Unrelated Donor Age and Recipient Outcomes After Posttransplant Cyclophosphamide vs Conventional Prophylaxis.

Importance: Advanced age in unrelated donors (URDs) is a well-established risk factor in allogeneic hematopoietic cell transplant (HCT), leading registries to prioritize younger donors. However, this paradigm relevance is uncertain in the era of posttransplant cyclophosphamide (PTCy) for graft-vs-host disease (GVHD) prophylaxis, a strategy increasingly adopted for its effectiveness. Clarifying this association is crucial for optimizing donor selection and potentially expanding the donor pool. Objective: To determine whether the association of older URD age with overall survival differs between patients receiving PTCy-based vs conventional calcineurin inhibitor (CNI)-based GVHD prophylaxis. Design, Setting, and Participants: This was a multicenter cohort study using registry data from the Center for International Blood and Marrow Transplant Research for January 2017 through June 2021. Eligible participants were adult patients with acute leukemia or myelodysplastic syndrome who underwent an allogeneic HCT from a URD who was fully matched for 8 of 8 human leukocyte antigen loci (MUD) or mismatched for 7 of 8 human leukocyte antigen loci (MMUD). Data were analyzed from January to June 2025. Exposures: GVHD prophylaxis regimen (PTCy-based vs CNI-based) and donor age (analyzed continuously and categorically). Main Outcomes and Measures: Overall survival was the primary outcome, with associations assessed using a multipronged approach including least absolute shrinkage and selection operator (LASSO)-penalized Cox proportional hazards models, inverse probability of treatment weighting (IPTW), and XGBoost machine learning. Results: The study analysis included 10 025 patients (mean [SD] age, 56.5 [14.4] years; 4379 female [43.7%] and 5646 male [56.3%] individuals) among whom 7272 (72.5%) had received MUD-CNI; 1681 (16.8%%) MUD-PTCy; 613 (6.1%) MMUD-PTCy; and 459 (4.6%) MMUD-CNI. Increasing donor age was associated with worse OS in CNI-based MUD (hazard ratio [HR], 1.004-1.009 per year increase) and MMUD (HR, 1.022-1.034) cohorts. Conversely, this association was not observed in the combined PTCy cohort (HR, 1.001-1.007). These findings were robust across standard and overlap weighted IPTW, LASSO-penalized models, and XGBoost analyses. The attenuated association in the PTCy cohort was primarily driven by a lack of association between donor age and nonrelapse mortality. Conclusions and Relevance: The findings of this cohort study indicate that the association of donor age with URD HCT outcomes appears to be mitigated in the PTCy setting, suggesting that PTCy may counteract some of the adverse effects associated with increased unrelated donor age. This observation challenges existing paradigms and warrants validation in independent cohorts, and if validated, could substantially expand the donor pool.