The Changing Impact of Human Cytomegalovirus Serology and Infection on Patient Outcome after Allogeneic Hematopoietic Stem Cell Transplantation: An Italian Prospective Multicenter Survey in the Era of Letermovir Prophylaxis

Background: In the letermovir primary prophylaxis (LET-PP) era, the epidemiology of human cytomegalovirus infection (HCMV-i) in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients has changed. Methods: We prospectively evaluated incidence and risk factors for clinically significant (CS) HCMV-i at 180 days from transplant and 1-year overall survival in 1310 allo-HSCTs performed from January 2021 to March 2022 according to LET-PP use. Results: The cumulative incidence of CS-HCMV-i at 100 and 180 days from transplant was 3.8% and 16%, respectively, in patients who received LET-PP, and 14% and 17% in patients who did not. Variables associated with increased risk of CS-HCMV-i in patients who received LET-PP included transplant from an HCMV-seronegative donor, transplant from a donor other than matched related, >20 days to engraftment, and acute graft-versus-host disease (GVHD). Transplant in HCMV-seropositive recipients was associated with increased risk of CS-HCMV-i in patients who did not receive LET-PP. One-year overall survival after transplant was 81.1%. Acute leukemia, disease not in remission at transplant, Eastern Cooperative Oncology Group performance status >1, >20 days to engraftment, acute GVHD, CS Epstein-Barr virus DNAemia, gram-negative bacteremia, and invasive fungal disease were associated with increased mortality in patients who received LET-PP. HCMV recipient seropositivity, Hematopoietic Cell Transplantation Comorbidity Index score ≥3, and gram-negative bacteremia were associated with increased mortality in patients who did not receive LET-PP. Conclusions: In patients who received LET-PP, recipient/donor serology no longer correlates with early CS-HCMV-i whereas it still predicts late CS-HCMV-i as well as risk of CS-HCMV-i in patients who did not receive LET-PP. Donor serology, CS-HCMV-i and HCMV disease no longer impact survival in allo-HSCT recipients who receive LET-PP.