*Purpose: Patients who are cytomegalovirus (CMV) seropositive (R+) prior to hematopoietic cell transplant (HCT), have a 30% incidence of clinically significant CMV reactivation in the absence of prophylaxis. At our institution, letermovir prophylaxis through approximately Day 100 is used in CMV R+ high-risk (HR) (cord blood, haplocord, haploidentical) HCT recipients. We hypothesized that clinically nonsignificant CMV reactivation during letermovir prophylaxis may lead to the reconstitution of CMV specific cell-mediated immunity (CMV CMI), which may protect the host against CMV disease after letermovir discontinuation.

*Methods: Blood samples from CMV R+ HR HCT recipients on letermovir were tested by dual color CMV specific IL2/IFNg FLUOROSpot pre-transplant and on Days 100, 182 and 360 post-transplant. Clinical and virologic information were obtained from medical records.

*Results: Among 41 participants enrolled to date, 26 were eligible for this analysis, which included participants with CMV CMI defined as ≥20 spot-forming cells/10⁶ PBMC pre or post HCT and follow up ≥80 days post-HCT. The median age was 55.5 years (range 23-75), 14 were women, 15 were white non-Hispanic, nine were Hispanic, 2 Asian and the most common underlying malignancy was acute myeloid leukemia (n=13). Twenty participants had CMV CMI reconstitution at Day 100; including 6 with and 14 without low-level CMV DNAemia, defined as <5000 international units/ml in whole blood quantitative polymerase chain reaction assay, while on letermovir prophylaxis. Among the 20 participants, 14 remained free of clinically significant CMV reactivation for a median (range) of 180 (80;180) days post-letermovir discontinuation, while 6 developed acute graft vs host disease (aGvHD) followed by clinically significant CMV reactivation. 6 participants did not reconstitute CMV CMI at Day 100, one of them had DNAemia while on letermovir. 1 of 6 participants without CMV CMI reconstitution or aGvHD developed CMV disease after letermovir discontinuation. Of the 41 participants, 11 participants had negative CMV CMI <20 spot-forming cells/10⁶ PBMC pre-HCT and remained CMV CMI negative at Days 80 and 180 and did not develop CMV infection.

*Conclusions: High-risk patient populations can reconstitute CMV CMI while on letermovir. 4.5% of CMV R+ participants had no CMV CMI response pre-HCT, consistently lacked CMV CMI response post-HCT and did not reactivate CMV, indicating that patients may be falsely characterized by CMV antibody assay. CMV CMI assays rather than CMV serologies pre-HCT may be a useful tool to guide risk stratification for CMV monitoring and letermovir usage.

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