Patterns of CMV Infection After Letermovir Withdrawal in Recipients of Post-Transplant Cyclophosphamide Based Transplant.

Reactivation of latent cytomegalovirus (CMV) is increased in CMV seropositive (CMV+) recipients of allogeneic hematopoietic cell transplantation (allo HCT) using post-transplant cyclophosphamide (PT-Cy) based graft versus host disease prophylaxis. Letermovir, a novel DNA terminase complex inhibitor, reduces the incidence of clinically significant CMV infection (csCMVi) in this population; however, parameters that predict csCMVi after letermovir withdrawal are not well described. Here, we examined clinical and immunological parameters in 294 recipients of PT-Cy based allo HCT, including 157 CMV+ patients of whom 80 completed letermovir prophylaxis without csCMVi, and subsequently stopped letermovir. In this population, the median duration of letermovir exposure was 203 days (interquartile range (IQR): 160 - 250 days). After letermovir withdrawal, the 90-day cumulative incidence of csCMVi was 23.0% (14.3 - 32.8). There were no episodes of CMV end-organ disease. Hypo-gammaglobulinemia prior to letermovir discontinuation was predictive of csCMVi (hazard ratio: 0.33, 95% confidence interval: 0.12-0.93, p = 0.03), whereas T-cell and B-cell reconstitution prior to letermovir withdrawal were not predictive of csCMVi. Higher numbers of NK cells were found prior to letermovir withdrawal in patients that experienced csCMVi (median 202 versus 160, p = 0.03). In CMV+ recipients, CD3+CD4-CD8+ T-cell reconstitution was faster in CMV+ patients regardless of letermovir exposure. Taken together, these data suggest that csCMVi after letermovir withdrawal was frequent in patients treated with PT-Cy, despite prolonged exposure. Strategies to boost CMV specific adaptive immunity in patients with persistent hypo-gammaglobulinemia is a logical pathway to reduce csCMVi after letermovir withdrawal.