Impact of Letermovir Prophylaxis for Cytomegalovirus Reactivation on Post-Transplant Outcomes 100 Days before and after Allogeneic Hematopoietic Cell Transplantation
Authors: Takenaka Katsuto , Fuji Shigeo , Matsukawa Toshihiro , Uchida Naoyuki , Kobayashi Takeshi , Tanaka Masatsugu , Ara Takahide , Ikegame Kazuhiro , Ozawa Yukiyasu , Kanda Yoshinobu , Sawa Masashi , Maruyama Yumiko , Fukuda Takahiro , Nakamae Hirohisa , Kimura Takafumi , Ogata Masao , Seo Sachiko , Atsuta Yoshiko , Matsuo Keitaro , Nakasone Hideki 
Published: December 2023

Background: Cytomegalovirus (CMV) infection is a major infectious complication following allogeneic hematopoietic cell transplantation (allo-HCT). Although letermovir (LMV) prophylaxis dramatically reduces the incidence of early clinically significant CMV (csCMV) infection, it remains unclear whether it has a beneficial effect on nonrelapse mortality (NRM) and overall survival (OS). Additionally, because the incidence of csCMV infection increases after completing LMV prophylaxis, the impact of late csCMV infection beyond 100 days after transplantation on posttransplant outcomes should also be verified.

Study Design: We included adult patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS) aged ≥16 years who underwent allo-HCT between 2017 and 2019. These patients' data were obtained from the registry database of the Japanese Society for Transplantation and Cellular Therapy (JSTCT).

Results: Donor CMV seronegativity (D-CMV −)/recipient CMV seronegativity (R-CMV −) was recorded in 558 cases (9.3%), and R-CMV +/D-CMV + or - was recorded in 4,562 cases (78.0%). The median age was 51 (range, 16-80) years. The median follow-up length was 389 (range, 0-1,334) days. LMV prophylaxis was administered to 1,640 patients (LMV group), and the median duration of LMV prophylaxis was 85 (range, 2-152) days. LMV prophylaxis significantly reduced the incidence of early csCMV infection compared with those not administered LMV prophylaxis (15.4% vs. 54.1%; p&lt;0.01, hazard ratio [HR], 0.30; p&lt;0.01)). However, LMV prophylaxis did not have any beneficial effect on the 1-year NRM (HR, 0.93; p=0.40) and OS (HR, 0.96; p=0.49) in multivariate analysis. The possible causes were breakthrough csCMV infection within 100 days after transplantation during LMV prophylaxis and late csCMV infection after 100 days after transplantation after completion of LMV prophylaxis.

Breakthrough csCMV infection during LMV prophylaxis developed in 74 (4.5%) of the 1,640 patients who had received LMV prophylaxis. Breakthrough csCMV infection occurred at a median of 33 (range, 6-139) days after transplantation. R-CMV +, prior transplantation, cord blood (CB) transplants, anti-thymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCY) use for GVHD prophylaxis, and grade II-IV acute GVHD were associated with an increased risk of breakthrough csCMV infection. The breakthrough csCMV infection group showed inferior NRM (HR, 3.44; p&lt;0.01) and OS (HR, 1.93; p=0.02) compared with those without infection among LMV prophylaxis group.

After completing LMV prophylaxis, 252 patients had late csCMV infection at a median of 134 (range, 101-405) days after transplantation. In multivariate analysis, R-CMV +, older age, CB transplantation, ATG and/or PTCY use for GVHD prophylaxis, grade II-IV acute GVHD, and LMV prophylaxis before day 100 after transplantation were associated with an increased risk of late csCMV infection. Late csCMV infection showed inferior NRM (HR, 1.83; p&lt;0.01) and OS (HR, 1.58; p&lt;0.01) in multivariate analysis.

Conclusion: LMV prophylaxis efficiently suppressed the development of early csCMV infection; however, this effect did not translate into improved posttransplant outcomes. Breakthrough csCMV infection during LMV prophylaxis and the development of late csCMV infection after completing LMV prophylaxis worsened transplant outcomes in the LMV prophylaxis group. Further improvements in posttransplant CMV management will be required to address these issues.