1 score were not observed to deviate significantly from patient selection trends in the HCT field. These findings suggest that public reporting of HCT outcomes in the United States does not result in unintended bias against HCT for high-risk patients.

BACKGROUND: Chronic 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. METHODS: We 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. RESULTS: ML 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. CONCLUSION: BIOPREVENT 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 REGISTRATION: BMTCTN 0201, BMTCTN 1202, and NCT02194439. FUNDING: R01CA264921, U10HL069294, U24HL138660, R01HD074587, and P01HL158505.

CD19 CAR T-cell therapy has significantly improved the survival of patients with relapsed or refractory large B cell lymphoma (R/R LBCL) and is considered standard of care for eligible patients in Canada. Axicabtagene ciloleucel (axi-cel) is an autologous CAR T-cell therapy, initially approved by Health Canada for adults with R/R LBCL after 2 or more lines of therapy. This multi-centre analysis, with registry data collected from CIBMTR, aims to present a Canadian perspective on the real-world experience of axi-cel in patients with R/R LBCL. With a median follow-up of 12.4 months, the best objective response rate (ORR) and complete response (CR) rate among all patients were 77% and 59%, respectively. At 12 months, estimated progression-free survival (PFS) and overall survival (OS) were 49% and 59%, respectively. Notably, the incidence and severity of adverse events were lower in this cohort compared to ZUMA-1 and other real-world reports, with CRS occurring in 77% (grade ≥ 3, 3%) and ICANS occurring in 38% (grade ≥ 3, 10%) of patients. Outcomes remained largely consistent across patient and disease characteristics. These findings demonstrate effectiveness and safety profiles comparable to international real-world studies and the ZUMA-1 trial, supporting the use of axi-cel as an effective treatment across broad Canadian populations.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe combined immunodeficiency (SCID). Since the initiation of newborn screening (NBS), survival rates have improved significantly, but the impact of HCT upon neurodevelopment for patients with SCID requires more investigation. We performed a cross-sectional study of subjects with SCID in North America to assess the impact of NBS, transplant conditioning regimen, and genotype on neurodevelopmental outcomes after HCT. 69 subjects with SCID from 17 PIDTC centers (excluding those with ADA deficiency), ages 6–16 years, received comprehensive standardized neurodevelopmental testing of cognitive, behavioral, and emotional function. Compared with the normative population, our subjects performed in the average range. We found no impact of NBS, chemotherapy conditioning, or genotype. Multivariate analysis revealed a significant decrease in IQ in subjects whose families earned <$50,000 per year. We recommend that children treated by HCT for SCID be monitored with periodic cognitive and behavioral assessments for deficits that could potentially impact long-term ND outcomes.

PURPOSE: The likelihood of finding a human leukocyte antigen (HLA)–matched unrelated donor (MUD) for hematopoietic cell transplantation can be predicted using a donor search prognosis score. Patients without a MUD may use alternative donors (haploidentical related, mismatched unrelated, or umbilical cord blood). METHODS: This multicenter biological assignment trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1702). Eligibility criteria were broad to mirror clinical practice. The primary end point was 2-year survival from evaluability and compared between those Very Likely (>90%) and Very Unlikely (P = .98) or multivariate (HR, 1.07 [95% CI, 0.86 to 1.33]; P = .56) analyses between the Very Unlikely and Very Likely groups, measured through 2 years from the beginning of a search for a MUD or alternative donor. Of the transplanted patients (n = 1,179), MUD was used for 94% of the Very Likely, 38% of Less Likely, and 9% of Very Unlikely patients. Multivariate analyses showed no differences in relapse, treatment-related mortality, disease-free survival, and acute and chronic graft-versus-host diseases for the three search prognosis groups after transplantation. CONCLUSION: Using a donor search prognosis strategy to prioritize an alternative donor for patients Very Unlikely to find a MUD resulted in survival and transplant outcomes that were not statistically different compared with those Very Likely to find a MUD.

PURPOSE: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for advanced hematologic malignancies. HSCT using human leukocyte antigen (HLA)-mismatched donors is historically associated with inferior survival. Patients from underrepresented racial and ethnic groups more frequently rely on HLA-mismatched donors. We hypothesized that post-transplant cyclophosphamide (PTCy) based graft versus host disease (GVHD) prophylaxis would improve outcomes for HSCT recipients using peripheral blood stem cells (PBSCs) from HLA-mismatched unrelated donors (MMUDs) by reducing the risk of GVHD. METHODS: This phase II, nonrandomized, multicenter trial assessed PBSCs in the setting of a GVHD prophylaxis regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil in two adult strata: myeloablative conditioning (MAC) and reduced-intensity or nonmyeloablative (RIC/NMA) conditioning before HSCT from a MMUD. The primary objective was to estimate 1 year overall survival (OS) for each stratum. Key secondary end points included incidences of acute and chronic GVHD. RESULTS: A total of 145 patients enrolled, with 59% self-identifying within an underrepresented group. The 1 year OS was 83.8% (95% CI, 73.1% to 90.4%) for MAC and 78.6% (95% CI, 67% to 86.5%) for RIC/NMA. Incidences of grades III to IV acute GVHD at 6 months were 8% (95% CI, 3.2 to 15.6) for MAC and 10% (95% CI, 4.4 to 18.4) for RIC/NMA. Moderate/severe chronic GVHD at 1 year was 10.3% (95% CI, 4.4 to 18.9) for MAC and 8.6% (95% CI, 3.5 to 16.6) for RIC/NMA. 32% of patients whose donors matched at fewer than seven of eight HLA alleles had similar OS compared with those with donor matched at seven of eight alleles. CONCLUSION: PTCy-based GVHD prophylaxis after MMUD HSCT with PBSC grafts results in favorable 1 year OS. Using MMUDs expands donor availability to all patients regardless of ancestry (ACCESS; ClinicalTrials.gov identifier: NCT04904588 ).

Study representation of underserved communities