Analysis of biomarkers and mechanisms of late effects after hematopoietic cell transplantation

• Project/Area Number: 18K08345
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: INAMOTO YOSHIHIRO 国立研究開発法人国立がん研究センター, 中央病院, 医長 (70730349)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 造血細胞移植 / 晩期障害 / バイオマーカー / 移植片対宿主病 / 二次がん / 遺伝子解析

Outline of Final Research Achievements

We identified Dickkopf-related protein 3 (DKK3), a Wnt signaling modulator, as a novel plasma biomarker for chronic graft-versus-host disease (GVHD) including fibrotic phenotype. We demonstrated the utility of plasma MMP9 for diagnosis and response prediction of bronchiolitis obliterans syndrome to FAM therapy. We characterized and compared the incidence, manifestations and treatment outcomes of chronic GVHD and late acute GVHD between Japanese and Caucasian patients. I participated in a member of 2020 NIH Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD and published several meeting reports. By using national transplant registry database and national cancer registration database, we reported outcomes of patients who developed subsequent solid cancer after hematopoietic cell transplantation. By using national transplant registry database, we characterized myeloid neoplasms following allogeneic hematopoietic cell transplantation.

Academic Significance and Societal Importance of the Research Achievements

本研究は海外との共同研究も行いながら、同種造血細胞移植後の大きな課題である慢性GVHDの診断や病態だけでなく治療効果と予後に関連した新規バイオマーカーを報告した。慢性GVHDの治療効果を予測するバイオマーカーの報告は現在限られており、貴重な学術成果が得られたものと考えられる。将来治療への応用が進めば、治療成績の向上につながる可能性があり、社会的意義は大きい。また、移植後の長期生存の妨げとなる二次がんのうち、固形がんと骨髄系腫瘍の大規模なレジストリコホート解析の結果を報告したことの意義は大きく、今後病態解明のためのゲノム解析を進める上での重要な基礎データとなる。

Research Products

• [Int'l Joint Research] CIBMTR/Fred Hutchinson Cancer Research Center(米国)
• [Int'l Joint Research] CIBMTR/Fred Hutchinson Cancer Research Center/ASTCT(米国)
• [Int'l Joint Research] CIBMTR/Fred Hutchinson Cancer Research Center(米国)
• [Int'l Joint Research] ASTCT/CIBMTR/Fred Hutchinson Cancer Research Center(米国)
• [Journal Article] National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report (2021)
  • Author(s): Inamoto Yoshihiro、Williams Kirsten M.、Im Annie、Hamilton Betty、Koreth John、Arora Mukta、Pusic Iskra、Mays Jacqueline W.、Carpenter Paul A.、Luznik Leo、Reddy Pavan、Ritz Jerome、Greinix Hildegard、Paczesny Sophie、Blazar Bruce R.、Pidala Joseph、Cutler Corey、Wolff Daniel、Schultz Kirk R.、Pavletic Steven Z. et al.
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 6 Pages: 452-466
  • DOI: 10.1016/j.jtct.2021.02.035
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The disposable bandage soft contact lenses therapy and anterior segment optical coherence tomography for management of ocular graft-versus-host disease (2021)
  • Author(s): Sun Yi-Chen、Inamoto Yoshihiro、Wang Ruikang K.、Lee Stephanie J.、Hung Kai-Feng、Shen Tueng T.
  • Journal Title: BMC Ophthalmology Volume: 21 Issue: 1 Pages: 1-8
  • DOI: 10.1186/s12886-021-02031-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIb. The 2020 Preemptive Therapy Working Group Report (2021)
  • Author(s): Pidala Joseph、Kitko Carrie、Lee Stephanie、Carpenter Paul、Cuvelier Geoffrey、Holtan Shernan、Flowers Mary、Cutler Corey、Jagasia Madan、Gooley Ted、Palmer Joycelynne、Randolph Tim、Levine John、Ayuk Francis、Dignan Fiona、others、Inamoto Yoshihiro et al.
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 8 Pages: 632-641
  • DOI: 10.1016/j.jtct.2021.03.029
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States (2021)
  • Author(s): Bhatt Neel.、Brazauskas Ruta、Salit Rachel、Syrjala Karen、Bo-Subait Stephanie、Tecca Heather、Badawy Sherif、Baker Scott、Beitinjaneh Amer、Bejanyan Nelli、Byrne Michael、Dias Ajoy、Farhadfar Nosha、Freytes C、Ganguly Siddhartha、Hashmi Shahrukh、Hayashi Robert、Hong Sanghee、Inamoto Yoshihiro et al.
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 8 Pages: 679.e1-679.e8
  • DOI: 10.1016/j.jtct.2021.04.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation (2021)
  • Author(s): Inamoto Yoshihiro、Martin Paul J.、Onstad Lynn E.、Cheng Guang-Shing、Williams Kirsten M.、Pusic Iskra、Ho Vincent T.、Arora Mukta、Pidala Joseph、Flowers Mary E.D.、Gooley Ted A.、Lawler Richard L.、Hansen John A.、Lee Stephanie J.
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 9 Pages: 759.e1-759.e8
  • DOI: 10.1016/j.jtct.2021.06.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2020 Treatment of Chronic GVHD Report (2021)
  • Author(s): DeFilipp Zachariah、Couriel Daniel R.、Lazaryan Aleksandr、Bhatt Vijaya Raj、Buxbaum Nataliya P.、Alousi Amin M.、Olivieri Attilio、Pulanic Drazen、Halter Joerg P.、Henderson Lori A.、Zeiser Robert、Gooley Ted A.、MacDonald Kelli P.A.、Wolff Daniel、Schultz Kirk R.、Paczesny Sophie、Inamoto Yoshihiro et al.
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 9 Pages: 729-737
  • DOI: 10.1016/j.jtct.2021.05.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic Impact of Pretransplantation Quality of Life and Its Post-Transplantation Longitudinal Change after Allogeneic Hematopoietic Cell Transplantation: A Prospective Study That Administered the Short-Form Health Survey (SF-12) and EuroQol 5 (2021)
  • Author(s): Kurosawa Saiko、Yamaguchi Takuhiro、Mori Ayako、Tsukagoshi Mayumi、Okuda Ikue、Ikeda Masako、Fuji Shigeo、Yamashita Takuya、Ogawa Chitose、Ito Ayumu、Tanaka Takashi、Inamoto Yoshihiro、Kim Sung-Won、Fukuda Takahiro
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 11 Pages: 935.e1-935.e9
  • DOI: 10.1016/j.jtct.2021.07.026
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults (2021)
  • Author(s): Metheny Leland、Callander Natalie、Hall Aric、Zhang Mei-Jei、Bo-Subait Khalid、Wang Hai-Lin、Agrawal Vaibhav、Al-Homsi Samer、Assal Amer、Bacher Ulrike、Beitinjaneh Amer、Bejanyan Nelli、Bhatt Vijaya、Bredeson Chris、others、Inamoto Yoshihiro et al.
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 11 Pages: 923.e1-923.e12
  • DOI: 10.1016/j.jtct.2021.08.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Outcomes of hematopoietic cell transplantation for transformed follicular lymphoma (2021)
  • Author(s): Ida Hanae、Inamoto Yoshihiro、Fukuhara Suguru、Maeshima Akiko Miyagi、Takeda Wataru、Hirakawa Tsuneaki、Kuno Masatomo、Aoki Jun、Tanaka Takashi、Ito Ayumu、Kim Sung‐Won、Izutsu Koji、Fukuda Takahiro
  • Journal Title: Hematological Oncology Volume: 39 Issue: 5 Pages: 650-657
  • DOI: 10.1002/hon.2917
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of myeloid neoplasms following allogeneic hematopoietic cell transplantation (2021)
  • Author(s): Kuno Masatomo、Yamasaki Satoshi、Fujii Nobuharu、Ishida Yasushi、Fukuda Takahiro、Kataoka Keisuke、Uchida Naoyuki、Katayama Yuta、Sato Maho、Onai Daishi、Miyamoto Toshihiro、Ota Shuichi、Yoshioka Satoshi、Ara Takahide、Hangaishi Akira、Hashii Yoshiko、Onizuka Makoto、Ichinohe Tatsuo、Atsuta Yoshiko、Inamoto Yoshihiro
  • Journal Title: American Journal of Hematology Volume: 97 Issue: 2 Pages: 185-193
  • DOI: 10.1002/ajh.26401
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Feasibility and usefulness of recommended screenings at long-term follow-up clinics for hematopoietic cell transplant survivors (2021)
  • Author(s): Kurosawa Saiko、Yamaguchi Takuhiro、Mori Ayako、Tsukagoshi Mayumi、Okuda Ikue、Ikeda Masako、Ueno Takao、Saito Yutaka、Aihara Yukiko、Matsuba Yuko、Fuji Shigeo、Yamashita Takuya、Ogawa Chitose、Ito Ayumu、Tanaka Takashi、Inamoto Yoshihiro、Kim Sung-Won、Fukuda Takahiro
  • Journal Title: Supportive Care in Cancer Volume: 30 Issue: 3 Pages: 2767-2776
  • DOI: 10.1007/s00520-021-06698-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of readmission after allogeneic hematopoietic cell transplantation (2021)
  • Author(s): Yamaguchi Kyosuke、Inamoto Yoshihiro、Tajima Kinuko、Sakatoku Kazuki、Kuno Masatomo、Kawajiri Akihisa、Takemura Tomonari、Tanaka Takashi、Ito Ayumu、Kurosawa Saiko、Kim Sung-Won、Fukuda Takahiro
  • Journal Title: Bone Marrow Transplantation Volume: - Issue: 6 Pages: 1335-1340
  • DOI: 10.1038/s41409-020-01190-w
  • Peer Reviewed
• [Journal Article] Current Status and Needs of Long-Term Follow-Up Clinics for Hematopoietic Cell Transplantation Survivors: Results of a Nationwide Survey in Japan (2020)
  • Author(s): Kurosawa Saiko、Mori Ayako、Tsukagoshi Mayumi、Onishi Yasushi、Ohwada Chikako、Mori Takehiko、Goto Hideki、Asano-Mori Yuki、Nawa Yuichiro、Hino Masayuki、Fukuchi Tomoko、Mori Yasuo、Yamahana Reiko、Inamoto Yoshihiro、Fukuda Takahiro
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 26 Issue: 5 Pages: 949-955
  • DOI: 10.1016/j.bbmt.2020.01.008
  • Peer Reviewed
• [Journal Article] Late effects after ablative allogeneic stem cell transplantation for adolescent and young adult acute myeloid leukemia (2020)
  • Author(s): Lee Catherine、Kim Soyoung、Tecca Heather、Bo-Subait Stephanie、Phelan Rachel、Brazauskas Ruta、Buchbinder David、Hamilton Betty K.、Battiwalla Minoo、Majhail Navneet S.、Lazarus Hillard M.、Shaw Peter J.、Marks David I.、Litzow Mark R.、Chhabra Saurabh、Inamoto Yoshihiro、et al.
  • Journal Title: Blood Advances Volume: 4 Issue: 6 Pages: 983-992
  • DOI: 10.1182/bloodadvances.2019001126
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Detrimental effects of pretransplant cisplatin-based chemotherapy on renal function after allogeneic hematopoietic cell transplantation for lymphoma (2020)
  • Author(s): Onishi Akio、Inamoto Yoshihiro、Tajima Kinuko、Yamaguchi Junko、Kawashima Ichiro、Kawajiri Akihisa、Takemura Tomonari、Ito Ayumu、Tanaka Takashi、Okinaka Keiji、Fuji Shigeo、Kurosawa Saiko、Kim Sung-Won、Fukuda Takahiro
  • Journal Title: Bone Marrow Transplantation Volume: 55 Issue: 11 Pages: 2196-2198
  • DOI: 10.1038/s41409-020-0917-2
  • Peer Reviewed
• [Journal Article] Subsequent neoplasms and late mortality in children undergoing allogeneic transplantation for nonmalignant diseases (2020)
  • Author(s): Kahn JM, Brazauskas R, Tecca HR, Bo-Subait S, Buchbinder D, Battiwala M, Flowers MED, Savani BN, Phelan R, Broglie L, Abraham AA, Keating AK, Daly A, Wirk B, George B, Alter BP, Ustun C, Freytes CO, Beitinjaneh AM, Duncan C, Copelan E, Hildebrandt GC, Murthy HS, Lazarus HM, Auletta JJ, Myers KC, Inamoto Y, et al.
  • Journal Title: Blood Advances Volume: 4 Issue: 9 Pages: 2084-2094
  • DOI: 10.1182/bloodadvances.2019000839
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dickkopf-related protein 3 is a novel biomarker for chronic GVHD after allogeneic hematopoietic cell transplantation (2020)
  • Author(s): Inamoto Yoshihiro、Martin Paul J.、Lee Stephanie J.、Momin Amin A.、Tabellini Laura、Onstad Lynn E.、Pidala Joseph、Flowers Mary E. D.、Lawler Richard L.、Katayama Hiroyuki、Hanash Samir、Hansen John A.
  • Journal Title: Blood Advances Volume: 4 Issue: 11 Pages: 2409-2417
  • DOI: 10.1182/bloodadvances.2020001485
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bone Health Management After Hematopoietic Cell Transplantation: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy (2020)
  • Author(s): Bar Merav、Ott Susan M.、Lewiecki E. Michael、Sarafoglou Kyriakie、Wu Joy Y.、Thompson Matthew J.、Vaux Jonathan J.、Dean David R.、Saag Kenneth G.、Hashmi Shahrukh K.、Inamoto Yoshihiro、et.al.
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 26 Issue: 10 Pages: 1784-1802
  • DOI: 10.1016/j.bbmt.2020.07.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Refined National Institutes of Health response algorithm for chronic graft-versus-host disease in joints and fascia (2020)
  • Author(s): Inamoto Y, Lee SJ, Onstad LE, Flowers MED, Hamilton BK, Jagasia MH, Martin PJ, Pavletic SZ, Pidala JA, Pusic I, Vogelsang GB, Wolff D, Carpenter PA.
  • Journal Title: Blood Adv. Volume: 4 Pages: 40-46
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of characteristics and outcomes of late acute and NIH chronic GVHD between Japanese and white patients (2019)
  • Author(s): Inamoto Y, White J, Ito R, Martin PJ, Fatobene G, Ito A, Tanaka T, Kurosawa S, Kim SW, Bar M, Sorror ML, Sandmaier BM, Lee SJ, Fukuda T, Flowers MED.
  • Journal Title: Blood Adv. Volume: 3 Pages: 2764-2777
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-GVHD ocular complications after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT (2019)
  • Author(s): Inamoto Y, Petricek I, Burns L, Chhabra S, DeFilipp Z, Hematti P, et al.
  • Journal Title: Bone Marrow Transplant. Volume: 54 Pages: 648-661
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ocular graft-versus-host disease after hematopoietic cell transplantation: Expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT (2019)
  • Author(s): Inamoto Y, Valdes-Sanz N, Ogawa Y, Alves M, Berchicci L, Galvin J, et al.
  • Journal Title: Bone Marrow Transplant. Volume: 54 Pages: 662-673
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High probability of follow-up termination among AYA survivors after allogeneic hematopoietic cell transplantation (2019)
  • Author(s): Miyamura K, Yamashita T, Atsuta Y, Ichinohe T, Kato K, Uchida N, Fukuda T, Ohashi K, Ogawa H, Eto T, Inoue M, Takahashi S, Mori T, Kanamori H, Yabe H, Hama A, Okamoto S, Inamoto Y.
  • Journal Title: Blood Adv. Volume: 3 Pages: 397-405
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of Late Acute and Chronic Graft-Versus-Host Disease according to the 2014 National Institutes of Health Consensus Criteria in Japanese Patients (2019)
  • Author(s): Ito R, Inamoto Y, Inoue Y, Ito A, Tanaka T, Fuji S, Okinaka K, Kurosawa S, Kim SW, Yamashita T, Fukuda T.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 25 Pages: 293-300
  • Peer Reviewed
• [Journal Article] Long-term outcomes among 2-year survivors of autologous hematopoietic cell transplantation for Hodgkin and diffuse large b-cell lymphoma. (2018)
  • Author(s): Myers RM, Hill BT, Shaw BE, Kim S, Millard HR, Battiwalla M, Majhail NS, Buchbinder D, Lazarus HM, Savani BN, Flowers MED, D'Souza A, Ehrhardt MJ, Langston A, Yared JA, Hayashi RJ, Daly A, Olsson RF, Inamoto Y et al.
  • Journal Title: Cancer. Volume: 124 Pages: 816-825
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ASBMT Practice Guidelines Committee Survey on Long-Term Follow-Up Clinics for Hematopoietic Cell Transplant Survivors. (2018)
  • Author(s): Hashmi SK, Lee SJ, Savani BN, Burns L, Wingard JR, Perales MA, Palmer J, Chow E, Meyer E, Marks D, Mohty M, Inamoto Y et al.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 24 Pages: 1119-1124
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma. (2018)
  • Author(s): Radivoyevitch T, Dean RM, Shaw BE, Brazauskas R, Tecca HR, Molenaar RJ, Battiwalla M, Savani BN, Flowers MED, Cooke KR, Hamilton BK, Kalaycio M, Maciejewski JP, Ahmed I, Akpek G, Bajel A, Buchbinder D, Cahn JY, D'Souza A, Daly A, DeFilipp Z, Ganguly S, Hamadani M, Hayashi RJ, Hematti P, Inamoto Y et al.
  • Journal Title: Leuk Res. Volume: 74 Pages: 130-136
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Outcomes of patients who developed subsequent solid cancer after hematopoietic cell transplantation. (2018)
  • Author(s): Inamoto Y, Matsuda T, Tabuchi K, Kurosawa S, Nakasone H, Nishimori H, Yamasaki S, Doki N, Iwato K, Mori T, Takahashi S, Yabe H, Kohno A, Nakamae H, Sakura T, Hashimoto H, Sugita J, Ago H, Fukuda T, Ichinohe T, Atsuta Y, Yamashita T
  • Journal Title: Blood Adv. Volume: 2 Pages: 1901-1913
  • NAID: 120006723411
  • Peer Reviewed / Open Access
• [Presentation] Incidence, Risk Factors and Outcomes of Therapy-Related Myeloid Malignancies after Hematopoietic Cell Transplantation: Analysis of the Japan Society for Hematopoietic Cell Transplantation Late Complications and QOL Working Group (2020)
  • Author(s): Kuno M, Yamasaki S, Fukuda T, Mori T, Uchida N, Katayama Y, Onizuka M, Ichinohe T, Atsuta Y, Inamoto Y
  • Organizer: Transplant and Cellular Therapy meeting
  • Int'l Joint Research
• [Presentation] Comparison of characteristics and outcomes of late acute and chronic graft-versus-host disease between Japanese and White patients (2019)
  • Author(s): Inamoto Y, White J, Ito R, Martin PJ, Fatobene G, Ito A, Tanaka T, Kurosawa S, Kim SW, Bar M, Lee SJ, Fukuda T, Flowers MED.
  • Organizer: 日本血液学会