Early CMV DNAemia during letermovir prophylaxis predicts lower risk of late CMV infection and is associated with enhanced T-cell immunity after alloHSCT.

CMV-specific immune monitoring may support individualized risk stratification after allogeneic hematopoietic stem cell transplantation (alloHSCT), but its role in the era of letermovir prophylaxis remains unclear. In this prospective single-center study, 45 CMV-seropositive alloHSCT recipients receiving letermovir prophylaxis for 100 days post-transplant were followed for 12 months. CMV-specific T-cell responses to IE-1 and pp65 were assessed by IFN-γ ELISpot on days 100 and 200, and at the time of CMV infection and follow-up. Early CMV infection occurred in 18/45 patients (40%) during prophylaxis, of which 16 (88.9%) were transient "blips" and required no pre-emptive therapy. In univariate logistic regression, early CMV infection was associated a significantly lower risk of late CMV infection (p = 0.0044). IE-1-specific responses at day 100 were significantly higher in patients without late infection (median 27.5 vs. 5.0 SFC/250,000 PBMCs; p = 0.0056), and in those with early CMV infection (p = 0.0351). T-cell responses were already detectable at the time of CMV infection and remained stable thereafter. In conclusion, early abortive CMV DNAemia during letermovir prophylaxis appears to induces rapid and durable T-cell immunity. Immune monitoring may not be required in these patients, whereas ELISpot testing at day 100 may guide risk-adapted management in those without early CMV exposure.