Clinical impact of Letermovir primary prophylaxis on cytomegalovirus-related complications and 1 survival in hematopoietic cell transplant recipients: Data from a prospective multicenter study in Latin

Abstract Purpose: To compare the incidence of clinically significant cytomegalovirus infection (CS-CMVi), CMV 84 disease (CMV-d) and CMV-related rehospitalization in patients with allogeneic hematopoietic cell transplant 85 (alloHCT) who received letermovir (LET) primary prophylaxis or were managed with preemptive therapy 86 (PET). We further aimed to identify risk factors for overall mortality at day 200 post-HCT. 87 Methods: A prospective, observational, multicenter cohort study was conducted at 9 centers in Argentina from 88 October 2020 to September 2025. Adult CMV-seropositive alloHCT recipients were included and followed 89 through day 200 post-HCT. A propensity score (PS) was used to balance baseline covariates. An adjusted 90 conditional multivariate logistic regression analysis including PS was implemented to identify independent risk 91 factors for 200-day overall mortality. 92 Results: Five hundred and fifty-one patients were included (PET: 346 and LET: 205). CMV seronegative 93 donors, alternative donors, and post-transplant cyclophosphamide administration were compared in PET vs. 94 LET groups: 12.4% vs. 30.7% (p<0.0001), 56.9% vs. 87.3% (p<0.0001), and 51.7% vs. 80.5% (p<0.0001), 95 respectively. High-risk stratification for the development of CMV-d was 88.2% in the PET group compared 96 with 97.1% in the LET group (p=0.0003). CS-CMVi, CMV-d, and CMV-related rehospitalization at day 100 97 post-HCT in the PET vs. LET groups were: 54.3% vs. 7.3% (p<0.0001), 7.5% vs. 0% (p=0.0001), and 37.9% 98 vs. 10.2% (p<0.0001), respectively. Multivariate analysis adjusted for PS identified the following risk factors 99 for mortality: primary graft failure, OR 16.57, 95% CI, 5.23-52.52 (p<0.0001), GvHD with high dose of 100 corticosteroids, OR 1.9, 95% CI, 1.19-3.04 (p=0.007), and lymphopenia < 300/ mm 3 , OR 1.78, 95% CI, 1.10-101 2.89 (p=0.019). LET primary prophylaxis was a protective factor for survival, OR 0.51, 95% CI, 0.29-0.89 (p=0.018). Conclusions: LET primary prophylaxis effectively prevented CMV-related complications, reduced rehospitalizations, and had a benefit on overall survival in seropositive alloHCT recipients.