To the Editor: Cytomegalovirus (CMV) infection remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, particularly in high-risk populations with human leukocyte antigen (HLA) mismatch, haploidentical donors, or intensive conditioning regimens.1 Letermovir, a selective inhibitor of the CMV terminase complex, has demonstrated efficacy in reducing CMV reactivation in phase 3 trials.2 However, the optimal time for initiating letermovir prophylaxis post-transplantation remains unclear, with clinical practices varying widely between institutions. Here, we report a multicenter retrospective study evaluating the impact of letermovir initiation timing on clinically significant CMV infection (csCMVi) in high-risk patients with allo-HSCT. This retrospective study included 488 adult patients with hematological malignancies who underwent allo-HSCT at four Chinese tertiary hospitals including (1) Department of Hematology, the First Affiliated Hospital of Zhengzhou University (n = 182); (2) Hematology Institution of Ruijin Hospital, Shanghai Jiao Tong University (n = 195); (3) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (n = 82); and (4) Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (n = 29) between January 2022 and March 2024. High risk for CMV infection is defined as meeting one or more of the following criteria: Having a haploidentical donor, using cord blood as the source of stem cells, a conditioning regimen of post-transplant cyclophosphamide (PT-Cy) or a regimen containing an antithymocyte globulin, having an unrelated donor with at least one mismatch at one of four specified HLA gene loci (HLA-A, B, C, and DRB1), patient aged 40 years or older, use of at least 1 mg/kg/per day of prednisone (or its equivalent) for not 500 IU/mL) requiring preemptive therapy or CMV end-organ disease.4 Cumulative incidences of csCMVi were compared using fine-gray regression (death as a competing risk). Multivariate Cox proportional hazards models were used to identify independent predictors of csCMVi-free survival. Statistical analyses were carried out using SPSS software (version 22.0, Chicago, IL,USA) and GraphPad Prism (ver. 5.0, La Jolla, CA, USA). Two-sided P value of 0.05). The median follow-up time of this study was 180 days (range: 90–360 days). At day+30 after allo-HSCT, nine patients in the early initiation group developed CMV viremia (9/354), which was significantly reduced when compared with the late initiation group (24/134) (2.5% vs. 17.9%, P <0.0001). Both groups had no CMV disease occurring at day +30 after transplantation Supplementary Table 1, https://links.lww.com/CM9/C907. Among the 354 patients in the early initiation cohort, the rate of CMV viremia at day+100 was 4.8% (17/354). Only one case in this group developed CMV pneumonia at day+100. Among the 134 patients who received letermovir prophylaxis beyond day +14 after allo-HSCT, 41 cases developed CMV viremia at day +100 after allo-HSCT, accounting for 30.6%. However, there was no CMV disease occurred in the late initiation group. The incidence of CMV viremia at day+100 was significantly reduced in the early initiation cohort compared with that in the late initiation group (P <0.0001). However, there was no remarkable difference between the two groups in terms of CMV disease. The cumulative incidence of csCMVi at 100 days after allo-HSCT among the early initiation cohort was 5.1% (18/354), and it was significantly lower than in patients receiving letermovir beyond +14 days after allo-HSCT (30.6% 41/134, P <0.0001) Supplementary Table 1, https://links.lww.com/CM9/C907. Among the early initiation group, 33 patients developed CMV viremia at day+180 after allo-HSCT, which was significantly lower than that in the late initiation group (9.3% 33/354 vs. 34.3% 46/134, P <0.0001). Furthermore, CMV disease occurred on 14 patients in the early initiation group and two cases in the late initiation group, with no significant difference (4.0% vs. 1.5%, P = 0.173) Supplementary Table 1, https://links.lww.com/CM9/C907. Regarding refractory CMV infection, defined as CMV viremia that persisted or recurred despite appropriate antiviral therapy, the cumulative incidence in the early initiation group was 5.9% (21/354) and in the late initiation group was 11.9% (16/134) (P = 0.025). No significant differences were observed in overall survival (OS), nonrelapse mortality (NRM), or GVHD incidence between groups Supplementary Table 1, https://links.lww.com/CM9/C907. Adverse events, including gastrointestinal symptoms and liver enzyme elevations, were mild and comparable across groups. Notably, there was no excess in nephrotoxicity or myelosuppression in the early initiation group. Letermovir is an important addition to the anti-CMV armamentarium and has the potential to induce a paradigm shift in preventing CMV manifestations after allogeneic HSCT. Hopff et al3 highlights the preventive effects of letermovir on csCMVi after allo-HSCT. The incidence of csCMVi after allo-HSCT was significantly reduced in the letermovir (34%, n = 68) compared with the control group (56%, n = 112; P <0.001). Furthermore, patients receiving letermovir showed significantly better survival compared with the control group (hazard ratio HR = 1.735, 95% confidence interval CI 1.111−2.712; P = 0.014).3 In addition, Marty et al2 reported that fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary endpoint event by week 24 after allo-HSCT (122 of 325 patients 37.5% vs. 103 of 170 60.6%, P <0.001).2 In our current study, the incidence of CMV reactivation at day +180 in late initiation group is 34.3%, which was in line with the above results obtained in the two main prospective clinical trials conducted in this field and with those from single-center studies conducted in different transplant institutions, indicating that letermovir is an effective drug for the prevention of CMV reactivation in the allo-HSCT setting.5,6 However, the incidence of csCMVi was still high after letermovir prophylaxis. This landscape highlights the critical need to identify the optimal time for letermovir initiation that could further reduce the incidence of CMV in recipients at risk of csCMVi. So far, the timing of initiating letermovir prophylaxis remains unclear. At Memorial Sloan Kettering Cancer Center, letermovir was started on day +7 for higher-risk HSCT recipients, as defined in the phase 3 clinical trial, and by day +28 for lower-risk patients, based on differences in time to CMV reactivation.7 At Fred Hutchinson Cancer Center, letermovir was initiated on day +2 for higher-risk umbilical cord blood transplant (UBCT) setting, on day +7 for higher-risk HSCT recipients, and by day +28 for lower-risk patients. Nevertheless, letermovir was given to all patients on day +7, regardless of risk stratification at City of Hope National Medical Center. Taken together, multiple studies have shown that most high-risk patients initiate prophylaxis within 10 days after transplantation, and their incidence of CMV infection is significantly lower than that of the control group.8–10 A study from Italy demonstrated that early initiation of letermovir prophylaxis reduces CMV-positive PCR results. Patients who started letermovir prophylaxis on days 0–1 after transplantation had a lower proportion of patients with at least one positive PCR result compared with those who started prophylaxis later after transplantation (days 2–27) (14.8% vs. 45.8%, P = 0.01).11 Interestingly, in our study, patients using letermovir starting at day +1 had remarkably lower incidence of CMV viremia compared with patients starting beyond day +14, regardless of the incidences at days +30, +100, and +180. This may be attributed to the rapid CMV reactivation kinetics in immunocompromised hosts, where delays in therapy could allow viral replication to surpass critical thresholds. However, there was no significant difference in terms of OS and NRM. This may be related to the fact that letermovir induced a protective effect on CMV reactivation risk, but its use was not associated with a significant reduction of CMV disease due to timely use of preemptive antiviral therapy. In conclusion, our study proved that early initiation of letermovir could significantly further reduce the incidence of csCMVi after allo-HSCT. However, it is crucial to conduct prospective controlled studies to thoroughly investigate the efficacy and safety of early initiation of letermovir in different transplantation scenarios. Further studies are warranted to validate these findings and elucidate the mechanisms underlying these new insights. Acknowledgments The authors sincerely thank Ms. Qiong Jiang for her scientific support. Funding This study was supported by grants from the National Natural Science Foundation of China (Nos. 81900181 and 82370219). Conflicts of interest None.
Zhang et al. (Mon,) studied this question.