C042 | DECIPHERING THE DYNAMICS OF CYTOMEGALOVIRUS-SPECIFIC T CELLS BY DEXTRAMERS AFTER ALLO-HSCT WITH PT-CY AND LETERMOVIR PROPHYLAXIS

Letermovir (LTV) prophylaxis after allogeneic-hematopoietic stem cell transplantation (allo-HSCT) has reduced the incidence of Cytomegalovirus (CMV) clinically relevant reactivations (CRE). CMV-specific T cells protect patients against CRE, but the driver of their emergence need to be explored, especially in the setting of LTV and post-transplant cyclophosphamide (PT-Cy). We analyzed 42 adult patients with hematological malignancies undergoing allo-HSCT with PT-Cy and calcineurin inhibitor-free GvHD prophylaxis in a single-center observational study. Fifteen patients received LTV in the first 100 days after HSCT. Host/donor CMV-serostatus was pos/pos in 24 patients and pos/neg in 18. The graft source was either mobilized peripheral blood from matched-unrelated (n=28), mismatched-related (n=7) or matched-related (n=4) donor, or cord blood (n=3). CMV-specific CD8+ T cells were quantified by flow cytometry using Dextramer® CMV-Kit (IVDR, Immudex) in PBMC frozen 90 (D90) and 180 (D180) days after allo-HSCT, and protective anti-viral immunity was defined based on a previously-identified threshold of 0.5 CMV-specific cells/ul. The incidence of CRE and overall CMV reactivations within D180 was lower in LTV than in no-LTV patients (CRE p=0.0067, reactivation p=0.0080). CMV-specific T cells were enriched from D90 to D180 in the overall population (p=0.02) and in patients treated with LTV (p=0.03) or receiving CMV-seronegative graft (p=0.03) (Figure 1A-B). In univariate tests, the presence of protective CMV-specific immunity was associated with LTV (D90, p=0.042, Figure 1C) and previous CMV reactivation (D90 p<0.001, D180 p=0.005), with a trend for donor CMV serostatus at D180 (p=0.058). Multivariate analysis confirmed the positive correlation with previous CMV reactivation for both timepoints (D90 p=0.004, D180 p=0.009). Interestingly, for D180 this correlation was significant only when the occurrence of CMV blips was included. In this study we quantified CMV-specific T cells by a IVDR kit, which provides reproducible and fast results, and we showed a delayed reconstitution of CMV-specific T cells after allo-HSCT with LTV. Interestingly, while our data underscore the role of antigen exposure in the expansion of these cells, they also show that CMV-specific immunity can be elicited also in the absence of CMV reactivation. The definition of the stimuli driving this emergence might allow the identification of patients who mostly benefit from extended LTV prophylaxis.