Impact of Donor Age and Donor Cytomegalovirus Serostatus on Outcomes After Related Donor Allogeneic Hematopoietic Stem Cell Transplantation

ABSTRACT Cytomegalovirus (CMV) infection post‐hematopoietic cell transplantation (HCT) remains a significant cause of morbidity and mortality. While letermovir prophylaxis is available for CMV‐seropositive recipients, optimal donor selection for CMV‐seronegative recipients remains unclear, with donor age often prioritized over CMV serostatus. We investigated the relative impact of donor age and CMV serostatus in CMV‐seronegative recipients ( n = 1013) with either CMV‐seropositive ( n = 318) or CMV‐seronegative donors ( n = 695), who underwent HCT with HLA‐matched sibling donors with calcineurin inhibitor‐based or post‐transplant cyclophosphamide (PTCy)‐based graft‐versus‐host disease prophylaxis, or haploidentical donors with PTCy. Multiple conventional and machine‐learning approaches were employed to account for confounding factors. Across all analyses, CMV‐seropositive donor status was consistently associated with significantly inferior overall survival (OS) and disease‐free survival, primarily driven by increased non‐relapse mortality (NRM). Older donor age showed a statistically significant association with OS and DFS in some but not all models, and its effect size was small (about 1% increased hazard per year in Cox proportional hazard model) compared to the substantial impact of CMV‐seropositive donors (about 27%–33% increased hazards for worse OS, approximately 50%–60% higher NRM in Cox proportional hazard model). However, our machine learning model revealed a more nuanced and complex non‐linear effect of donor age, further demonstrating the adverse impact of donor CMV serostatus. Our findings suggest that prioritizing a CMV‐seronegative donor may be associated with improved outcomes in CMV‐seronegative recipients. Further research is needed to validate these findings and explore underlying mechanisms.