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Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study

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Abstract

Mutation status of FLT3, NPM1, and CEBPA is used to classify the prognosis of acute myeloid leukemia, but its significance in patients with cytogenetically normal (CN) AML is unclear. We prospectively analyzed these genes in 295 patients with CN-AML and identified 76 (25.8%) FLT3-ITD, 113 (38.3%) NPM1 mutations, and 30 (10.2%) CEBPA biallelic mutations. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. The results suggest that analyzing these gene mutations at diagnosis can inform selection of the optimal intensity of therapy for patients with CN-AML.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all physicians for their contributions to this study and their dedicated care of the patients. We thank Satoshi Oguri and Kaori Sato for FLT3-ITD analysis. We thank Chiaki Yokoyama and Fumina Kusaka for management of patients’ samples and data integrity.

Funding

This work was supported by North Japan Hematology Study Group (NJHSG) and partly by Japan Society for the Promotion of Science KAKENHI, Grant-in-Aid for scientific research (20K08745 [M.O.]).

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Authors and Affiliations

  1. Department of Hematology, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-Ku, Sapporo, 0608638, Japan

    Naoki Miyashita, Masahiro Onozawa, Shota Yoshida, Hiroyuki Kimura, Shogo Takahashi, Shota Yokoyama, Toshihiro Matsukawa & Takanori Teshima

  2. Department of Pediatrics, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Shinsuke Hirabayashi

  3. Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan

    Shinichi Fujisawa & Takanori Teshima

  4. Blood Disorders Center, Aiiku Hospital, Sapporo, Japan

    Akio Mori & Takeshi Kondo

  5. Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan

    Shuichi Ota

  6. Department of Hematology, Asahikawa City Hospital, Asahikawa, Japan

    Yasutaka Kakinoki

  7. Department of Hematology, Hakodate Municipal Hospital, Hakodate, Japan

    Yutaka Tsutsumi

  8. Department of Hematology, Sapporo City General Hospital, Sapporo, Japan

    Satoshi Yamamoto

  9. Department of Hematology, Kushiro Rosai Hospital, Kushiro, Japan

    Takuto Miyagishima

  10. Department of Internal Medicine/General Medicine, Kitami Red Cross Hospital, Kitami, Japan

    Takahiro Nagashima

  11. Department of Hematology, Sapporo Kosei General Hospital, Sapporo, Japan

    Makoto Ibata

  12. Department of Hematology, Obihiro Kosei Hospital, Obihiro, Japan

    Kentaro Wakasa

  13. Department of Hematology, Tonan Hospital, Sapporo, Japan

    Yoshihito Haseyama

  14. Department of Hematology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan

    Katsuya Fujimoto

  15. Department of Hematology, Kin-Ikyo Chuo Hospital, Sapporo, Japan

    Toshimichi Ishihara

  16. Department of Hematology, Teine Keijinkai Hospital, Sapporo, Japan

    Hajime Sakai

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  1. Naoki Miyashita
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  2. Masahiro Onozawa
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  3. Shota Yoshida
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  4. Hiroyuki Kimura
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Contributions

N.M. and M.O. designed the study, analyzed the data and wrote the manuscript; N.M., S.Yoshida, H.K., S.T., S.Yokoyama, and S.F. performed the molecular analysis; T.M., S.H., M.A., S.O., Y.K., Y.T., S.Y., T.M., T.N., M.I., H.K., Y.H., K.F., T.I., H.S., T.K. contributed to the data collection and provided critique to the manuscript; T.T. revised and approved the manuscript; All authors read and approved the final manuscript.

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Correspondence to Masahiro Onozawa.

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Miyashita, N., Onozawa, M., Yoshida, S. et al. Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study. Int J Hematol 118, 36–46 (2023). https://doi.org/10.1007/s12185-023-03567-1

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