Late-phase impact of CMV/EBV reactivation on survival after hematopoietic stem-cell transplantation: a 5-year single-center cohort study

Background Whether simultaneous cytomegalovirus (CMV) and Epstein–Barr virus (EBV) reactivation confers additional late mortality beyond isolated CMV remains controversial. Methods We retrospectively analyzed 202 consecutive first-ever hematopoietic stem cell transplantations performed between 2018 and 2019, using twice-weekly PCR surveillance and uniform preemptive therapy. Cox models were used to estimate hazard ratios (HRs) for overall survival (OS) and leukemia-free survival (LFS) at the 1-, 3-, and 5-year landmarks. Results Although 1-year outcomes were similar, divergence emerged thereafter: 5-year OS was 19.4% with coreactivation, 36.6% with isolated CMV, and 25.1% with no reactivation ( p = 0.041); corresponding LFS was 19.4%, 36.6%, and 25.2% ( p = 0.060). Multivariate analysis identified sustained CMV replication as the dominant late risk factor (OS HR 5.295, 95% CI 1.5888–17.6464; p = 0.0067), whereas coreactivation lost significance because EBV clearance shortened the overall viral window. Interestingly, viral enteritis was identified as an independent adverse predictor of 1-year LFS (HR 6.2453, 95% CI 1.3245–7.2376; p = 0.0010). Conclusions Late mortality is driven by persistent CMV-driven endothelial injury rather than transient EBV coreactivation. Extending PCR surveillance from day 100 to year 2 and targeting chronic low-level CMV should be prioritized to improve long-term transplantation success.