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The impacts of BCR-ABL1 mutations in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation

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Abstract

The prognostic impacts of BCR-ABL1 fusion gene mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remain unknown. Using data from a nationwide Japanese registry, we have evaluated the prognostic impact of BCR-ABL1 mutations prior to the first allogeneic hematopoietic cell transplantation (HCT). The cohort included 289 patients with a median of 48 years of age (range: 16–70). Point mutations were detected in 110 patients. Of these, 90 (82%) harbored T315I mutations, while 20 had other mutations. With a median follow-up period of 29 months (range: 1–125), outcomes after 2 years were worse with mutations than without (overall survival [OS]: 34% vs 68%, p < 0.001; relapse rate [RR]: 48% vs 18%, p < 0.001), particularly with the presence of the T315I mutation (OS: 29% vs 68%, p < 0.001; RR: 54% vs 18%, p < 0.001). OS was significantly worse in the T315I group even among the cohort with hematological (p < 0.001) or molecular complete remission (p = 0.025) as compared to the no mutation group. Multivariate analysis determined the prognostic impact of the T315I mutation (OS: hazard ratio [HR] = 2.19, 95% confidence interval [CI]: 1.5–3.3, p < 0.001; RR: HR = 2.51, 95% CI: 1.5–4.2, p < 0.001). This study is the first to report on the prognostic significance of BCR-ABL1 mutations in Ph + ALL.

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Acknowledgments

We would like to thank all members of the Japan Society for Hematopoietic Cell Transplantation and members of the Japanese Data Center for Hematopoietic Cell Transplantation.

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Authors and Affiliations

  1. Department of Hematology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama, 241-8515, Japan

    Takayoshi Tachibana & Masatsugu Tanaka

  2. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Yuho Najima & Noriko Doki

  3. Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan

    Yu Akahoshi & Shinichi Kako

  4. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Shigeki Hirabayashi

  5. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan

    Kaito Harada & Makoto Onizuka

  6. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital, Tokyo, Japan

    Naoyuki Uchida

  7. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

    Takahiro Fukuda

  8. Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan

    Masashi Sawa

  9. Department of Hematology, Oita University Hospital, Oita, Japan

    Masao Ogata

  10. Leukemia Research Center, Saiseikai Mabashi Hospital, Gunma, Japan

    Satoru Takada

  11. Department of Hematology, Kawasaki Medical School Hospital, Kurashiki, Japan

    Yoshiko Matsuhashi

  12. Department of Hematology, Tokyo Women’s Medical University, Tokyo, Japan

    Junji Tanaka

  13. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Tatsuo Ichinohe

  14. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Yoshiko Atsuta

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  1. Takayoshi Tachibana
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  2. Yuho Najima
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  18. Shinichi Kako
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On Behalf of the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation

Contributions

T.T. designed the research, analyzed data, and wrote the paper. T.T., Y.N., Y.A, S.H., K.H., and S.K. supported the data analysis and manuscript preparation. N.D., N.U., T.F., M.S., M.O., S.T., M.T., and Y.M. treated patients and collected the data. M.O., T.I., J.T., and Y.A. collected and assemblied the data.

Corresponding author

Correspondence to Takayoshi Tachibana.

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Conflict of interest

M.S. reports personal fees from Chugai, personal fees from Pfizer, personal fees from Astellas, personal fees from Nippon-Shinyaku, personal fees from Ono, personal fees from MSD, personal fees from Bristol-Myers Squibb, personal fees from Kyowa-Hakko Kirin, personal fees from Asahi-Kasei, personal fees from Novartis, personal fees from Eisai, personal fees from Otsuka, personal fees from Sumitomo Dainippon, personal fees from Sanofi, personal fees from Takeda, personal fees from Celgene, personal fees from Mochida, personal fees from Shire, personal fees from Mundipharma, outside the submitted work. S. H. reports stock ownership in Revorf Co.,ltd. outside the submitted work.

Ethical approval

This study was approved by the data management committee of the Japanese Society for Hematopoietic Cell Transplantation and the Ethics Committee of Kanagawa Cancer Center. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

The TRUMP database includes physician-reviewed data. Observational studies based on the TRUMP database are performed with an informed consent.

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Supplementary Figure Comparison of variables according to mutation status. A The average WBC counts in the non-T315I and T315I mutation cohorts were higher compared to the no mutation cohort (p = 0.002). B The median time from diagnosis to HCT was significantly longer in the non-T315I and T315I mutation cohorts compared to the no mutation cohort (p < 0.001). C The performance status (PS) of patients at allogeneic hematopoietic cell transplantation (HCT) was significantly higher in the T315I mutation cohort (p = 0.006, calculated by Fischer’s exact test) (PDF 62 kb).

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Tachibana, T., Najima, Y., Akahoshi, Y. et al. The impacts of BCR-ABL1 mutations in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation. Ann Hematol 99, 2393–2404 (2020). https://doi.org/10.1007/s00277-020-04212-1

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  • DOI: https://doi.org/10.1007/s00277-020-04212-1

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