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.
Keywords: CMV; CNI; HLA matched sibling donor; Haploidentical; PTCy; calcineurin inhibitor; cytomegalovirus; donor age; post‐transplantation cyclophosphamide.
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