Multilateral prognostic factor analysis for Ph+ALL in the era of TKI

• Project/Area Number: 20K08730
• 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: Nagoya University
• Principal Investigator: Nishiwaki Satoshi 名古屋大学, 医学部附属病院, 講師 (80753037)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: フィラデルフィア染色体陽性急性リンパ性白血病 / チロシンキナーゼ阻害剤 / 予後因子 / 付加的染色体異常 / +der(22)t(9;22) / 複雑核型 / JALSG試験 / TRUMPデータ

Outline of Research at the Start

難治性白血病であるフィラデルフィア染色体陽性急性リンパ性白血病（Ph+ALL）は、チロシンキナーゼ阻害剤（TKI）の登場により、治療強度を弱めて治療関連死亡を減らすという方向に治療戦略の転換期を迎えている。そこで、わが国の代表的な白血病研究グループである成人白血病治療共同研究支援機構（JALSG）のTKI時代の３つの臨床試験データと日本造血細胞移植学会の移植登録一元管理（TRUMP）データベースを統合し、Ph+ALLの全治療期間にわたるオールジャパンのデータを解析することで、TKI時代の予後因子を明らかにする。これにより、リスクに合わせた個別化治療を可能とし、患者にやさしい治療戦略を実現する。

Outline of Final Research Achievements

Additional chromosomal abnormalities other than the Philadelphia chromosome were found in 63.6% of 206 cases of de novo Ph+ALL. The most frequent structural abnormality was +der(22)t(9;22). Among the 43 cases with +der(22)t(9;22), 67.4% had a complex karyotype with three or more chromosomal aberrations. Coexistence of +der(22)t(9;22) and complex karyotype was associated with significantly poorer survival and shorter time to recurrence. In multivariate analysis, +der(22)t(9;22) alone or complex karyotype alone were not significant factors, but coexistence of +der(22)t(9;22) and complex karyotype was a significant risk factor for survival. This study demonstrated that the coexistence of +der(22)t(9;22) and complex karyotype was a significant prognostic factor in Ph+ALL.

Academic Significance and Societal Importance of the Research Achievements

Ph+ALLにおいて+der(22)t(9;22)と複雑核型の併存が予後不良因子であることを明らかとした。Ph＋ALLでは微小残存病変など治療反応性が予後因子として重要視されてきたが、染色体異常という白血病の本質的な部分でも予後を層別化できることが示された。これは、Ph＋ALLの治療の層別化につながる重要な意味を持つ。予後不良な群では同種移植を含む治療の強化により治療成績の改善を目指す一方、予後良好群では、治療強度を弱め、治療成績を維持したまま治療関連毒性を減らすことに結びつく。予後因子を明確化していくことで、個々の患者の病態に合わせた過不足ない治療選択を行うことが可能となる。

Research Products

• [Journal Article] Autologous peripheral blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia is safe but poses challenges for long-term maintenance of molecular remission: Results of the Auto-Ph17 study (2023)
  • Author(s): Nishiwaki S, Sugiura I, Sato T, Kobayashi M, Osaki M, Sawa M, Adachi Y, Okabe M, Saito S, Morishita T, Kohno A, Nishiyama T, Iida H, Kurahashi S, Kuwatsuka Y, Sugiyama D, Ito S, Nishikawa H, Kiyoi H
  • Journal Title: eJHaem Volume: - Issue: 2 Pages: 358-369
  • DOI: 10.1002/jha2.677
  • Peer Reviewed / Open Access
• [Journal Article] High-risk Combinations of Additional Chromosomal Abnormalities in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia: JALSG Ph+ALL TKI-SCT study (2023)
  • Author(s): Nishiwaki S, Sugiura I, Fujisawa S, Hatta Y, Atsuta Y, Doki N, Kurahashi S, Ueda Y, Dobashi N, Maeda T, Taniguchi Y, Tanaka M, Kako S, Ichinohe T, Fukuda T, Ohtake S, Ishikawa Y, Kiyoi H, Matsumura I, Miyazaki Y
  • Journal Title: HemaSphere Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Improvements in allogeneic hematopoietic cell transplantation outcomes for adults with ALL over the past 3 decades (2022)
  • Author(s): Nishiwaki S, Yu Akahoshi Y, Morita-Fujita M, Shimizu H, Uchida N, Ozawa Y, Fukuda T, Tanaka M, Ikegame K, Ota S, Katayama Y, Takahashi S, Kawakita T , Ara T, Onizuka M, Kimura T, Tanaka J, Atsuta Y, Arai Y
  • Journal Title: Blood Advances Volume: 6 Issue: 15 Pages: 4558-4569
  • DOI: 10.1182/bloodadvances.2022008032
  • Peer Reviewed / Open Access
• [Journal Article] Newly proposed threshold and validation of white blood cell count at diagnosis for Philadelphia chromosome-positive acute lymphoblastic leukemia: risk assessment of relapse in patients with negative minimal residual disease at transplantation?a report from the Adult Acute Lymphoblastic Leukemia Working Group of the JSTCT (2021)
  • Author(s): Akahoshi Yu、Arai Yasuyuki、Nishiwaki Satoshi、Tachibana Takayoshi、Shinohara Akihito、Doki Noriko、Uchida Naoyuki、Tanaka Masatsugu、Kanda Yoshinobu、Shiratori Souichi、Ozawa Yukiyasu、Shono Katsuhiro、Katayama Yuta、Tanaka Junji、Fukuda Takahiro、Atsuta Yoshiko、Kako Shinichi
  • Journal Title: Bone Marrow Transplantation Volume: 56 Issue: 11 Pages: 2842-2848
  • DOI: 10.1038/s41409-021-01422-7
  • Peer Reviewed
• [Journal Article] COVID-19 Pandemic and Trends in Clinical Trials: A Multi-Region and Global Perspective (2021)
  • Author(s): Satoshi Nishiwaki, Yuichi Ando
  • Journal Title: Frontiers in Medicine Volume: 8 Pages: 812370-812370
  • DOI: 10.3389/fmed.2021.812370
  • Peer Reviewed / Open Access
• [Journal Article] Machine learning-aided risk stratification in Philadelphia chromosome-positive acute lymphoblastic leukemia (2021)
  • Author(s): Nishiwaki S, Sugiura I, Koyama D, Ozawa Y, Osaki M, Ishikawa Y, Kiyoi H
  • Journal Title: Biomarker Research Volume: 9 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s40364-021-00268-x
  • Peer Reviewed / Open Access
• [Journal Article] Measurable residual disease affects allogeneic hematopoietic cell transplantation in Ph+ ALL during both CR1 and CR2 (2021)
  • Author(s): Nishiwaki S, Akahoshi Y, Mizuta S, Shinohara A, Hirabayashi S, Noguchi Y, Fukuda T, Uchida N, Tanaka M, Onizuka M, Ozawa Y, Ota S, Shiratori S, Onishi Y, Kanda Y, Sawa M, Tanaka J, Atsuta Y, Kako S
  • Journal Title: Blood Advances Volume: 5 Issue: 2 Pages: 584-592
  • DOI: 10.1182/bloodadvances.2020003536
  • Peer Reviewed / Open Access
• [Presentation] Poor Prognostic Combination of Additional Chromosomal Abnormalities in Ph+ALL (JALSG Ph+ALL TKI- SCT study) (2022)
  • Author(s): Nishiwaki S, Sugiura I, Fujisawa S, Hatta Y, Doki N, Kurahashi S, Ueda Y, Dobashi N, Maeda T, Taniguchi Y, Tanaka M, Kako S, Ichinohe T, Fukuda T, Atsuta Y, Ohtake S, Ishikawa Y, Kiyoi H, Matsumura I, Miyazaki Y
  • Organizer: 64th ASH Annual Meeting and Exposition
  • Int'l Joint Research