Clonal Hematopoiesis in Long-term Survivors after Allogeneic Stem Cell Transplantation

• Project/Area Number: 19K17848
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tokyo Metropolitan Komagome Hospital (Clinical research laboratory)
• Principal Investigator: Toya Takashi 東京都立駒込病院(臨床研究室), 血液内科, 医員 (40732805)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: クローン性造血 / 同種造血幹細胞移植 / クローン造血

Outline of Research at the Start

本研究では、造血幹細胞移植後長期生存患者におけるクローン造血の頻度と臨床的意義を調べる。一般に高齢者で高頻度に見つかるクローン造血は、明らかな血液疾患がないにも関わらず関連した遺伝子異常が指摘される状態で、血液腫瘍や虚血性心疾患の発症リスクとなる。移植による各種ストレスはクローン造血を惹起する可能性があるが、これまでほぼ調べられていない。我々は移植後長期生存患者から文書による同意を得て得られた検体を用いて次世代シーケンスを行い、クローン造血の頻度とその内容、臨床的特徴や晩期合併症との関連を探索するとともに、クローン造血の経時的変化も調べる。

Outline of Final Research Achievements

101 patients who survived without relapse at least 10 years after allogeneic SCT were included. PB samples were collected and targeted sequencing was done. Calculated copy number variations (CNVs) were statistically evaluated based on the NGS data.
Median interval from SCT to sampling was 13.8 years. 44 gene mutations and 5 CNVs were detected in 34 patients (33.7%). DNMT3A was most common (26.5%). CH was frequent when both the patient and the donor were old. Multivariate analysis showed that Higher donor age and CML were associated with CH. Mutations in samples collected 28 days after SCT were also assessed in 12 CH-positive patients. Among 17 CHs, 4 were also detected in day-28 samples, but others were newly detected in 10-year. RDW in 10-year sample was higher in patients with CH in day-28 sample.
In conclusion, CH was common after SCT, especially in patients with CML. Both of donor/recipient age was important. Some CHs were derived from donor; others seemed to be achieved after SCT.

Academic Significance and Societal Importance of the Research Achievements

同種造血幹細胞移植後長期生存者でクローン性造血が高頻度に認められることを明らかにした。ドナー由来造血細胞のCHの有無に患者年齢や基礎疾患との関係が見られたことは、骨髄微小環境の関与を示唆するものと考えられた。
がんや心血管イベントは移植後晩期合併症としてしばしば認められ長期生存の障壁となりうるが、一方でこれらの疾患はクローン性造血とも関連があることが知られている。移植患者のクローン性造血の有無を調べることでこれら晩期合併症の発症予測や予防、移植患者の長期予後改善に資する可能性があるが、今後前方視的解析を行うことでより明確な結果を出すことが必要である。

Research Products

• [Journal Article] Donor‐derived gene mutations in sex chromosome loss after stem cell transplantation (2021)
  • Author(s): Adachi Hiroto、Sadato Daichi、Toya Takashi、Hirama Chizuko、Haraguchi Kyoko、Mukae Junichi、Shingai Naoki、Shimizu Hiroaki、Najima Yuho、Kobayashi Takeshi、Okuyama Yoshiki、Oboki Keisuke、Harada Hironori、Sakamaki Hisashi、Ohashi Kazuteru、Harada Yuka、Doki Noriko
  • Journal Title: British Journal of Haematology Volume: 195 Issue: 3 Pages: 142-146
  • DOI: 10.1111/bjh.17716
  • Peer Reviewed / Open Access
• [Journal Article] T-cell receptor repertoire of cytomegalovirus-specific cytotoxic T-cells after allogeneic stem cell transplantation (2020)
  • Author(s): Toya Takashi、Taguchi Ayumi、et al.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1
  • DOI: 10.1038/s41598-020-79363-2
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic impact of TP53 mutation, monosomal karyotype, and prior myeloid disorder in nonremission acute myeloid leukemia at allo-HSCT (2020)
  • Author(s): Najima Yuho、Sadato Daichi、Harada Yuka、Oboki Keisuke、Hirama Chizuko、Toya Takashi、Doki Noriko、Haraguchi Kyoko、Yoshifuji Kota、Akiyama Megumi、Inamoto Kyoko、Igarashi Aiko、Kobayashi Takeshi、Kakihana Kazuhiko、Okuyama Yoshiki、Sakamaki Hisashi、Harada Hironori、Ohashi Kazuteru
  • Journal Title: Bone Marrow Transplantation Volume: 56 Issue: 2 Pages: 334-346
  • DOI: 10.1038/s41409-020-01016-9
  • Peer Reviewed
• [Journal Article] Time-Varying Effects of Graft Type on Outcomes for Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation (2020)
  • Author(s): Yanada M, Konuma T, Yamasaki S, Kuwatsuka Y, Masuko M, Tanaka M, Ozawa Y, Toya T, Fukuda T, Ota S, Sawa M, Uchida N, Nakamae H, Eto T, Kanda J, Takanashi M, Kanda Y, Atsuta Y, Yano S.
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 26 Issue: 2 Pages: 307-315
  • DOI: 10.1016/j.bbmt.2019.09.036
  • Peer Reviewed
• [Journal Article] Heterogeneous impact of cytomegalovirus reactivation on nonrelapse mortality in hematopoietic stem cell transplantation (2020)
  • Author(s): Kaito Satoshi、Nakajima Yujiro、Hara Konan、Toya Takashi、Nishida Tetsuya、Uchida Naoyuki、Mukae Junichi、Fukuda Takahiro、Ozawa Yukiyasu、Tanaka Masatsugu、Ikegame Kazuhiro、Katayama Yuta、Kuriyama Takuro、Kanda Junya、Atsuta Yoshiko、Ogata Masao、Taguchi Ayumi、Ohashi Kazuteru
  • Journal Title: Blood Advances Volume: 4 Issue: 6 Pages: 1051-1061
  • DOI: 10.1182/bloodadvances.2019000814
  • Peer Reviewed / Open Access
• [Journal Article] Tyrosine kinase inhibitor maintenance therapy following allogenic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia (2020)
  • Author(s): 内田 智之、白根 脩一、稲本 恭子、遠矢 嵩、五十嵐 愛子、名島 悠峰、武藤 秀治、小林 武、垣花 和彦、坂巻 壽、大橋 一輝、土岐 典子、岸田 侑也、永田 啓人、山田 裕太、小西 達矢、海渡 智史、黒澤 修兵、吉藤 康太
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 1 Pages: 11-19
  • DOI: 10.11406/rinketsu.61.11
  • NAID: 130007794715
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Late appearance of eosinophilia in myeloid blast phase of myeloid neoplasm with rearrangement of PDGFRβ (2020)
  • Author(s): Nagata A, Doki N, Harada H, Takezaki T, Konishi T, Yamada Y, Kaito S, Kurosawa S, Yoshifuji K, Harada K, Sakaguchi M, Yasuda S, Yoshioka K, Watakabe-Inamoto K, Toya T, Igarashi A, Najima Y, Muto H, Kobayashi T, Kakihana K, Harada Y, Sakamaki H, Ohashi K
  • Journal Title: Leukemia & Lymphoma Volume: - Issue: 7 Pages: 1-4
  • DOI: 10.1080/10428194.2020.1731499
  • Peer Reviewed
• [Journal Article] Long-term results of reduced-intensity conditioning allogeneic hematopoietic cell transplantation for older patients with acute myeloid leukemia: a retrospective analysis of 10-year follow-up data (2020)
  • Author(s): Yanada Masamitsu、Fukuda Takahiro、Tanaka Masatsugu、Ota Shuichi、Toya Takashi、Mori Takehiko、Uchida Naoyuki、Ozawa Yukiyasu、Nakamae Hirohisa、Kanda Yoshinobu、Ichinohe Tatsuo、Atsuta Yoshiko、Yano Shingo
  • Journal Title: Bone Marrow Transplantation Volume: - Issue: 10 Pages: 2008-2016
  • DOI: 10.1038/s41409-020-0868-7
  • Peer Reviewed
• [Journal Article] 誌上再現!Clinical Debate at JSH2019【Clinical Debate 5:AML】FLT3-ITD陽性急性骨髄性白血病は第一寛解期に同種造血幹細胞移植の適応があるのか? (2020)
  • Author(s): 遠矢 嵩, 吉本 五一, 山口 博樹
  • Journal Title: 臨床血液 Volume: 61 Pages: 150-155
• [Journal Article] Nutritional risk index as a risk factor for breakthrough candidemia in allogeneic hematopoietic stem cell transplantation (2019)
  • Author(s): Kaito Satoshi、Sekiya Noritaka、Najima Yuho、Suzuki Tomokazu、Wada Atsushi、Adachi Hiroto、Konuma Ryosuke、Kishida Yuya、Nagata Akihito、Konishi Tatsuya、Yamada Yuta、Kumagai Takuma、Inamoto Kyoko、Yoshifuji Kota、Akiyama Megumi、Toya Takashi、et al.
  • Journal Title: Bone Marrow Transplantation Volume: 55 Issue: 3 Pages: 661-664
  • DOI: 10.1038/s41409-019-0541-1
  • Peer Reviewed
• [Journal Article] The emergence of rare nocardiosis following allogeneic hematopoietic stem cell transplantation in the era of molecular taxonomy (2019)
  • Author(s): Kurosawa Shuhei、Sekiya Noritaka、Doki Noriko、Yaguchi Takashi、Kishida Yuya、Nagata Akihito、Yamada Yuta、Konishi Tatsuya、Kaito Satoshi、Yoshifuji Kota、Shirane Shuichi、Uchida Tomoyuki、Inamoto Kyoko、Toya Takashi、et al.
  • Journal Title: International Journal of Infectious Diseases Volume: 89 Pages: 154-162
  • DOI: 10.1016/j.ijid.2019.10.003
  • Peer Reviewed
• [Journal Article] Successful hematopoietic stem-cell mobilization with plerixafor plus granulocyte-colony stimulating factor in multiple myeloma patients treated with pomalidomide (2019)
  • Author(s): Yoshifuji K, Toya T, Adachi H, Fujita M, Wada A, Konuma R, Kishida Y, Konishi T, Nagata A, Yamada Y, Kaito S, Kumagai T, Inamoto K, Akiyama M, Igarashi A, Najima Y, Doki N, Kobayashi T, Kakihana K, Sakamaki H, Ohashi K.
  • Journal Title: Int J Hematol Volume: 110 Issue: 1 Pages: 115-118
  • DOI: 10.1007/s12185-019-02622-0
  • Peer Reviewed
• [Journal Article] Unmanipulated haploidentical hematopoietic stem cell transplantation using very low-dose antithymocyte globulin and methylprednisolone in adults with relapsed/refractory acute leukemia (2019)
  • Author(s): Konishi T, Doki N, Nagata A, Yamada Y, Takezaki T, Kaito S, Kurosawa S, Sakaguchi M, Harada K, Yasuda S, Yoshioka K, Inamoto K, Toya T, Igarashi A, Najima Y, Kobayashi T, Kakihana K, Sakamaki H, Ohashi K.
  • Journal Title: Ann Hematol Volume: 99 Issue: 1 Pages: 147-155
  • DOI: 10.1007/s00277-019-03865-x
• [Presentation] Mutation Analysis of Very Late Relapse of Myeloid Malignancies after Stem Cell Transplantation. (2021)
  • Author(s): Takashi Toya, Daichi Sadato, Yasuhiro Kanbara, Chizuko Hirama, Kyoko Haraguchi, Hiroaki Shimizu, Yuho Najima, Takeshi Kobayashi, Yoshiki Okuyama, Keisuke Oboki, Hironori Harada, Kazuteru Ohashi, Yuka Harada, Noriko Doki
  • Organizer: 12th JSH International Symposium
• [Presentation] 移植後超晩期再発骨髄系腫瘍の遺伝子変異動態 (2021)
  • Author(s): 遠矢 嵩、貞任大地、平間千津子、大保木啓介、原田浩徳、原田結花
  • Organizer: 第80回日本癌学会学術集会
• [Presentation] 同種造血幹細胞移植後長期生存者のクローン造血の特徴 (2021)
  • Author(s): 遠矢 嵩、貞任大地、平間千津子、原口京子、神原康弘、熱田雄也、須崎 賢、小沼亮介、安達弘人、和田敦司、岸田侑也、内堀雄介、迎 純一、新谷 直樹、清水 啓明、名島悠峰、小林 武、奥山美樹、大保木啓介、原田浩徳、坂巻 壽、大橋一輝、原田結花、土岐典子
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] 同種移植後長期生存者のクローン造血 (2021)
  • Author(s): 遠矢 嵩
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] Sex chromosome loss after allogeneic hematopoietic stem cell transplant (2020)
  • Author(s): 安達 弘人、遠矢 嵩
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 同種造血幹細胞移植後の性染色体欠失 (2020)
  • Author(s): 安達 弘人、遠矢 嵩、貞任 大地、原田 結花、大塚 友貴、当真 賢也、 小沼 亮介、和田 敦司、岸田 佑也、小西 達也、永田 啓人、山田 裕太、 永田 亮介、丸毛 淳史、野口 佑真、迎 純一、五十嵐愛子、名島 悠峰、 小林 武、垣花 和彦、大保木亮介、原田 浩徳、坂巻 壽、大橋 一輝、 土岐 典子
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] 同種造血幹細胞移植後CMV特異的T細胞受容体のクローン変化 (2019)
  • Author(s): 遠矢 嵩, 田口 歩, 北浦 一孝, 安達 弘人, 藤田 昌宏, 和田 敦司, 小沼 亮介, 岸田 侑也, 小西 達矢, 永田 啓人, 山田 裕太, 熊谷 拓磨, 海渡 智史, 吉藤 康太, 迎 純一, 秋山 めぐみ, 稲本 恭子, 五十嵐 愛子, 名島 悠峰, 土岐 典子, 小林 武, 垣花 和彦, 坂巻 壽, 鈴木 隆二, 大橋 一輝
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Clinical Debate 5 AML (2019)
  • Author(s): 遠矢 嵩, 吉本 五一, 山口 博樹
  • Organizer: 第81回日本血液学会学術集会
  • Invited
• [Presentation] Clonal Dynamics and Publicness of CMV-Specific TCR Repertoire after Allogeneic Stem Cell Transplantation (2019)
  • Author(s): Takashi Toya, MD PhD, Ayumi Taguchi, MD PhD, et al.
  • Organizer: 61th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Clinical and Genetic Characteristics of Adolescent and Young Adult Patients with Myelodysplastic Syndromes (2019)
  • Author(s): Tatsuya Konishi, Yuka Harada, MD PhD, Daichi Sadato, MS, Yuki Otsuka, MD, Ryosuke Konuma, MD, Hiroto Adachi, MD, Atsushi Wada, MD, Yuya Kishida, MD, Akihito Nagata, Yuta Yamada, MD, Atsushi Marumo, MD, Yuma Noguchi, MD, Junichi Mukae, MD, Kyoko Inamoto, MD, Takashi Toya, MD PhD, et al.
  • Organizer: 61th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Weight Adjusted Urinary Creatinine Excretion Predicts Transplant Outcomes in Adult Patients with Acute Myeloid Leukemia in Complete Remission (2019)
  • Author(s): Akihito Nagata , Noriko Doki, MD PhD , Yuki Otsuka, MD , Ryosuke Konuma, MD , Hiroto Adachi, MD , Atsushi Wada, MD , Kenya Toma, MD , Yuya Kishida, MD , Tatsuya Konishi , Yuta Yamada, MD , Ryohei Nagata, MD , Yuma Noguchi, MD , Atsushi Marumo, MD , Junichi Mukae, MD , Kyoko Inamoto, MD , Takashi Toya, MD PhD , et al.
  • Organizer: 61th American Society of Hematology Annual Meeting
  • Int'l Joint Research