Introduction: Cytomegalovirus (CMV) reactivation remains a significant complication following allogeneic hematopoietic-cell transplantation (allo-HCT), particularly in regions with high CMV endemicity. Letermovir, a CMV-specific antiviral agent, has emerged as a promising prophylactic strategy to mitigate CMV-related morbidity and mortality. This study presents real-world evidence evaluating the effectiveness of letermovir prophylaxis among allo-HCT recipients in high endemic settings.

Method:

This was a retrospective cohort study conducted at a tertiary transplant center in a region with high CMV endemicity. The study included adult patients who underwent allogeneic hematopoietic-cell transplantation (allo-HCT) and were CMV-seropositive prior to transplant. Patients were categorized into two groups:

  • Study Group: Patients at ultra-high risk for CMV reactivation—defined as those who received haploidentical or mismatched transplants, had R+/D− CMV serostatus, or received T-cell depletion with anti-thymocyte globulin (ATG) or alemtuzumab (Campath)—who received letermovir prophylaxis and completed at least one year of post-transplant follow-up.

  • Control Group: Patients with similar risk profiles who did not receive letermovir prophylaxis but completed at least one year of follow-up.

The primary objective was to assess the proportion of patients with clinically significant CMV infection (csCMVi) through Week 24 post-transplant among those without detectable CMV DNA at baseline.

Secondary objectives included:

  • Proportion of patients with csCMVi through Week 14

  • Time to csCMVi through Week 24

  • Transplant-related mortality (TRM)

  • Graft failure

  • Incidence and severity of graft-versus-host disease (GVHD)

Clinical and laboratory data were collected from electronic medical records. CMV DNAemia was monitored using quantitative PCR. Statistical analyses included time-to-event methods and comparative statistics to evaluate outcomes between groups.

Results: A total of 84 patients were included: 43 in the letermovir group and 41 in the control group. The median age was lower in the letermovir group (24 years; range 15–63) compared to the control group (31 years; range 17–63). Male patients comprised 60% of the letermovir group and 43% of the control group.

CMV-seropositive donors were more frequent in the control group (100%) compared to letermovir group (72%). The most common indication for transplantation in the letermovir group was sickle cell disease or thalassemia (58%), while acute leukemia (AML/ALL) was more prevalent in the placebo group.

Donor types were comparable, with haploidentical transplants being the most common in both groups. Peripheral blood was the predominant stem cell source. Reduced-intensity conditioning (RIC) was used more frequently in the letermovir group (60%) than in the control group (46%).

T-cell depletion strategies varied, with higher use of ATG and Campath in the letermovir group, while PTCy was more common in the control group. GVHD requiring steroid treatment occurred in 15 patients in the letermovir group and 12 in the control group.

Clinically significant CMV infection by Week 24 occurred in 37% of the Letermovir group compared to 68% in the control group (p = 0.0051). At Week 14, the rates were 20.5% and 65.8%, respectively (p = 0.0084). CMV recurrence was noted in 2.3% of Letermovir patients and 10% of cotorol patients (p = 0.1965), while CMV disease occurred only in the control group (5%) (p = 0.2352). Transplant-related mortality (TRM) was 11% in the Letermovir group and 7% in the control group (p = 0.7133).

Conclusion: In this real-world retrospective study conducted in a high CMV endemic region, letermovir prophylaxis significantly reduced the incidence of clinically significant CMV infection in ultra-high-risk allogeneic hematopoietic-cell transplant recipients. Patients receiving letermovir demonstrated lower rates of CMV infection at both Week 14 and Week 24 post-transplant, with delayed onset of CMV reactivation and no observed CMV disease. These findings support the effectiveness of letermovir in mitigating CMV-related complications in high-risk populations and reinforce its role as a valuable component of post-transplant antiviral prophylaxis strategies.

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2025
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