The impact of letermovir prophylaxis in matched sibling donor haematopoietic stem cell transplantation: Selecting the appropriate population for optimal prophylactic therapy

Letermovir (LTV) effectively prevents cytomegalovirus (CMV) reactivation in CMV-seropositive patients. To evaluate the impact of LTV in matched sibling haematopoietic stem cell transplantation (HSCT) recipients, we retrospectively compared 72 matched sibling transplantation recipients receiving LTV with 134 controls. LTV significantly reduced 200-day CMV viraemia incidence (5.6% vs. 33.3%, p < 0.001). Multivariable analysis identified anti-thymocyte globulin (ATG) use (p = 0.005) and grade III-IV acute graft-versus-host disease (aGVHD; p < 0.001) as independent risk factors for CMV viraemia, while CMV serostatus did not significantly affect CMV viraemia (p = 0.448). Stratification based on risk factors (ATG, grade III-IV aGVHD) showed that LTV had a more significant effect on high-risk patients compared to low-risk patients. Also, LTV prophylaxis was associated with increased Epstein-Barr virus (EBV) viraemia (13.9% vs. 1.4%, p = 0.025) and higher CD20 monoclonal antibody utilization (11.1% vs. 1.4%, p = 0.046). Long-term survival remained similar between both groups. Results were validated in a second cohort from our centre. In conclusion, LTV prophylaxis significantly reduced CMV viraemia, especially in high-risk patients (ATG/grade III-IV aGVHD). However, the LTV group showed an elevated risk of EBV-related complications. Risk stratification-rather than CMV serostatus alone-should guide CMV prevention strategies in matched sibling HSCT. Larger clinical studies are needed for validation.