Letermovir Prophylaxis Is Effective in Preventing CMV Reactivation and Is Associated with Decreased Non-Relapse Mortality in Two-Step Allogeneic Stem Cell Transplantation

Background

Allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients are at increased risk for a variety of infections, which represent a significant cause of mortality and morbidity in these patients. Cytomegalovirus (CMV) is the most common clinically significant viral infection despite emerging strategies to prevent infection, such as letermovir prophylaxis. The impact of letermovir prophylaxis on CMV infection in patients receiving 2-step allogeneic HSCT has not been adequately reported.

Methods

Our study aimed to retrospectively analyze the rate of CMV reactivation, progression-free survival (PFS), overall survival (OS), and non-relapse mortality (NRM) in patients at risk for CMV infection with and without letermovir prophylaxis following 2-step alloHSCT. In this process, after administration of a transplant conditioning regimen, patients receive a fixed dose of CD3+ T cells (step one) followed by cyclophosphamide and CD34-selected stem cells (step two). This allows for a consistent T cell dosing for outcome comparison and spares the stem cells from the effects of cyclophosphamide.

Following IRB approval, a retrospective database was created using patients who underwent alloHSCT at Thomas Jefferson University Hospital from 2017 to 2022. Multiple clinical variables such as basic demographics, diagnoses, conditioning intensity, CMV serostatus of donor/ recipient pairs, acute and chronic graft vs. host disease (GVHD), letermovir use, relapse rates, and non-relapse mortality were collected. Subgroup analysis was then performed to compare patients before and after letermovir became routine prophylaxis. The primary outcome of our analysis was to compare the rate of CMV reactivation (defined as detectable CMV viremia or clinical CMV infection) with and without letermovir prophylaxis in patients at risk for CMV (defined as seropositive recipients).

Results

In total, 150 patients who underwent 2-step alloHSCT between 2017 and 2022 were included in the analysis, with a median follow up of 559 days. Median age was 59 years (range, 26 to 76 years), and 55% were female. Ethnicity included 60% Caucasians, 29% AA, 7% Hispanic, and 3% Asian.

Fifty-eight patients were CMV seropositive prior to transplant and represented the “at risk” population. Thirty-six (62%) of these at-risk patients received seropositive grafts and 22 (38%) patients received seronegative grafts. Letermovir prophylaxis was used in 35 (60%) of seropositive patients and was started on day +7 and continued until day +100 post-transplant.

The 3-year cumulative incidence of CMV reactivation was 47.8% (95% CI, 22.8% to 64.7%) in patients who did not receive letermovir and 8.6% (95% CI, 0% to 17.4%, p = 0.0018) in patients who received letermovir. CMV reactivation in the letermovir group had a median peak CMV copies 247 UI/ml [153, 634.5] compared with 1780 Ul/ml [1063.5, 3812] in those without prophylaxis. The hazard ratio for CMV infection was 0.34 (95% CI, .13 to .66; P = .003) in patients who received primary prophylaxis with letermovir.

The 1-year cumulative incidence of NRM was lower in at risk patients with letermovir prophylaxis compared to those without prophylaxis (11.9% versus 26.1%, p-value < 0.05). Overall survival (74.3% versus 69.3%) and progression-free survival (70.9% versus 69.6%) were similar between the two groups.

Conclusion

Our results indicate that letermovir is effective in preventing early and late CMV reactivation and is associated with decreased NRM in high-risk patients who undergo transplantation using the 2-step alloHSCT.

Gergis:Incyte: Other: Travel Support, Speakers Bureau; VOR: Consultancy; Biontech: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Jazz: Other: Travel Support, Speakers Bureau; Autolus: Consultancy; Kite: Other: Travel Support, Speakers Bureau; Iovance: Current equity holder in publicly-traded company; Astellas: Other: Travel Support, Speakers Bureau. Keiffer:Prelude: Research Funding; AbbVie: Research Funding; Cyteir: Research Funding; Schrodinger: Research Funding; Sumitomo Pharma America: Research Funding; Astellas: Honoraria.