Donor leukocyte telomere length emerges as a prognostic factor for transplantation outcomes.

Younger donors are preferred in allogeneic hematopoietic stem cell transplantation (allo-HSCT), but this preference may limit access for patients whose only available donors are older. This study evaluated whether donor leukocyte telomere length (LTL), in conjunction with donor age, refines donor selection strategies to improve outcomes in recipients with acute leukemia. The discovery analysis included 1,049 acute leukemia patients who underwent allo-HSCT at the First Affiliated Hospital of Zhejiang University School of Medicine, while the replication cohort included 153 recipients from three additional centers. Donor LTL was measured using real-time quantitative PCR and categorized into quartiles: short (Q1) and long (Q2-Q4). Donor age was prespecified as <40 (younger) vs. ≥40 (older) years based on clinical practice. Long donor LTL was associated with a lower cumulative incidence of relapse (CIR), improved overall survival (OS), and better relapse-free survival (RFS) in allo-HSCT recipients. Recipients of grafts from donors aged ≥40 years with short LTL had higher CIR (adjusted hazard ratio [aHR] = 1.51; 95% confidence interval [CI], 1.04-2.19), worse OS (aHR = 1.76; 95% CI, 1.20-2.58), and worse RFS (aHR = 1.53; 95% CI, 1.06-2.20) compared with recipients of grafts from donors <40 years. Immune cell profiling showed that older donors with short LTL had more CD8+CD57+HLA-DR- cells. In the replication cohort, recipients of grafts from older donors with long LTL had outcomes comparable with those of recipients with younger donors, while those with older donors and short LTL had inferior outcomes. These findings support considering donor LTL as a supplemental factor during donor evaluation, especially when younger donors are not available.