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

Abstract

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. Clinical Trials Registration. NCT04412811.

Keywords: allogeneic hematopoietic stem cell transplant; epidemiology; human cytomegalovirus; letermovir prophylaxis; survival.

Figure 1.

A, The cumulative incidence of clinically significant human cytomegalovirus (CS-HCMV) infections at 100 d and 180 d in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients who received letermovir primary prophylaxis (LET-PP) was 3.8% and 16%, respectively. The low rate of infections during the prophylaxis period was balanced by a rebound of infections in the late posttransplant phase, when prophylaxis was discontinued. B, The cumulative incidence of CS-HCMV infections at 100 d and 180 d in allo-HSCT recipients who did not receive LET-PP was 14% and 17%, respectively, with infections occurring mainly in the early period after transplant. Abbreviations: CI, confidence interval; CS-HCMV, clinically significant human cytomegalovirus; Cum Inc., cumulative incidence.

Figure 2.

Cumulative incidence of clinically significant human cytomegalovirus (HCMV) infections at 6 mo from transplant in seropositive allogeneic hematopoietic stem cell transplant recipients who received letermovir primary prophylaxis (LET-PP) according to donor HCMV serology (P value univariate model). Transplant from a HCMV-seronegative donor was characterized by a significantly higher rebound of infections in the late posttransplant phase, when LET-PP was discontinued, compared to transplant from a seropositive donor. During prophylaxis, there was no difference in the incidence of clinically significant HCMV infections in the 2 groups. Abbreviations: CS-HCMV, clinically significant human cytomegalovirus; D⁺, donor seropositive; D^–, donor seronegative; R⁺, recipient seropositive.

Figure 3.

Cumulative incidence of clinically significant human cytomegalovirus (CS-HCMV) infections in allogeneic hematopoietic stem cell transplant recipients who did not receive letermovir primary prophylaxis (LET-PP) according to recipient/donor HCMV serology (P value univariate model). Seropositive patients who did not receive LET-PP (in most of cases being ineligible to LET-PP as they were <18 y of age) experienced several early CS-HCMV infections in the absence of LET-PP. Abbreviations: CS-HCMV, clinically significant human cytomegalovirus; D⁺, donor seropositive; D^–, donor seronegative; R⁺, recipient seropositive; R^–, recipient seronegative.