Real-World Off-Label Use of Letermovir Prophylaxis for Cytomegalovirus Prevention in Non-Kidney Solid Organ Transplant Recipients: Outcomes, Safety, and Review of Literature

Introduction: Cytomegalovirus (CMV) causes substantial morbidity after solid organ transplantation. Valganciclovir (VGCV) remains a first-line prophylactic agent, but it has significant myelosuppressive effect. Letermovir is approved for CMV prophylaxis in high-risk kidney transplant recipients, but data on its use outside of that population are limited. We describe characteristics and outcomes of letermovir prophylaxis in non-kidney transplant recipients. Methods: We performed a retrospective, multi-center study of all adult non-kidney solid organ transplant recipients (SOTr) who received letermovir (March 2018–June 2024) for CMV prophylaxis. Outcomes included breakthrough and post-prophylaxis delayed-onset CMV infections, adverse events, and survival. Results: A total of 64 patients were included in the final analysis. Of those, letermovir was used for primary prophylaxis in 56.2% of patients, while the remainder received it for secondary prophylaxis. The main rationale behind selecting letermovir was myelosuppression related to VGCV. During the median follow-up of 361 days (IQR, 190–536), 40.6% remained on letermovir (median, 387 days); 25.0% completed prophylaxis (median, 116 days); and 34.3% discontinued prematurely (median, 49 days), mainly for cost barriers or adverse effects. Breakthrough infections occurred in 9 patients (14.1%), but only three (4.7%) were clinically significant. After stopping letermovir, 39.5% (15/38 among those who discontinued letermovir) developed post-prophylaxis delayed-onset CMV infection. Overall survival was 81.2%; there was one death attributed to CMV. Conclusion: In this cohort of non-kidney solid organ recipients, letermovir was well tolerated with low rates of clinically significant breakthrough infections. Early discontinuation was commonly cost-driven. Post-prophylaxis delayed-onset CMV infections remain common. Large-scale registry studies are needed to provide evidence for use of letermovir in non-kidney transplant recipients.