Real-World Efficacy and Safety of Letermovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Analysis at a Single Center

Abstract

Introduction Cytomegalovirus (CMV) infection is related with significant morbidity and mortality in the patients undergoing allogeneic hematopoietic cell transplantation (HSCT). Agents used to treat CMV infection can be associated with toxicities including renal impairment or myelosuppression. Letermovir is a novel viral terminase complex inhibitor that has efficacy in preventing clinically significant CMV infection (csCMV) in allogeneic HSCT recipients with minimal associated toxicities. Objectives This study aims to analyze the efficacy and toxicity of letermovir as CMV prophylaxis in patients with allogeneic HSCT. Letermovir was started within 5 days of stem cell infusion and was administered for a total of 100 days or until csCMV or unacceptable toxicity, whichever happens first. CMV monitoring was performed using CMV antigenemia immunocytochemical stain every week from neutrophil engraftment until the immunosuppressive agent discontinuation. Retrospective medical record review was conducted for the patients who received letermovir during allogeneic HSCT in Seoul National University Bundang Hospital. Results From September 2020 to May 2023, a total of 139 patients received letermovir for CMV prophylaxis. Median age of the patients was 54 (range, 19 - 73) years with 76 (54.7%) male patients. Diagnosis for allogeneic HSCT included acute myeloid leukemia (n = 55), acute lymphoblastic leukemia (n = 34), myelodysplastic syndrome (n = 25), lymphoma (n = 6), primary myelofibrosis (n = 5). The patient cohort included 2 aplastic anemia patients, 1 atypical chronic myeloid leukemia, and 1 chronic myelomonocytic leukemia. For our patent cohort, all the recipients were seropositive for CMV. Among the patients, 32 patients (23.0%) received HSCT from matched sibling donor, 36 patients (25.9%) from matched unrelated donor, and 54 patients (38.8%) from haploidentical donor. Rest of the patients received HSCT from mismatched unrelated donor (n = 17, 12.2%). 56 patients (40.3%) underwent myeloablative conditioning regimen. For T-cell depletion, antithymocyte globulin was administered in 133 patients (95.7%). Post-transplantation cyclophosphamide was administered in 9 patients (6.5%). Overall, median time on letermovir was 90 (range, 2 - 158) days. Thirty-three patients (23.7%) discontinued Letermovir before completing planned period. In about half of the cases, the reason for drug discontinuation was related to the underlying hematologic disease, not to the side effects or low efficacy of the drug itself (disease progression, infection, or graft-versus-host disease; n = 16). Eight patients discontinued Letermovir due to adverse events (n = 8): gastrointestinal discomfort in 6 patients, edema in 1 patient, and intolerance in 1 patient. During follow-up period, CMV antigenemia positivity was perceived in 55 patients. Cumulative incidence of CMV antigenemia positivity was 61.1%. Cumulative incidence of csCMV and CMV disease was 25.3% and 8.4%, respectively. Of the 55 CMV positive cases, 11 cases (7.9%) occurred during letermovir prophylaxis. However, only 4 cases required ganciclovir preemptive treatment. The remaining 44 cases occurred after discontinuation of the drug. Nineteen cases needed ganciclovir treatment, including 7 CMV disease cases (5 colitis, 1 retinitis, and 1 pneumonitis). Conclusions Letermovir was effective in CMV prophylaxis and well tolerated. Adherence to the drug was mostly associated with general medical condition including underlying hematologic disease and complication of HSCT. Close monitoring is warranted following discontinuation of CMV prophylaxis.