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4898 Impact of Letermovir Prophylaxis for Cytomegalovirus Reactivation on Post-Transplant Outcomes 100 Days before and after Allogeneic Hematopoietic Cell Transplantation

Program: Oral and Poster Abstracts
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster III
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality)
Monday, December 11, 2023, 6:00 PM-8:00 PM

Katsuto Takenaka1, Shigeo Fuji, MD, PhD2*, Toshihiro Matsukawa, M.D., Ph.D.3*, Naoyuki Uchida, MD, PhD4, Takeshi Kobayashi, MD, PhD5*, Masatsugu Tanaka, M.D., Ph.D.6*, Takahide Ara, MD, PhD7*, Kazuhiro Ikegame, MD, PhD8*, Yukiyasu Ozawa, MD, PhD9, Yoshinobu Kanda10*, Masashi Sawa, MD, PhD11*, Yumiko Maruyama, MD, PhD12*, Takahiro Fukuda, MD, PhD13*, Hirohisa Nakamae, MD, PhD14*, Takafumi Kimura, MD, PhD15*, Masao Ogata, MD, PhD16*, Sachiko Seo, MD, PhD17, Yoshiko Atsuta, MD, PhD18,19*, Keitaro Matsuo, MD, PhD20* and Hideki Nakasone, MD, PhD21

1Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan
2Osaka International Cancer Center Institute, Osaka, Japan
3Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
4Department of Hematology, Toranomon Hospital, Tokyo, Japan
5Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
6Department of Hematology, Kanagawa Cancer Center, Kanagawa, Japan
7Department of Hematology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
8Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Japan
9Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, JPN
10Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
11Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
12Department of Hematology, University of Tsukuba Hospital, Tsukuba, JPN
13Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
14Department of Hematology, Osaka Metropolitan University Hospital, Osaka, Japan
15Preparation Department, Japanese Red Cross Kinki Block Blood Center, Osaka, Japan
16Department of Hematology, Oita University Hospital, Yufu-City, JPN
17Department of Hematology and Oncology, Dokkyo Medical University,, Tochigi, JPN
18Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
19Japanese Data Center For Hematopoietic Cell Transplantation, Nagakute, Japan
20Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
21Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan

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<0.01, hazard ratio [HR], 0.30; p<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<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<0.01) and OS (HR, 1.58; p<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.

Disclosures: Takenaka: Japan Blood Products Organization: Research Funding; Daiichi Sankyo Company, limited: Research Funding; Novartis Pharma: Honoraria; MSD: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Janssen Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria; Bristol Myers Squibb: Honoraria; Asahi Kasei Pharma: Research Funding. Tanaka: Kyowa-Kirin: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; MSD: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Astellas Phrama: Speakers Bureau; Asahi Kasei Pharma: Speakers Bureau; Abbvie: Speakers Bureau; Pfizer: Speakers Bureau; Sumitomo Pharma: Speakers Bureau. Kanda: AbbVie: Research Funding, Speakers Bureau; Towa Pharma: Speakers Bureau; CSL Behring: Speakers Bureau; Japan Blood Products Organization: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Human Life CORD: Speakers Bureau; Sumitomo Pharma: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceutical: Research Funding, Speakers Bureau; Meiji Seika Pharma: Speakers Bureau; Asahi Kasei Pharma: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Saitama Hokeni Kyokai: Speakers Bureau; MSD: Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau; Sanofi: Speakers Bureau; Pfizer: Speakers Bureau; Chugai Pharmaceutical: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Shionogi Pharma: Research Funding; FUJIFILM Wako Pure Chemical: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Precision: Speakers Bureau; Eisai: Research Funding, Speakers Bureau; Wakunaga Pharmaceutical: Speakers Bureau; Alexion Pharma: Speakers Bureau; Taiho Pharmaceutical: Research Funding; Nippon Kayaku: Research Funding; JCR Pharmaceuticals: Research Funding. Sawa: Janssen: Honoraria; Sanofi: Honoraria. Nakamae: CMIC Company: Research Funding; Parexel International Inc: Research Funding; Novartis: Research Funding; Takeda Pharmaceutical Company: Honoraria; Alexion Pharma: Research Funding; Meiji Seika Pharma: Research Funding; DAIICHI SANKYO COMPANY: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Nihon Shinyaku: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria; Otsuka: Honoraria; Abbvie: Honoraria; Astellas: Honoraria. Atsuta: Novartis Pharma KK: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd: Speakers Bureau; JCR Pharmaceuticals Co., Ltd.: Consultancy; Meiji Seika Pharma Co, Ltd.: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Speakers Bureau. Nakasone: Eisai: Honoraria; Novartis: Honoraria; Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Meiji Seika Pharma: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical: Honoraria; Pfizer: Honoraria.

*signifies non-member of ASH