Development of novel biomarkers and international evaluation methods of chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation

• Project/Area Number: 15K19563
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• 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, 医員 (70730349)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 移植片対宿主病 / 造血細胞移植 / バイオマーカー / 同種造血細胞移植 / 予後 / 臨床研究 / 評価法

Outline of Final Research Achievements

There is an unmet need for identifying useful biomarkers to predict onset and outcomes of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. We performed international collaborative studies of novel biomarkers for chronic GVHD. Using tandem mass spectrometry, we have identified plasma CD163 protein as a novel biomarker for predicting chronic GVHD, and have identified plasma MMP3 as a novel biomarker related to bronchiolitis obliterans. We also evaluated Japanese patients with chronic GVHD using the 2014 NIH consensus criteria and have characterized clinical manifestations of chronic GVHD in Japanese patients. The results would serve as a benchmark for Japanese patients with chronic GVHD.

Academic Significance and Societal Importance of the Research Achievements

本研究は海外との共同研究という形で、同種造血細胞移植後の大きな課題である慢性GVHDの予測や病態に関連した新規血漿蛋白バイオマーカーを発見した。慢性GVHDの新規バイオマーカーは、現在も知見が限られており、貴重な学術成果が得られたものと考えられる。また、臨床応用が進めば、治療成績の向上につながる可能性もある。次に、国際評価法を用いて日本人患者の慢性GVHDの特徴を明らかに出来たことは、2014年NIH新基準の有用性を日本から海外に向けて示したという意義が大きい。さらに、今後のGVHDに関する国際共同研究や治験において、日本人の基礎データとして役立つものと考える。

Research Products

• [Int'l Joint Research] Fred Hutchinson Cancer research Center/MD Anderson cancer Center(米国)
• [Int'l Joint Research] Fred Hutchinson Cancer Research Center/MD Anderson Cancer Center(米国)
• [Int'l Joint Research] Fred Hutchinson Cancer Research Center/MD Anderson Cancer Center(米国)
• [Journal Article] Double-Expressor Lymphoma Is Associated with Poor Outcomes after Allogeneic Hematopoietic Cell Transplantation. (2018)
  • Author(s): Kawashima I, Inamoto Y, Maeshima AM, Nomoto J, Tajima K, Honda T, Shichijo T, Kawajiri A, Takemura T, Onishi A, Ito A, Tanaka T, Fuji S, Kurosawa S, Kim SW, Maruyama D, Tobinai K, Kobayashi Y, Fukuda T.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 24 Pages: 294-300
  • Peer Reviewed
• [Journal Article] Donor body mass index does not predict graft versus host disease following hematopoietic cell transplantation. (2018)
  • Author(s): Turcotte LM, Wang T, Hemmer MT, Spellman SR, Arora M, Couriel D, Alousi A, Pidala J, Abdel-Azim H, Ahmed I, Beitinjaneh A, Buchbinder D, Byrne M, Callander N, Chao N, Choi SW, DeFilipp Z, Gadalla SM, Gale RP, Gergis U, Hashmi S, Hematti P, Holmberg L, Inamoto Y, et al.
  • Journal Title: Bone Marrow Transplant. Volume: 53 Pages: 932-937
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Graft-versus-host disease in recipients of male unrelated donor compared with parous female sibling donor transplants. (2018)
  • Author(s): Kumar AJ, Kim S, Hemmer MT, Arora M, Spellman SR, Pidala JA, Couriel DR, Alousi AM, Aljurf MD, Cahn JY, Cairo MS, Cutler CS, Farhan S, Gergis U, Hale GA, Hashmi SK, Inamoto Y, et al.
  • Journal Title: Blood Adv. Volume: 2 Pages: 1022-1031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Upper gastrointestinal acute graft-versus-host disease adds minimal prognostic value in isolation or with other graft-versus-host disease symptoms as currently diagnosed and treated. (2018)
  • Author(s): Nikiforow S, Wang T, Hemmer M, Spellman S, Akpek G, Antin JH, Choi SW, Inamoto Y, Khoury HJ, MacMillan M, Marks DI, Meehan K, Nakasone H, Nishihori T, Olsson R, Paczesny S, Przepiorka D, Reddy V, Reshef R, Schoemans H, Waller N, Weisdorf D, Wirk B, Horowitz M, Alousi A, Couriel D, Pidala J, Arora M, Cutler C
  • Journal Title: Haematologica. Volume: 103 Pages: 1708-1708
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802. (2018)
  • Author(s): Holtan SG, DeFor TE, Panoskaltsis-Mortari A, Khera N, Levine JE, Flowers MED, Lee SJ, Inamoto Y, et al.
  • Journal Title: Blood Adv. Volume: 2 Pages: 1882-1888
  • Peer Reviewed / Open Access / 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 / Int'l Joint Research
• [Journal Article] 慢性GVHDについての最新知見 (2018)
  • Author(s): 稲本賢弘
  • Journal Title: 臨床血液 Volume: 59 Pages: 2300-2306
  • NAID: 130007496820
  • Peer Reviewed
• [Journal Article] Quality of Life after Allogeneic Hematopoietic Cell Transplantation According to Affected Organ and Severity of Chronic Graft-versus-Host Disease (2017)
  • Author(s): Kurosawa S, Oshima K, Yamaguchi T, Yanagisawa A, Fukuda T, Kanamori H, Mori T, Takahashi S, Kondo T, Kohno A, Miyamura K, Umemoto Y, Teshima T, Taniguchi S, Yamashita T1 Inamoto Y, Kanda Y, Okamoto S, Atsuta Y.
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 23 Issue: 10 Pages: 1749-1758
  • DOI: 10.1016/j.bbmt.2017.06.011
  • Peer Reviewed
• [Journal Article] GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia. (2017)
  • Author(s): Terakura S, Kuwatsuka Y, Yamasaki S, Wake A, Kanda J, Inamoto Y, Mizuta S, Yamaguchi T, Uchida N, Kouzai Y, Aotsuka N, Ogawa H, Kanamori H, Nishiwaki K, Miyakoshi S, Onizuka M, Amano I, Fukuda T, Ichinohe T, Atsuta Y, Murata M, Teshima T.
  • Journal Title: Bone Marrow Transplant. Volume: 52 Pages: 1261-1267
  • NAID: 120006367975
  • Peer Reviewed
• [Journal Article] An endpoint associated with clinical benefit after initial treatment of chronic graft-versus-host disease. (2017)
  • Author(s): Martin PJ, Storer BE, Inamoto Y, Flowers MED, Carpenter PA, Pidala J, Palmer J, Arora M, Jagasia M, Arai S, Cutler CS, Lee SJ.
  • Journal Title: Blood. Volume: 130 Issue: 3 Pages: 360-367
  • DOI: 10.1182/blood-2017-03-775767
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Association of Plasma CD163 Concentration with De Novo-Onset Chronic Graft-versus-Host Disease. (2017)
  • Author(s): Inamoto Y, Martin PJ, Paczesny S, Tabellini L, Momin AA, Mumaw CL, Flowers MED, Lee SJ, Carpenter PA, Storer BE, Hanash S, Hansen JA.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 23 Issue: 8 Pages: 1250-1256
  • DOI: 10.1016/j.bbmt.2017.04.019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Late effects of blood and marrow transplantation. (2017)
  • Author(s): Inamoto Y, Lee SJ.
  • Journal Title: Haematologica. Volume: 102 Issue: 4 Pages: 614-625
  • DOI: 10.3324/haematol.2016.150250
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes. (2017)
  • Author(s): Chen YB, Wang T, Hemmer MT, Brady C, Couriel DR, Alousi A, Pidala J, Urbano-Ispizua A, Choi SW, Nishihori T, Teshima T, Inamoto Y, et al.
  • Journal Title: Bone Marrow Transplant. Volume: 52 Issue: 3 Pages: 400-408
  • DOI: 10.1038/bmt.2016.265
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A combined biomarker and clinical panel for chronic graft versus host disease diagnosis (2017)
  • Author(s): Pidala J, Sigdel TK, Wang A, Hsieh S, Inamoto Y, Martin PJ, Flowers ME, Hansen JA, Lee SJ, Sarwal MM.
  • Journal Title: J Pathol Clin Res. Volume: 3 Issue: 1 Pages: 3-16
  • DOI: 10.1002/cjp2.58
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups. (2016)
  • Author(s): Inamoto Y, Kimura F, Kanda J, Sugita J, Ikegame K, Nakasone H, Nannya Y, Uchida N, Fukuda T, Yoshioka K, Ozawa Y, Kawano I, Atsuta Y, Kato K, Ichinohe T, Inoue M, Teshima T
  • Journal Title: Haematologica. Volume: 101 Issue: 12 Pages: 1592-1602
  • DOI: 10.3324/haematol.2016.149427
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic risk factors for sclerotic graft-versus-host disease. (2016)
  • Author(s): Inamoto Y, Martin PJ, Flowers ME, Lee SJ, Carpenter PA, Warren EH, Geraghty DE, Lee N, Boeckh MJ, Storer BE, Levine DM, Fan W, Zhao LP, Hansen JA.
  • Journal Title: Blood Volume: 128 Issue: 11 Pages: 1516-1524
  • DOI: 10.1182/blood-2016-05-715342
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Proteomic Characterization Reveals That MMP-3 Correlates With Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Cell and Lung Transplantation. (2016)
  • Author(s): Liu X, Yue Z, Yu J, Daguindau E, Kushekhar K, Zhang Q, Ogata Y, Gafken PR, Inamoto Y, Gracon A, Wilkes DS, Hansen JA, Lee SJ, Chen JY, Paczesny S.
  • Journal Title: Am J Transplant. Volume: 16 Issue: 8 Pages: 2342-2351
  • DOI: 10.1111/ajt.13750
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Association of Cumulative Steroid Dose with Risk of Infection after Treatment for Severe Acute Graft-versus-Host Disease. (2016)
  • Author(s): Matsumura-Kimoto Y, Inamoto Y, Tajima K, Kawajiri A, Tanaka T, Hirakawa T, Ino K, Asao Y, Tamogami H, Kono C, Takeda W, Okinaka K, Fuji S, Kurosawa S, Kim SW, Tanosaki R, Yamashita T, Fukuda T.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 22 Issue: 6 Pages: 1102-1107
  • DOI: 10.1016/j.bbmt.2016.02.020
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Eltrombopag for Treatment of Thrombocytopenia after Allogeneic Hematopoietic Cell Transplantation. (2016)
  • Author(s): Tanaka T, Inamoto Y, Yamashita T, Fuji S, Okinaka K, Kurosawa S, Kim SW, Tanosaki R, Fukuda T.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 22 Issue: 5 Pages: 919-924
  • DOI: 10.1016/j.bbmt.2016.01.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Late Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation. (2016)
  • Author(s): Arora M, Cutler CS, Jagasia MH, Pidala J, Chai X, Martin PJ, Flowers ME, Inamoto Y, Chen GL, Wood WA, Khera N, Palmer J, Duong H, Arai S, Mayer S, Pusic I, Lee SJ.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 22 Issue: 3 Pages: 449-455
  • DOI: 10.1016/j.bbmt.2015.10.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Predictors of survival, nonrelapse mortality, and failure-free survival in patients treated for chronic graft-versus-host disease. (2016)
  • Author(s): Palmer J, Chai X, Pidala J, Inamoto Y, Martin PJ, Storer B, Pusic I, Flowers ME, Arora M, Pavletic SZ, Lee SJ.
  • Journal Title: Blood. Volume: 127 Issue: 1 Pages: 160-166
  • DOI: 10.1182/blood-2015-08-662874
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation. (2016)
  • Author(s): Williams KM, Cheng GS, Pusic I, Jagasia M, Burns L, Ho VT, Pidala J, Palmer J, Johnston L, Mayer S, Chien JW, Jacobsohn DA, Pavletic SZ, Martin PJ, Storer BE, Inamoto Y, Chai X, Flowers ME, Lee SJ.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 22 Issue: 4 Pages: 710-716
  • DOI: 10.1016/j.bbmt.2015.10.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation. (2016)
  • Author(s): Arai S, Pidala J, Pusic I, Chai X, Jaglowski S, Khera N, Palmer J, Chen GL, Jagasia MH, Mayer SA, Wood WA, Green M, Hyun TS, Inamoto Y, Storer BE, Miklos DB, Shulman HM, Martin PJ, Sarantopoulos S, Lee SJ, Flowers ME.
  • Journal Title: Clin Cancer Res. Volume: 22 Issue: 2 Pages: 319-327
  • DOI: 10.1158/1078-0432.ccr-15-1443
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bandage Soft Contact Lenses for Ocular Graft-versus-Host Disease. (2015)
  • Author(s): Inamoto Y, Sun YC, Flowers ME, Carpenter PA, Martin PJ, Li P, Wang R, Chai X, Storer BE, Shen TT, Lee SJ.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 21 Issue: 11 Pages: 2002-2007
  • DOI: 10.1016/j.bbmt.2015.07.013
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Impact of Ocular Chronic Graft-versus-Host Disease on Quality of Life. (2015)
  • Author(s): Sun YC, Chai X, Inamoto Y, Pidala J, Martin PJ, Flowers ME, Shen TT, Lee SJ, Jagasia M.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 21 Issue: 9 Pages: 1687-1691
  • DOI: 10.1016/j.bbmt.2015.05.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia. (2015)
  • Author(s): Inamoto Y, Flowers ME, Wang T, Urbano-Ispizua A, Hemmer MT, Cutler CS, Couriel DR, Alousi AM, Antin JH, Gale RP, Gupta V, Hamilton BK, Kharfan-Dabaja MA, Marks DI, Ringdén OT, Socié G, Solh MM, Akpek G, Cairo MS, Chao NJ, Hayashi RJ, Nishihori T, Reshef R, Saad A, Shah A, Teshima T, Tallman MS, et al.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 21 Issue: 10 Pages: 1776-1782
  • DOI: 10.1016/j.bbmt.2015.05.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 慢性GVHDについての最新知見 (2018)
  • Author(s): 稲本賢弘
  • Organizer: 第80回日本血液学会学術集会
  • Invited
• [Presentation] Characteristics of cGVHD in Japanese and results of physician survey (2017)
  • Author(s): 稲本賢弘
  • Organizer: 日本造血細胞移植学会総会
  • Place of Presentation: くにびきメッセ(島根県松江市)
  • Year and Date: 2017-03-02
  • Invited
• [Presentation] 悪性リンパ腫に対する白金製剤を含んだ同種移植前化学療法が腎機能および予後に及ぼす影響 (2017)
  • Author(s): 大西朗生、稲本賢弘、田島絹子、山口順子、久保博之、七條敬文、本田匡宏、久保由起子、川島一郎、越智清純、川尻昭寿、竹村兼成、伊藤歩、田中喬、冲中敬二、藤重夫、黒澤彩子、金成元、福田隆浩
  • Organizer: 日本造血細胞移植学会総会
  • Place of Presentation: くにびきメッセ(島根県松江市)
  • Year and Date: 2017-03-02
• [Presentation] Influence of pretransplant platinum-based chemotherapy on renal function and outcomes after allogeneic hematopoietic cell transplantation for lymphoma (2017)
  • Author(s): Akio Onishi, Yoshihiro Inamoto, Kinuko Tajima, Junko Yamaguchi, Hiroyuki Kubo, Takafumi Hichijyou, Tadahiro Honda, Yukiko Kubo, Ichiro Kawashima, Kiyosumi Ochi, Akihisa Kawajiri, Tomonari Takemura, Ayumu Ito, Takashi Tanaka, Keiji Okinaka, Shigeo Fuji, Saiko Kurosawa, Sung-Won Kim, Takahiro Fukuda
  • Organizer: ASBMT Tandem meeting
  • Place of Presentation: オーランド（アメリカ）
  • Year and Date: 2017-02-22
  • Int'l Joint Research
• [Presentation] Comparison of Graft-versus-Host Disease-Free, Relapse-Free Survival According to a Variety of Graft Sources (2017)
  • Author(s): Yoshihiro Inamoto
  • Organizer: 第79回日本血液学会総会
  • Invited
• [Presentation] 皮膚GVHDの病理学的検討 (2016)
  • Author(s): 伊藤礼子、稲本賢弘、前島亜希子、山下卓也、金成元、黒澤彩子、藤重夫、冲中敬二、福田隆浩
  • Organizer: 日本造血細胞移植学会総会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2016-03-05
• [Presentation] 血液悪性疾患における移植ソース別GRFSの解析: JSHCT Working Group研究 (2016)
  • Author(s): 稲本賢弘, 木村文彦, 諌田淳也, 杉田純一, 池亀和博, 仲宗根秀樹, 南谷泰仁, 内田直之, 福田隆浩, 吉岡康介, 河野一郎, 小澤幸泰, 熱田由子, 加藤剛二, 一戸辰夫, 井上雅美, 豊嶋崇徳
  • Organizer: 日本造血細胞移植学会総会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2016-03-04
• [Presentation] Comparison of Graft-versus-Host Disease-Free, Relapse-Free Survival (GRFS) of Patients with Hematological Malignancy According to Donor Type: JSHCT Working Group Study (2016)
  • Author(s): Yoshihiro Inamoto, Fumihiko Kimura, Junya Kanda, Junichi Sugita, Kazuhiro Ikegame, Hideki Nakasone, Yasuhito Nannya, Naoyuki Uchida, Takahiro Fukuda, Kosuke Yoshioka, Yukiyasu Ozawa, Ichiro Kawano, Yoshiko Atsuta, Koji Kato, Tatsuo Ichinohe, Masami Inoue, and Takanori Teshima
  • Organizer: ASBMT Tandem meeting
  • Place of Presentation: ホノルル（アメリカ）
  • Year and Date: 2016-02-21
  • Int'l Joint Research
• [Presentation] 2014 National Institutes of HealthCriteria for Chronic GVHD (2015)
  • Author(s): Yoshihiro Inamoto
  • Organizer: Asian Pacific BMT meeting
  • Place of Presentation: 万国津梁館（沖縄）
  • Year and Date: 2015-10-30
  • Int'l Joint Research / Invited
• [Presentation] 2014年NIH分類を用いた慢性GVHDの後方視的検討 (2015)
  • Author(s): 伊藤礼子、稲本賢弘、山下卓也、金成元、黒澤彩子、藤重夫、冲中敬二、田中喬、福田隆浩
  • Organizer: 日本血液学会総会
  • Place of Presentation: ホテル金沢（金沢）
  • Year and Date: 2015-10-17