Letermovir Prophylaxis Reduced Cytomegalovirus Reactivation and Resistance Post Umbilical Cord Blood Transplantation

Abstract

Objective: Umbilical cord blood transplantation (UCBT) has proved to be an effective treatment with its own unique advantages nowadays, while long-lasting immunosuppression and delayed immune recovery make the UCBT recipients susceptible to a range of infections. Human cytomegalovirus (HCMV) is the main cause of viral complications post transplantation, which is associated with poor prognosis. Although the implementation of pre-emptive therapy (PET) has significantly reduced the incidence of CMV disease, the long-time antigenemia and the toxicity of antiviral drug remains challenging and risky. Letermovir (LET), a kind of CMV DNA terminase complex inhibitor, is a relatively new antiviral drug for prophylaxis against CMV and has received positive opinion in adult CMV-seropositive recipients of allogeneic haematopoietic stem cell transplant (allo-HSCT). Nevertheless, the clinical efficacy of LET prophylaxis on CMV reactivation and resistance post UCBT remained unknown. Methods: We retrospectively analyzed 43 UCBT patients with hematological diseases at the First Affiliated Hospital of University of Science and Technology of China between August 2022 and May 2023, who received LET prophylaxis since the first day post transplantation until 100d or CMV reactivation occurred, whichever came first. A historical cohort of 208 UCBT patients also from our transplant center between 2021 and 2022 without LET prophylaxis was compared as control group. The CMV DNA testing was performed using the quantitative real-time PCR (RT-PCR) method and CMV monitoring was examined twice per week for at least 100 days and once a week for at least half a year after UCBT. The 180-day cumulative incidences of CMV reactivation (defined as DNA achieved 500 copies/ml or 1000 copies/ml) and refractory CMV infection (defined as CMV viral load remains the same level or increases after at least 2 weeks of appropriately dosed antiviral therapy) were compared between the two groups. To explore independent predictors of the development of CMV reactivation and resistance, univariate and multivariate analyses were performed by using Fine-Gray proportional hazard regression. Results: The two groups were similar in demographic and transplant characteristics, and in the LET group, patients received LET for a median of 100 days (range, 16-100). The 180-day cumulative incidence of CMV DNA achieved 500 copies/ml and 1000 copies/ml and refractory CMV infection in the LET group were significantly lower than that in the control group [500 copies/ml: 33.8% vs. 78.4%, P < 0.001; 1000 copies/ml: 30.2% vs. 74.0%, P < 0.001; refractory CMV: 4.7% vs. 31.7%, P < 0.001]. Furthermore, multivariate competing risk analysis identified LET prophylaxis as an independent protective factor for CMV reactivation (adjusted hazard ratio [HR] 0.27, 95% CI 0.15 to 0.48, P < 0.001) and refractory CMV infection ([HR] 0.16, 95% CI 0.04 to 0.62, P = 0.004). However no significantly lower incidences of CMV disease (4.7% vs. 8.8%, P = 0.542) and recurrent CMV infection (3.7% vs. 9.6%, P = 0.386) were found in LET group. Among the patients who developed CMV reactivation, there was no significant difference in the time from UCBT to CMV reactivation between two groups (39 days vs. 41 days, P = 0.367). LET prophylaxis was associated with a shorter duration of CMV DNAemia (median 27 days vs. 42 days, P = 0.014), and there was a trend towards lower peak CMV viral load in the LET group (median 2620 copies/ml vs. 5380 copies/ml, P = 0.165). Conclusion: We demonstrated that LET is highly effective at preventing CMV reactivation and resistance after UCBT, and its benefit for UCBT patients perhaps will be observed in a longer-time following time.