Letermovir Primary Prophylaxis in Preventing Cytomegalovirus (CMV) Reactivation in Ex-Vivo Tcrαβ-Depleted Haploidentical Allogeneic Haematopoietic Cell Transplantation with Memory T Cell Add-Back
Authors: Boo Ao Ran , Yuen Yi Ching , Woon Chin Menn , Poon Michelle , Tan Lip Kun , Lee Joanne Shu Xian , Ling Victor , Linn Yeh Ching , Than Hein , LIM Zi YI , Diong Colin Phipps , Koh Liang Piu 
Published: December 2024

BACKGROUND
Cytomegalovirus (CMV) is a common cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT), especially with T-cell depleted (TCD) haploidentical HCT (haplo-HCT). The use of letermovir (LET) for CMV prophylaxis has been shown to reduce clinically significant CMV infection (cs-CMVi), but its beneficial effect on non-relapse mortality (NRM) in the setting of haplo-HCT remains undefined. In this multicenter retrospective real-world study, we analysed patients who underwent haplo-HCT using ex-vivo TCRαβ+ depleted graft, with upfront add-back of CD45RA+ depleted memory T cells, (Ref: Koh LP et al, Blood 2022; 140:4707-8), to study the impact of LET prophylaxis on NRM and survival.
METHODS
Between January 2017 and December 2023, 148 CMV seropositive patients (median age 54 years, range 18-70) with various haematological malignancies received TCRαβ+ depleted haplo-HCT using myeloablative (N=2) or reduced toxicity conditioning (N=146), followed by post-transplant pharmacologic immunosuppression tapering over 1-2 months. We compared the outcome of 75 patients who received LET prophylaxis for the first 3 months of the HCT versus 73 patients who were on the standard pre-emptive therapy (PET) approach (no LET prophylaxis). The primary endpoint was the incidence of clinically significant CMV infection (cs-CMVi) by day 180. Secondary endpoints were the cumulative incidence of NRM, relapse, 3-year overall survival (OS) and event free survival (EFS).
RESULTS
Baseline clinical characteristics were comparable between the 2 cohorts, with the exception that the LET cohort had higher proportion of seronegative donors (49% vs 10%; p&lt;0.001) and HCT Comorbidity Index (HCT-CI) ≥ 1 (63% vs 38%; p=0.005). Overall, 51 patients developed cs-CMVi, with a median onset of 37 days (range, 6-179 days). The day 180 cumulative incidence of cs-CMVi was 34% (95% confidence interval [CI], 26% to 42%) in the entire cohort; 17% (95% CI 9-26) in the patients who received LET prophylaxis, and 52% (95% CI, 40-64) in PET patients (HR 0.25, 95% CI 0.13-0.47; p&lt;0.001). As compared to PET patients, patients given LET prophylaxis experienced a significantly delayed onset of cs-CMVi, at a median time of 100 days (range, 15-179) versus 37 days (range, 6-61) for PET (p&lt;0.001). CMV end-organ disease only occurred in 4 (5%) patients on PET.
In univariate analysis, LET prophylaxis was associated with significantly lower 3-year NRM [ LET 11.7% (95% CI 5.2-19.6) vs PET 20.7% (95% CI 12.3-30.7); HR 0.44, CI 95% 0.19-0.99; p=0.049], which was translated into more favourable 3-year OS [ LET 82% (95% 70.9-89.1) vs PET 65.5% (95% CI 53.4-75.2); HR 0.48, 95% CI 0.26-0.90; p=0.02] and 3-year EFS [ LET 76.4% (95% CI 64.8-84.7) vs PET 58.7% (95% CI 46.5-69); HR 0.48, 95% CI 0.28-0.84; p=0.011]. There was no significant difference in relapse risk between the two cohorts (p=0.12). Notably, the impact of LET prophylaxis remained significant on OS (HR 0.36, 95% CI 0.19-0.69; p=0.002), EFS (HR 0.44, 95% CI 0.25-0.77; p=0.004) and NRM (HR 0.30, 95% CI 0.13-0.72; p=0.007) in the multivariate analyses.
CONCLUSION
As compared to PET strategy, LET prophylaxis effectively reduced the risk of CMV infection in our high-risk patients undergoing ex vivo T-cell-depleted haplo-HCT, and was associated with reduced non-relapse mortality and improved overall and event-free survival. Delayed CMV infection remains a major concern, further studies are needed to identify subgroup of patients who may benefit from extended letermovir prophylaxis.
No conflict of interest to disclose.