Post-prophylaxis CMV in the letermovir era: Incidence, risk factors, and outcomes following HCT.

6561 Background: Cytomegalovirus (CMV) is a major infectious complication after allogeneic hematopoietic cell transplantation (HCT). Letermovir prophylaxis (ppx) effectively reduces clinically significant CMV infection (csCMVi) within 100 days, but csCMVi after ppx discontinuation occurs in 7–16%. Extended letermovir ppx has been proposed for high-risk patients, though optimal patient selection is uncertain. Our study aims to define the incidence, risk factors, and outcomes for post-ppx csCMVi to guide extended ppx strategies. Methods: We analyzed adult CMV-seropositive (+) HCT recipients at Cleveland Clinic who received ≥45 days of Letermovir primary ppx between 1/1/2018-12/31/2024. The primary outcome was post-ppx csCMVi, defined as CMV disease or asymptomatic viremia requiring preemptive therapy. Secondary outcomes included overall and non-relapse mortality. Patients with csCMVi during standard ppx were excluded. Associations with csCMVi were evaluated using competing-risk models accounting for mortality, with multivariable Cox analyses adjusting for age, sex, Karnofsky score. Results: Among 311 CMV+ recipients of HCT, 62% were donor-CMV negative and 50% were male. Median age was 59 (47-67) years. HCT was most commonly for AML (48%), with matched unrelated donors (54%), peripheral blood graft (76%), myeloablative conditioning (45%), and GVHD ppx with post-transplant cyclophosphamide (PTCy) (63%). Grade ≥2 acute GVHD (36%), chronic GVHD (53%), and relapse (22%) were common in the cohort. Post-ppx infection occurred in 64 patients (21%), including 8 (13%) with tissue-invasive disease. Median duration of Letermovir was 75 days, typically initiated on day 28 post-transplant. Median time to csCMVi was 123 days from transplant. Cumulative incidence of post-ppx csCMVi was 9% at 60 days, 11% at 90 days, and 12% at 180 and 360 days. Risk factors included older age (HR 1.04 per year, 95% CI=1.01-1.07, p=0.014), female sex (HR 3.3, 95% CI=1.5-7.1, p=0.003), chronic GVHD (HR 9.9, 95% CI=1.2-5.6, p=0.024), and GVHD treated with steroids (HR 9.86, 95% CI=1.4-71.5, p=0.024) or ruxolitinib (HR 2.8, 95% CI= 1.3-6.3, p=0.011). Primary disease, donor CMV status, donor relationship, graft source, conditioning intensity, ATG, and PTCy were not associated with csCMVi. All-cause mortality was high in the cohort (37%), particularly in the late csCMVi group (52%). Post-ppx csCMVi was associated with increased non-relapse (HR 2.36, 95% CI= 1.37-4.07, p=0.002) and overall mortality (HR 2.41, 95% CI= 1.43-4.06, p<0.001) in multivariable analysis adjusted for age and sex. Conclusions: Late csCMVi occurs in 12% of CMV+ HCT recipients after prophylaxis discontinuation and may confer additional mortality risk. These findings support risk-adapted surveillance and extended prophylaxis in high-risk groups, particularly recipients who are older, female, and have chronic GVHD requiring immunosuppression.