Establishment of prognosis prediction model after hematopoietic stem cell transplantation based on pretransplantation data

• Project/Area Number: 20K07788
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Osaka Metropolitan University (2022-2023); Osaka City University (2020-2021)
• Principal Investigator: Masayuki Hino 大阪公立大学, 大学院医学研究科, 教授 (50244637)
• Co-Investigator(Kenkyū-buntansha): 中前 博久 大阪公立大学, 大学院医学研究科, 准教授 (30364003) ; 幕内 陽介 大阪公立大学, 大学院医学研究科, 病院講師 (70881176)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 造血幹細胞移植 / 移植後シクロホスファミド / バイオマーカー / 同種造血幹細胞移植 / WT1 / オートタキシン / 移植関連血栓性微小血管症 / 補体 / NK細胞活性化受容体 / PTCYハプロ移植 / BNP / NT-proBNP / 辺縁系脳炎 / カルシニューリン阻害剤誘発性脳症 / 機械学習

Outline of Research at the Start

同種造血幹細胞移植は治癒が望める治療法であるが、リスクの高い治療法であり、移植の選択が最良でない場合もある。一般的にはHCT-CIやDRIなどの層別化された予後因子が用いられるが、これらに含まれない多くの因子も報告されており、個々の患者の予後を適切に評価するツールはない。本研究では新たな予後因子の探索に加えて、患者情報、ドナー情報、移植情報、各種病態のバイオマーカーの解析で得られた予後に影響する因子を機械学習を用いて個々の患者に合わせた生存、合併症発症、再発を予測できるツールを開発し、患者の意思決定支援、最適なドナー選択、移植法選択を補助し、移植成績の向上を図ることを目的とする。

Outline of Final Research Achievements

Post-transplant cyclophosphamide (PTCy) haphloidentical hematopoietic stem cell transplantation (HSCT) has been found beneficial for refractory hematologic malignancies. In investigating biomarkers influencing HSCT outcomes, it was observed that in PTCy haphloidentical HSCT, the presence of the donor NK cell activating receptor NKG2D gene polymorphism rs1049174CC in the donor led to lower rates of relapse/progression. Elevated levels of NT-proBNP and BNP before transplantation were associated with decreased overall survival and increased non-relapse mortality. In AML/MDS patients, the pre-transplant liver index/height ratio on ultrasound examination was associated with relapse in non-remission patients. We are currently offering an application for calculating individualized hematopoietic stem cell transplant outcomes using machine learning.

Academic Significance and Societal Importance of the Research Achievements

同種造血幹細胞移植前及び移植後のバイオマーカーを測定することで、合併症や移植予後の予測が可能となり、移植適応、移植ソース、移植方法の変更、早期の合併症対応により、移植成績の向上、患者QOLの改善、医療費の削減などに貢献できる可能性がある。

Research Products

• [Journal Article] Pretransplant hepatomegaly is linked to relapse in patients with leukemia and myelodysplastic syndrome not in remission (2024)
  • Author(s): Okayama Y, Harada N, Makuuchi Y, Kuno M, Takakuwa T, Okamura H, Hirose A, Nakamae M, Nishimoto M, Nakashima Y, Koh H, Hino M, Nakamae H
  • Journal Title: Int J Hematol Volume: 119 Issue: 3 Pages: 316-326
  • DOI: 10.1007/s12185-023-03707-7
  • Peer Reviewed
• [Journal Article] Comparison of long-term outcomes after first HLA-mismatched unrelated donor transplantation with single unrelated cord blood transplantation using reduced-intensity or reduced-toxicity conditioning (2024)
  • Author(s): Kuno Masatomo、Koh Hideo、Ido Kentaro、Sakatoku Kazuki、Makuuchi Yosuke、Takakuwa Teruhito、Hirose Asao、Okamura Hiroshi、Nishimoto Mitsutaka、Nakashima Yasuhiro、Nakamae Mika、Hino Masayuki、Nakamae Hirohisa
  • Journal Title: Transplant Immunology Volume: 82 Pages: 101988-101988
  • DOI: 10.1016/j.trim.2024.101988
  • Peer Reviewed / Open Access
• [Journal Article] A comparison of long-term outcomes by donor type in the era of post-transplantation cyclophosphamide for aggressive adult T-cell leukemia/lymphoma. (2024)
  • Author(s): Hirose A, Koh H, Nakamae M, Nakashima Y, Nishimoto M, Okamura H, Makuuchi Y, Kuno M, Takakuwa T, Ido K, Sakatoku K, Hino M, Nakamae H.
  • Journal Title: Bone Marrow Transplant. Volume: - Issue: 5 Pages: 695-698
  • DOI: 10.1038/s41409-024-02231-4
  • Peer Reviewed
• [Journal Article] Third HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide for relapsed acute leukemia. (2023)
  • Author(s): Harada N, Okamura H, Makuuchi Y, Kuno M, Takakuwa T, Nakamae M, Nishimoto M, Nakashima Y, Koh H, Hino M, Nakamae H
  • Journal Title: Bone Marrow Transplant Volume: 58 Issue: 12 Pages: 1403-1405
  • DOI: 10.1038/s41409-023-02108-y
  • Peer Reviewed
• [Journal Article] Severe short-term adverse events in related bone marrow or peripheral blood stem cell donors (2023)
  • Author(s): Yanagisawa R, Hirakawa T, Doki N, Ikegame K, Matsuoka K, Fukuda T, Nakamae H, Ota S, Hiramoto N, Ishikawa J, Ara T, Tanaka M, Koga Y, Kawakita T, Maruyama Y, Kanda Y, Hino M, Atsuta Y, Yabe H, Tsukada N
  • Journal Title: International Journal of Hematology volume Volume: 117 Issue: 3 Pages: 421-427
  • DOI: 10.1007/s12185-022-03489-4
  • Peer Reviewed
• [Journal Article] A Prospective Study of an HLA-Haploidentical Peripheral Blood Stem Cell Transplantation Regimen Based on Modification of the Dose of Posttransplant Cyclophosphamide for Poor Prognosis or Refractory Hematological Malignancies (2022)
  • Author(s): Nakamae H, Okamura H, Hirose A, Koh H, Nakashima Y, Nakamae M, Nishimoto M, Makuuchi Y, Kuno M, Harada N, Takakuwa T, Hino M
  • Journal Title: Cell Transplantation Volume: 31
  • DOI: 10.1177/09636897221112098
  • Peer Reviewed / Open Access
• [Journal Article] Long-term use of foscarnet is associated with an increased incidence of acute kidney injury in hematopoietic stem cell transplant patients: A retrospective observational study (2022)
  • Author(s): Inose R, Takahashi K, Takahashi M, Sugimoto T, Nanno S, Hino M, Nagayama K
  • Journal Title: Transpl Infect Dis Volume: - Issue: 2
  • DOI: 10.1111/tid.13804
  • Peer Reviewed
• [Journal Article] A phase II study of post-transplant cyclophosphamide combined with tacrolimus for GVHD prophylaxis after HLA-matched related/unrelated allogeneic hematopoietic stem cell transplantation (2022)
  • Author(s): Nakamae H, Nakane T, Okamura H, Koh H, Nakashima Y, Hirose A, Nakamae M, Nishimoto M, Kuno M, Makuuchi Y, Harada N, Takakuwa T, Hino M
  • Journal Title: Int J Hematol. Volume: 115 Issue: 1 Pages: 77-86
  • DOI: 10.1007/s12185-021-03228-1
  • Peer Reviewed
• [Journal Article] Effect of Donor NKG2D Polymorphism on Relapse after Haploidentical Transplantation with Post-Transplantation Cyclophosphamide (2022)
  • Author(s): Ido K, Koh H, Hirose A, Seto T, Makuuchi Y, Kuno M, Takakuwa T, Okamura H, Nanno S, Nakamae M, Nishimoto M, Nakashima Y, Hino M, Nakamae H.
  • Journal Title: Transplant Cell Ther Volume: 28 Issue: 1 Pages: 20.e1-20.e10
  • DOI: 10.1016/j.jtct.2021.09.019
  • Peer Reviewed
• [Journal Article] Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy (2021)
  • Author(s): Okamura Hiroshi、Nakamae Hirohisa、Shindo Takero、Ohtani Katsuki、Hidaka Yoshihiko、Ohtsuka Yasufumi、Makuuchi Yosuke、Kuno Masatomo、Takakuwa Teruhito、Harada Naonori、Nishimoto Mitsutaka、Nakashima Yasuhiro、Koh Hideo、Hirose Asao、Nakamae Mika、Wakamiya Nobutaka、Hino Masayuki、Inoue Norimitsu
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 695037-695037
  • DOI: 10.3389/fimmu.2021.695037
  • NAID: 120007124372
  • Peer Reviewed / Open Access
• [Journal Article] Kinetics of IgG subclasses and their effects on the incidence of infection after allogeneic hematopoietic stem cell transplantation (2021)
  • Author(s): Koh S, Koh H, Nanno S, Okamura H, Nakashima Y, Nakamae M, Hirose A, Hino M, Nakamae H
  • Journal Title: Transpl Immunol Volume: 67 Pages: 101413-101413
  • DOI: 10.1016/j.trim.2021.101413
  • Peer Reviewed
• [Journal Article] Risk Factor and Long-Term Outcome Analyses for Acute Limbic Encephalitis and Calcineurin Inhibitor-Induced Encephalopathy in Adults following Allogeneic Hematopoietic Cell Transplantation (2021)
  • Author(s): Tanizawa N, Koh H, Okamura H, Yamamoto K, Makuuchi Y, Kuno M, Takakuwa T, Koh S, Nanno S, Nishimoto M, Hirose A, Nakamae M, Nakashima Y, Nakane T, Hino M, Nakamae H.
  • Journal Title: Transplant Cell Ther Volume: 27 Issue: 5 Pages: 437.e1-437.e9
  • DOI: 10.1016/j.jtct.2021.01.021
  • Peer Reviewed
• [Journal Article] Pretransplant plasma brain natriuretic peptide and N-terminal probrain natriuretic peptide are more useful prognostic markers of overall survival after allogeneic hematopoietic cell transplantation than echocardiography (2021)
  • Author(s): Harada N, Okamura H, Nakane T, Koh S, Nanno S, Nishimoto M, Hirose A, Nakamae M, Nakashima Y, Koh H, Hino M, Nakamae H.
  • Journal Title: Bone Marrow Transplant Volume: 56 Issue: 6 Pages: 1467-1470
  • DOI: 10.1038/s41409-021-01224-x
  • Peer Reviewed
• [Journal Article] Effect of allogeneic HCT from unrelated donors in AML patients with intermediate- or poor-risk cytogenetics: a retrospective study from the Japanese Society for HCT (2020)
  • Author(s): Yamasaki S, Mori J, Kanda J, Imahashi N, Uchida N, Doki N, Tanaka M, Katayama Y, Eto T, Ozawa Y, Takada S, Onizuka M, Hino M, Kanda Y, Fukuda T, Atsuta Y, Yanada M.
  • Journal Title: Ann Hematol. Volume: 99 Issue: 12 Pages: 2927-2937
  • DOI: 10.1007/s00277-020-04261-6
  • Peer Reviewed
• [Journal Article] Effect of Prophylactic Post-transplant Ponatinib Administration on Outcomes in Patients With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (2020)
  • Author(s): Nanno S, Matsumoto K, Nakamae M, Okamura H, Nishimoto M, Hirose A, Koh H, Nakashima Y, Nakane T, Morita K, Hino M, Nakamae H.
  • Journal Title: Clin Lymphoma Myeloma Leuk Volume: 20 Issue: 12 Pages: 813-819
  • DOI: 10.1016/j.clml.2020.07.005
  • Peer Reviewed
• [Presentation] 移植後再発難治性急性白血病に対するPTCyハプロ移植を用いた再移植における輸注細胞数の影響 (2023)
  • Author(s): 中舎洋輔、中前博久、原田尚憲、岡村浩史、酒徳一希、井戸健太郎、幕内陽介、久野雅智、高桑輝人、廣瀬朝生、中前美佳、西本光孝、中嶋康博、康 秀男、日野雅之
  • Organizer: 第85回日本血液学会
• [Presentation] ベネトクラックスによるBCL-2高発現T細胞の誘導とGVL効果への影響 (2023)
  • Author(s): 長崎譲慈 、西本光孝、康 秀男、中前美佳、井戸健太郎、酒徳一希、久野雅智、幕内陽介 、 岡村浩史、中嶋康博、日野雅之、中前博久
  • Organizer: 第85回日本血液学会
• [Presentation] ePROモバイルアプリケーションを用いた移植後合併症による緊急入院の予測 (2023)
  • Author(s): 幕内陽介、岡村浩史、西川彰則、仲子聡一郎、熊谷宗久、糸藤一郎、梅本由香里、大亦由紀。西川真紀、高木 良、上田かやこ、堀内美令、井戸健太郎、酒徳一希、久野雅智、高桑輝人、康 秀男、西本光孝、中嶋康博、中前美佳、日野雅之、中前博久
  • Organizer: 第85回日本血液学会
• [Presentation] ATL の長期移植成績に移植法が与える影響 (2023)
  • Author(s): 廣瀬朝生、康 秀男、中嶋康博、西本光孝、岡村浩史、久野雅智、 高桑輝人、幕内陽介、井戸健太郎、酒徳一希、中前美佳、日野雅之、中前 博久
  • Organizer: 第45回日本造血・免疫細胞療法学会
• [Presentation] 骨髄系腫瘍の移植後再発に対する WT1mRNA の予測能の経時変化および動的再発予測 モデルの検討 (2023)
  • Author(s): 仲子聡一郎、岡村浩史、横田 勲、梅本由香里、酒徳一希、井戸健太郎、久野雅智、幕内陽介、髙桑輝人、廣瀬朝生、西本光孝、中嶋康博、康 秀男、中前美佳、日野雅之、中前博久
  • Organizer: 第45回日本造血・免疫細胞療法学会
• [Presentation] 同種造血幹細胞移植後の肝類洞閉塞症候群発症予測に関するオートタキシンの有用性 (2023)
  • Author(s): 武村和哉、中前美佳、岡村浩史、酒徳一希、井戸健太郎、幕内陽介、久野雅智、高桑輝人、廣瀬朝生、西本光孝、中嶋康博、康 秀男、五十嵐浩二、久保田 浩、日野雅之、中前博久
  • Organizer: 第45回日本造血・免疫細胞療法学会
• [Presentation] Time-Sequential Change of the Predictive Power of Peripheral Blood WT1mRNA Levels after Allogeneic Stem Cell Transplantation for Myeloid Neoplasm Relapse and Development of a Dynamic Relapse Prediction Model. (2022)
  • Author(s): Nakako S, Okamura H, Yokota I, Makuuchi Y, Kuno M, Takakuwa T, Nishimoto M, Hirose A, Nakamae M, Nakashima Y, Koh H, Hino M, Nakamae H
  • Organizer: 64th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Personalized strategy for allogeneic stem cell transplantation guided by machine learinig: a real-world data analysis of the Japanese transplant registry unified management program. (2022)
  • Author(s): Okamura H, Nakamae H, Nakamae M, Kabata D, Yoshida H, Shintani A, Uchida H, Doki N, Fukuda T, Ozawa Y, Tanaka M, Ikegame K, Eto T, Sawa M, Kimura T, Kanda J, Atsuta Y, Hino M
  • Organizer: 48th EBMT
  • Int'l Joint Research
• [Presentation] Comparison of the long-term outcomes of HLA-mismatced unrelated donor transplantation and single unrelated cord blood transplantation after reduced intensity/toxicity conditioning (2022)
  • Author(s): Kuno M, Koh H, Makuuchi Y, Harada H, Takakuwa T, Okamura H, Hirose A, Nishimoto M, Nakashima Y, Nakamae M, Hino M, Nakamae H
  • Organizer: 48th EBMT
  • Int'l Joint Research
• [Presentation] 移植後早期の補体Ba上昇は移植関連血栓性微小血管症の発症予測マーカーになり得る (2021)
  • Author(s): 岡山裕介、岡村浩史、中前博久、進藤岳郎、大谷克城、日高義彦、大塚泰史、幕内陽介、久野雅智、高桑輝人、原田尚憲、西本光孝、中嶋康博、康 秀男、廣瀬朝生、中前美佳、日野雅之、若宮伸隆、井上徳光
  • Organizer: 第57回日本補体学会
• [Presentation] BNPとNTproBNPは心臓超音波検査より有用な同種造血幹細胞移植後全生存率に対する予後予測因子である (2021)
  • Author(s): 原田尚憲、岡村浩史、中根孝彦、康 史朗、南野 智、西本光孝、廣瀬朝生、中前美佳、中嶋康博、康 秀男、日野雅之、中前博久
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] 急性GVHDバイオマーカーの同種造血細胞移植後予後への影響 (2020)
  • Author(s): 井戸健太郎、西本光孝、久野雅智、高桑輝人、岡村浩史、南野 智、廣瀬朝生、中前美佳、中嶋康博、康 秀男、日野 雅之、中前博久
  • Organizer: 第82回日本血液学会総会
• [Presentation] 小児急性白血病に対する非血縁者間骨髄移植におけるドナー自己血貯血の臨床的意義 (2020)
  • Author(s): 坂口大俊、石丸紗恵、荒川ゆうき、加藤元博、岡本康裕、塚田信弘、野口磨依子、吉田奈央、康 勝好、佐藤真穂、後藤裕明、藤田直人、矢部普正、日野雅之、熱田由子
  • Organizer: 第82回日本血液学会総会
• [Remarks] 業績
  • URL: http://www.med.osaka-cu.ac.jp/labmed/