Choosing Between HLA-Mismatched Unrelated and Haploidentical Donors: Donor Age Considerations

Haploidentical donors and HLA-mismatched unrelated donors (MMUDs) are increasingly utilized for hematopoietic cell transplantation (HCT), with post-transplantation cyclophosphamide (PTCy) emerging as an effective graft-versus-host disease (GVHD) prophylaxis strategy. Despite the growing use of these donor types, comparative data to guide donor selection remain limited. Donor age is a known predictor of HCT outcomes, yet its specific impact when choosing between haploidentical and MMUD donors with PTCy-based prophylaxis has not been thoroughly explored. This study aimed to evaluate the influence of donor age on HCT outcomes in patients receiving haploidentical or MMUD HCT with PTCy-based GVHD prophylaxis, hypothesizing that younger donors (<30 years) would be associated with improved outcomes compared to older donors (≥30 years) regardless of donor type. We conducted a retrospective analysis of 7116 patients with hematologic malignancies from the Center for International Blood and Marrow Transplant Research database, transplanted between 2013 and 2021. Donors were categorized into four groups: younger haploidentical (<30 years), older haploidentical (≥30 years), younger MMUD (<30 years), and older MMUD (≥30 years). The primary outcome was GVHD-free relapse-free survival (GRFS), defined as the absence of grade III to IV acute GVHD, chronic GVHD requiring systemic immunosuppressive therapy (IST), relapse, or death. Secondary outcomes included overall survival, treatment-related mortality (TRM), relapse, grade III to IV acute GVHD, overall chronic GVHD, and chronic GVHD requiring IST. Comparisons were made between (1) younger MMUD versus older haploidentical and (2) younger haploidentical versus older MMUD groups using multivariable Cox proportional hazards models. In multivariable analysis, the older MMUD group exhibited inferior GRFS (hazard ratio [HR] 1.20; 95% confidence interval [CI], 1.06 to 1.36; P = .003), higher TRM (HR 1.49; 95% CI, 1.13 to 1.96; P = .005), and increased grade III to IV acute GVHD (HR 2.88; 95% CI, 1.43 to 5.80; P = .003) compared to the younger haploidentical group. The younger MMUD group had modest GRFS improvement over the older haploidentical group (HR 0.87; 95% CI, 0.78 to 0.98; P = .02) and significantly reduced risks of grade II to IV acute GVHD (HR 0.67; 95% CI, 0.51 to 0.88; P = .003) and chronic GVHD (HR 0.78; 95% CI, 0.65 to 0.94; P = .009). Younger donor age is associated with superior HCT outcomes, emphasizing the importance of prioritizing donors aged <30 years regardless of donor type when feasible.