Background Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the standard curative therapy for high-risk hematologic malignancies. Post-transplant viral infections—particularly cytomegalovirus (CMV), Epstein–Barr virus (EBV), and human herpesvirus-6 (HHV-6)—remain the most common infectious complications. Letermovir (LTV) prophylaxis markedly reduces CMV reactivation and disease, yet some Chinese reports suggest it may increase EBV reactivation or post-transplant lymphoproliferative disorder (PTLD). Our center employs a distinctive graft-versus-host disease (GVHD) prophylaxis regimen: post-transplant cyclophosphamide (PTCy) plus tacrolimus for HLA-matched sibling donors (MSD), with additional low-dose anti-thymocyte globulin (ATG) after engraftment for HLA-matched unrelated (URD) or haploidentical (Haplo) donors. This strategy achieves low rates of acute and chronic GVHD. In this study we assessed the impact of LTV prophylaxis on CMV, EBV, and HHV-6 reactivation and related outcomes based on the specific GVHD prophylaxis setting.

Methods We performed a single-center, retrospective cohort study of 300 consecutive adult patients who underwent first allo-HSCT at Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, between September 2019 and June 2024. All donor-recipient pairs were CMV-seronegative, GVHD prophylaxis consisted of PTCy 40 or 50mg/kg on days +3 and +4, followed by tacrolimus from day +5; URD or haplo donor grafts received ATG 2.5mg/kg after 72 hours after neutrophil engraftment. From 2022 onward, LTV 480mg once daily was administered from engraftment to day +100 as standard of care. Clinical, laboratory and virologic data were collected through day +100 and at last follow-up (median 791 days; range 102–1,186). Primary endpoints were 100-day cumulative incidence of CMV, EBV and HHV-6 DNAemia; secondary endpoints included viral disease, non-relapse mortality (NRM), overall survival (OS) and disease-free survival (DFS). Multivariate Cox proportional hazards regression was performed; variables with p<0.20 in univariate screening were retained in the final model.

Results The median age of all enrolled patients was 38 years (18-65). Two-hundred-six patients did not receive LTV prophylaxis (pre-LTV group) and 94 received LTV (LTV group). Baseline characteristics were balanced between the two groups except for donor type (MSD 13.6 % vs 7.4 %, URD 5.8% vs 16.0%, Haplo 80.6% vs 76.6% p=0.008) and dose of PTCy (100 mg/kg 69.9% vs 26.6 %, p<0.001). Overall the day-100 II-IV aGVHD and III-IV aGVHD were 14.4% ± 2.0% and 3.0% ± 1.0% respective. The incidence of cGVHD and moderate to chronic cGVHD were 39.4% ± 2.9% and 14.0% ± 2.0% respectively. There was no difference of aGVHD and cGVHD in the pre-LTV and LTV group.

LTV prophylaxis markedly reduced 100-day CMV DNAemia (23.4 % vs 57.8 %, p<0.001) and CMV disease (0 % vs 6.3 %, p=0.02) without increasing late CMV reactivation after day +100 (19.3 % vs 11.3 %, p=0.21). EBV DNAemia was also lower in the LTV group (2.1 % vs 6.8 %, p=0.03) and there was no significant difference in the incidence of PTLD (2.1% vs. 1.0%, p=0.42). HHV-6 reactivation (33.3 % vs 39.7 %, p=0.37) and HHV-6 disease events (1 vs 4, p=0.58) were comparable. Multivariable analysis identified that haploidentical donor as an independent risk factor for CMV DNAemia (HR 2.54; 95 % CI 1.57–4.13; p<0.001), whereas LTV prophylaxis remained strongly protective (HR 0.41; 95 % CI 0.27–0.62; p<0.001). At 2 years,

In subgroup analysis of Haplo and URD recipients, the 100-day cumulative incidence of CMV DNAemia was 62.9%±3.6% in the pre-LTV group versus 24.1% ± 4.6% in the LTV group（p<0.001), after day+100, no differences of CMV DNAemia were observed. As to the EBV and HHV-6, there was no significant differences between LTV and pre-LTV group in reactivation, PTLD and disease.

Overall, the NRM was significantly lower in the LTV group (4.3 % vs 14.2 %, p=0.01), yielding superior OS (94.5 % vs 79.9 %, p=0.004) and DFS (83.9 % vs 73.7 %, p=0.008), while the relapse incidence did not differ (p=0.64).

ConclusionsIn the context of PTCy, tacrolimus and low-dose ATG as GVHD prophylaxis, LTV effectively prevents early CMV infection without increasing the risk of EBV reactivation or PTLD. These findings support LTV as an effective antiviral prophylaxis in allo-HSCT and suggest its use contributes to improved transplantation outcomes.

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2025
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