Letermovir Provides Protection Against Clinically Significant CMV Infections in CMV-Seronegative Recipients of an Allotransplant from a CMV-Seropositive Donor
Authors: Letailleur Valentin , Jullien Maxime , Le Bourgeois Amandine , Garnier Alice , Peterlin Pierre , Vantyghem Sophie , Fourmont Aude-Marie , Guillaume Thierry , Chevallier Patrice 
Published: December 2024

Letermovir, an inhibitor of the cytomegalovirus (CMV) DNA terminase complex, has been a major breakthrough for the prophylaxis of CMV infection and disease in recipients of both organ or allogeneic hematopoietic stem cell (allo-HSCT) transplant. It is now approved up to day +200 post-transplant in CMV-seropositive (R+) allo-HSCT patients (pts) whatever the CMV status of the donor and in CMV-negative (R-) recipients of renal transplant from a a CMV-positive donor (D+). Little is known however about letermovir efficacy in a D+/R- situation after allo-HSCT. Here, a retrospective monocentric study is presented, that aimed at demonstrating that letermovir could be of benefit this context. As D+/R- Allo-HSCT may represent a risk of CMV reactivation, infection or disease post-transplant, some D+/R- pts in our department have been proposed letermovir as part of a local practice. A retrospective analysis of Allo-HSCT performed between January 2015 and December 2023 allowed to retrieve 49 CMV D+R- cases. The incidence of CMV clinically significant (CS) infections (requiring antiviral treatment or resulting in CMV disease) was then compared, according to the use of letermovir or not. High-risk CMV patients were defined as per Marty et al. (NEJM 2017), i.e. unrelated donor with at least one mismatch at one of the HLA gene loci HLA-A, B, C, and DRB1, haploidentical donor or acute graft-versus-host disease (aGVHD) of grade 2 or greater that led to the use of 1 mg/kg or more of prednisone (or its equivalent) daily. Univariate and multivariate analyses were performed using R version 4.2.2 in July 2024.

Among the 49 D+/R- pts retrieved, 15 (median age 56 years, median follow-up [FU] 86.1 months [interquartile range, IQR] 35.6-88.4) were treated with letermovir while 34 (median age 56 years, median FU 16 months [IQR 14.6-19.2]) did not receive CMV prophylaxis. There was no statistically significant difference between the two groups in terms of age, gender, disease, donor type, conditioning, high-risk of CS CMV infections and steroid-treated aGVHD incidence.

In the letermovir group, no CS CMV infection was documented. Conversely, in the absence of prophylaxis, 7 CS CMV infections were observed, including 1 CMV-related meningoencephalitis, at a median time of 44 days post-transplant. The 1-year cumulative incidence of CS CMV infections was thus 0% in the letermovir group vs 19% (95% confidence interval [CI] 4-31) in the group without letermovir (p=0.08). Comparable cumulative incidences of CS CMV infections were observed between pts who received steroid for aGVHD (14%; 95%CI 0-28) or not (12%; 95%CI 0-23, p=0.8), and patients with haplo/mis-matched unrelated donors (12%; 95%CI 0-26) vs other donors (13%; 95%CI 0.3-25, p=0.9). The use of letermovir was not associated with overall (p=0.13) nor disease-free (p=0.11) survival, non-relapse-mortality (p=0.15), nor cumulative incidence of relapse (p=0.6). Also, letermovir was not associated with significant toxicity. Given the low number of CMV events, a bootstrap resampling approach was used, combined with Cox regression, to evaluate the effect of letermovir on CS CMV infections incidence in a multivariate analysis, considering notably other factors such as aGVHD (as a time-dependent covariate) and donor type (matched vs haplo/mismatched unrelated donor). With this approach, the use of letermovir was the sole factor found to be highly significantly protective for CS CMV infections (Hazard Ratio: 2.55 10-9, 95%CI: 4.38 10-10-3.77 10-9, p=0.001).

As for renal transplant, letermovir therefore appears to provide an efficient non-toxic protection against CS CMV infections in D+/R- allo-HSCT. Larger cohorts and comparative prospective studies are needed to confirm these results.