Elucidation of mechanism of HBV reactivation associated with mogamulizumab-containing chemotherapy

• Project/Area Number: 16K09876
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagoya City University
• Principal Investigator: Kusumoto Shigeru 名古屋市立大学, 医薬学総合研究院(医学), 准教授 (90423855)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: モガムリズマブ / HBV再活性化 / 免疫不全 / B型肝炎再活性化 / ウィルス / 癌

Outline of Final Research Achievements

The risk of hepatitis B virus reactivation (HBV-R) in adult T-cell leukemia-lymphoma (ATL) patients with resolved HBV infection treated with mogamulizumab (MOGA) was analyzed in a post hoc analysis.Of 102 patients with ATL who were enrolled in a multicenter prospective observational study (MIMOGA study;UMIN000008696), 39 (38%) had resolved HBV infection based on the serological results at each institute. Of these 39 patients , 34 who underwent periodic HBV DNA monitoring at least once after enrollment were included in this study. HBV-R was defined as HBV DNA levels of 1.3 log IU/mL or more. With a median HBV DNA follow-up period of 467 days, HBV-R was observed in three patients, one of which developed HBV-related hepatitis. The incidence of resolved HBV infection was 38%, while HBV-R following MOGA administration, including one case with HBV-R that developed after umbilical cord blood transplantation, occurred in approximately 9% (3 of 34 patients) in the MIMOGA study.

Academic Significance and Societal Importance of the Research Achievements

CCR4抗体モガムリズマブは、難治性の成人T細胞白血病リンパ腫（ATL）治療において高い有効性が報告されてきたが、末梢血中に存在する正常のCD4リンパ球の一部を除去することによる免疫不全がB型肝炎ウイルス（HBV）の再活性化と関連することが本研究によって示された。日本肝臓学会が提唱するガイドラインに従い、定期的なHBV DNAモニタリングにより早期にHBV再活性化を診断し、適切なタイミングで核酸アナログを投与することで、HBV既往感染歴を有するATL治療が安全に実施可能であることが示された。同種移植後の免疫再構築による遅発発症のHBV再活性化例への対策は今後の課題と考えられた。

Research Products

• [Journal Article] Clinical evaluation of a novel and highly sensitive immunoassay for anti-hepatitis B core antigen using a fully automated immunochemical analyzer. (2018)
  • Author(s): Izumida K, Kaneko A, Takahashi K, Kusumoto S, Narita T, Takami A, Iida S, Aoyagi K, Tanaka Y.
  • Journal Title: Hepatol Res. Volume: 48 Issue: 13 Pages: 1081-1091
  • DOI: 10.1111/hepr.13229
  • Peer Reviewed
• [Journal Article] Novel monitoring of hepatitis B reactivation based on ultra-high sensitive hepatitis B surface antigen assay (2017)
  • Author(s): Shinkai N, Kusumoto S, Murakami S, Ogawa S, Ri M, Matsui T, Tamori A, Toyoda H, Ishida T, Iida S, Tanaka Y.
  • Journal Title: Liver Int. Volume: 印刷中 Issue: 8 Pages: 1138-1147
  • DOI: 10.1111/liv.13349
  • Peer Reviewed
• [Journal Article] Nationwide prospective and retrospective surveys for hepatitis B virus reactivation during immunosuppressive therapies. (2016)
  • Author(s): Mochida S, Nakao M, Nakayama N, Uchida Y, Nagoshi S, Ido A, Mimura T, Harigai M, Kaneko H, Kobayashi H, Tsuchida T, Suzuki H, Ura N, Nakamura Y, Bessho M, Dan K, Kusumoto S, Sasaki Y, Fujii H, Suzuki F, Ikeda K, Yamamoto K, Takikawa H, Tsubouchi H, Mizokami M.
  • Journal Title: J Gastroenterol. Volume: 51 Issue: 10 Pages: 999-1010
  • DOI: 10.1007/s00535-016-1168-2
  • Peer Reviewed
• [Presentation] B型肝炎ウイルス（HBV）既往感染を有する成人T細胞白血病リンパ腫のモガムリズマブ投与後のHBV再活性化 (2019)
  • Author(s): 戸谷治人
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Clinical significance of an ultra-high sensitive HBsAg assay to diagnosing HBV reactivation using stored samples of a prospective HBV DNA monitoring study (C-SHOT 0802) (2017)
  • Author(s): Shigeru Kusumoto, Yasuhito Tanaka, Masashi Mizokami.
  • Organizer: JDDW2017, symposium 1: Liver S1-7
• [Presentation] Clinical significance of an ultra-high sensitive HBsAg assay to diagnosing HBV reactivation using stored samples of a prospective HBV DNA monitoring study in B-cell non-Hodgkin lymphoma patients. (2017)
  • Author(s): Shigeru Kusumoto, Yasuhito Tanaka, Ritsuro Suzuki, Takashi Watanabe, Dai Maruyama, Eiji Tanaka, Takayo Suzuki, Tomohiro Kinoshita, Michinori Ogura, Ryuzo Ueda, Masashi Mizokami.
  • Organizer: AASLD 2017
• [Presentation] Acute liver failure in a HBsAg-positive ATL patient after mogamulizumab monotherapy (2017)
  • Author(s): Takahiro Nakashima, Shigeru Kusumoto, Hirokazu Sasaki, Yoshiaki Marumo, Chie Kato, Takashi Kanamori, Satsuki Murakami, Tomoko Narita, Asahi Ito, Masaki Ri, Takashi Ishida, Hirokazu Komatsu, Yasuhito Tanaka, Shinsuke Iida.
  • Organizer: 第18回国際ヒトレトロウイルスHTLV会議
  • Place of Presentation: ホテルグランドマーク半蔵門（東京都・千代田区）
  • Int'l Joint Research
• [Presentation] Acute liver failure in a HBsAg-positive ATL patient after mogamulizumab monotherapy (2016)
  • Author(s): Takahiro Nakashima, Shigeru Kusumoto, Hirokazu Sasaki, Yoshiaki Marumo, Chie Kato, Takashi Kanamori, Satsuki Murakami, Tomoko Narita, Asahi Ito, Masaki Ri, Takashi Ishida, Hirokazu Komatsu, Yasuhito Tanaka, Shinsuke Iida.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
• [Book] 造血器腫瘍アトラス 第5版 第11章 抗CCR4抗体によるATLの治療 谷脇雅史，横田昇平，黒田純也 編 (2016)
  • Author(s): 楠本茂、石田高司
  • Publisher: 日本医事新報社