Letermovir for CMV prophylaxis after haploidentical HSCT: A prospective study of direct and indirect effects

Objective To assess the direct and indirect effects of letermovir in haploidentical hematopoietic stem cell transplantation (HSCT) recipients. Methods This prospective, single-arm study (April 2023 to April 2024) compared 200 haploidentical-HSCT recipients who received letermovir prophylaxis (median follow-up: 359 d) with 440 historical controls who received pre-emptive therapy. Results Of the patients who received letermovir, 15.2% developed breakthrough clinically significant cytomegalovirus infection (csCMVi) by 14 weeks, and 16.5% developed late csCMVi in weeks 14–24. No patients developed CMV end-organ disease by 24 weeks; however, 35.0% developed Epstein–Barr virus infection by 14 weeks. Patients with breakthrough csCMVi had significantly lower CD3⁺, CD4⁺, and CD8⁺ T-cell proportions and higher CD16⁺CD56⁺ natural killer cell proportions at 4 weeks post-HSCT. Patients with late csCMVi had lower lymphocyte counts and T-cell subsets at 14 weeks post-HSCT. Post-HSCT organ dysfunction (hazard ratio [HR]: 2.43, P = 0.033) and letermovir initiation >2 weeks post-HSCT (HR: 2.34, P = 0.035) were independent risk factors for breakthrough csCMVi. Breakthrough csCMVi (HR: 2.14, P < 0.001), elevated CMV DNAemia (HR: 4.12, P < 0.001), and relapsed/refractory csCMVi (HR: 4.62, P < 0.001) were independent risk factors for late csCMVi. Although letermovir was associated with delayed T-cell reconstitution, immune recovery normalized by 14 weeks. Survival benefits were evident at 24 weeks and persisted for ≥1 y. Conclusions High-risk patients warrant enhanced immunological monitoring and extended letermovir prophylaxis. Registration: ClinicalTrials.gov (#NCT05789615).