Re-Evaluating Donor Selection Priorities for Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide

The prognostic significance of traditional donor selection criteria for human leukocyte antigen (HLA)-matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) is uncertain in the era of post-transplant cyclophosphamide (PTCy). We re-evaluated the impact of donor age, sex, cytomegalovirus (CMV) serostatus, and ABO compatibility in a large, contemporary cohort of patients receiving PTCy-based graft-versus-host disease (GVHD) prophylaxis.

We retrospectively analyzed 699 patients who underwent an 8/8 HLA-matched MUD HCT with PTCy. We assessed the impact of donor characteristics on overall survival (OS), progression-free survival (PFS), relapse, nonrelapse mortality, GVHD, and engraftment. Least absolute shrinkage and selection operator regression confirmed variable selection.

Recipient-related factors, specifically the disease risk index and HCT-comorbidity index, were the primary determinants of OS and PFS. By contrast, traditional donor characteristics had a limited impact on survival. Donor age, analyzed as a continuous variable, was not associated with OS (hazard ratio [HR], 0.99 [95% CI, 0.978 to 1.011]; P = .524). Similarly, donor CMV and ABO compatibility did not influence survival. The effect of donor-recipient sex mismatch was primarily limited to modulating GVHD risk. Female-to-male sex mismatch had higher hazard for grade 3-4 acute GVHD (aGVHD) (HR, 3.08 [95% CI, 1.15 to 8.20]; P = .025; adjusted P = .222), whereas male-to-female grafts were associated with a 42% reduction in the hazard for grade 2-4 aGVHD (95% CI, 0.39 to 0.87; P = .009; adjusted P = .045). Major ABO mismatch was associated with delayed neutrophil engraftment in bone marrow grafts but not in peripheral blood grafts.

Collectively, these findings suggest that for patients receiving PTCy, the hierarchy of donor selection factors might have evolved, allowing for greater flexibility in donor choice. Our findings provide a solid foundation for future larger external validation studies.