*Purpose: In the absence of antiviral prophylaxis following Hematopoietic Cell Transplant (HCT), the incidence of clinically significant cytomegalovirus reactivation (cCMV) is 30% in CMV seropositive HCT recipients (CMV R+). At our institution, letermovir prophylaxis through approximately Day 100 is used in CMV R+ high-risk (HR) (cord blood, haplocord) HCT recipients. We hypothesized that clinically nonsignificant CMV reactivation (nCMV) during letermovir prophylaxis may lead to the reconstitution of CMV specific cell-mediated immunity (CMV-IR), which may protect the host against CMV disease after letermovir discontinuation.

*Methods: Blood samples from CMV R+ HR on letermovir were tested by dual color CMV specific IL2/IFNg FLUOROSpot pre-transplant and on Days 100, 182 and 360 post-HCT. Clinical and virologic information were obtained from medical records. cCMV was defined by CMV DNA ≥5000 IU /ml of whole blood.

*Results: Among 64 participants enrolled to date, 43 were eligible for this interim analysis, which included participants with CMV FLUOROSpot results ≥20 IFNg spot-forming cells/10⁶ PBMC at any study timepoint pre- or post-HCT and/or CMV reactivation and follow up ≥100 days post-HCT. The median age was 49 years (range 23-75), 23 were women, 28 were white non-Hispanic, 12 Hispanic, 3 Asian, 1 Black. The most common underlying malignancy was acute myeloid leukemia (n=22), followed by acute lymphocytic leukemia (n=14). 27 participants had early CMV-IR at Day 100 albeit only 17 had detectable CMV DNAemia during prophylaxis. Among participants with early CMV-IR, 4 developed CMV disease at Day >100, 1 cCMV, and 12 nCMV. Acute graft versus host disease (aGVHD) preceded all episodes of CMV disease and cCMV, and 4 nCMV episodes.

Five of the 16 participants with late (Day >100) or no CMV-IR had CMV reactivation during prophylaxis, including 2 participants who developed CMV disease, 3 cCMV, and 13 nCMV. The episodes of CMV disease and cCMV and 5 nCMV were preceded by aGVHD. Interestingly, 4 participants with CMV reactivation while on letermovir prophylaxis, including 2 with CMV disease, did not have early CMV-IR.

*Conclusions: Most CMV R+ HR HCT recipients developed early CMV-IR while on letermovir prophylaxis, presumably in response to CMV reactivation. However, CMV reactivation during letermovir prophylaxis was not always accompanied by viremia and not all documented episodes of CMV reactivation were accompanied by early CMV-IR. aGVHD was an important contributor to symptomatic or asymptomatic cCMV.

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