Abstract Background: Donor age is a recognized factor influencing outcomes after allogeneic hematopoietic cell transplantation (allo-HCT), with younger donors often preferred due to better immune reconstitution and graft-versus-leukemia activity. However, in the context of post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis, the effect of donor age remains uncertain. This study aimed to evaluate the impact of donor age on transplant outcomes in unrelated donor allo-HCT recipients receiving PTCy. Methods: A retrospective multicenter analysis was conducted, including allo-HCT patients in the publicly available Center for International Blood and Marrow Transplant Research (CIBMTR) registry from 2017 to 2021 using P5891 data by Shaffer et al. Adult patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) who underwent first unrelated donor allo-HCT and received PTCy-based GVHD prophylaxis were included. Patients were stratified by donor age into two groups: ≤30 years and 30 years. Outcomes assessed included overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), relapse incidence, grade II–IV and III–IV acute GVHD (aGVHD), moderate/severe chronic GVHD (cGVHD), and GVHD-free relapse-free survival (GRFS). Univariable and multivariable Cox proportional hazards or Fine-Gray competing risks models were used as appropriate. Variables with p 0.2 in univariable analysis and clinically relevant factors were included in multivariable models. Analyses were performed using SAS 9.4 and R 4.3.3. Results: A total of 1,897 patients met the inclusion criteria, including 1,227 (65%) who received grafts from donors aged ≤30 years and 670 (35%) from donors 30 years. Baseline characteristics were largely similar between groups, with no differences in disease type (AML 64.5% vs. 65.1%, P=0.858), conditioning intensity (RIC/NMA 62.9% vs. 64.6%, P=0.491), graft source (PBSC 90.5% vs. 90.9%, P=0.822), or comorbidity burden (HCT-CI ≥3 in 52.7% vs. 54.5%, P=0.457). However, recipients of younger donors were more likely to be White (90.3% vs. 84.9%, P=0.001), have a CMV D-/R- serostatus (27.5% vs. 22.5%, P0.001), and receive 8/8 HLA-matched grafts (77.1% vs. 71.5%, P=0.008). At a median follow-up of 35.1 months, 3-year OS was 58.5% in the ≤30 group and 57.2% in the 30 group (P=0.50). The 3-year cumulative incidences of relapse (30% vs. 30%, Gray's P=0.9), NRM (18% for both; P0.9), and GRFS event-free status (46.3% vs. 43.1%, P=0.388) were comparable. Moderate to severe chronic GVHD (10.7% vs. 13.6%, P=0.153) and grade III–IV aGVHD (5.7% vs. 6.6%, P=0.54) were not significantly different. However, grade II–IV acute GVHD at day 100 was higher in the 30 group (30.7% vs. 26.6%, P=0.030). On univariable Cox regression, donor age was not significantly associated with OS (HR 0.95, 95% CI 0.81–1.10, P=0.485), relapse (HR 0.98, 95% CI 0.82–1.17, P=0.838), NRM (HR 0.99, 95% CI 0.79–1.24, P=0.921), or GRFS (HR 0.90, 95% CI 0.79–1.03, P=0.107). Similarly, donor age 30 years was not associated with inferior outcomes compared to ≤30 years in multivariable analysis: OS (HR 0.98, 95% CI 0.84–1.15, P=0.823), RFS (HR 1.00, 95% CI 0.86–1.16, P=0.962), NRM (HR 0.96, 95% CI 0.76–1.21, P=0.712), grade III–IV aGVHD (HR 0.95, 95% CI 0.54–1.67, P=0.786), moderate/severe cGVHD (HR 0.81, 95% CI 0.61–1.06, P=0.128), or GRFS (HR 0.94, 95% CI 0.82–1.07, P=0.358). However, younger donors (≤30 years) were associated with a modestly lower incidence of grade II–IV aGVHD (HR 0.83, 95% CI 0.70–0.99, P=0.039). Conclusion: In unrelated donor allo-HCT with PTCy-based GVHD prophylaxis, donor age greater than 30 years was not associated with differences in overall survival, relapse, non-relapse mortality, chronic GVHD, or GRFS. While older donor age was linked to a modest increase in grade II–IV acute GVHD, this did not impact long-term outcomes. Donor age alone may not be a key determinant of post-transplant outcomes in this setting.
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