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Predictors of early death, serious hemorrhage, and differentiation syndrome in Japanese patients with acute promyelocytic leukemia

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Abstract

Significant advancements have been achieved with regard to the outcomes of acute promyelocytic leukemia (APL) patients through the introduction of all-trans retinoic acid; however, early hemorrhagic death and differentiation syndrome remain the major causes of remission induction failure in patients with APL. To investigate early death, serious hemorrhage, and differentiation syndrome during remission induction therapy in terms of incidence, risk factors, influence on outcomes, and prophylactic effects of several new anticoagulants, the results of 344 patients enrolled in the Acute Promyelocytic Leukemia 204 study conducted by the Japan Adult Leukemia Study Group were analyzed. Early death was observed in 16 patients (4.7%), of whom 14 had serious hemorrhage and 2 had differentiation syndrome. Serious hemorrhage and differentiation syndrome of grade 2 or higher were observed in 21 and 54 patients, respectively. Patients who achieved complete remission had a 7-year disease-free survival of 84.8% if they did not experience serious hemorrhage and 40.0% if they experienced serious hemorrhage during remission induction therapy (P = 0.001). Risk factor analyses showed that higher white blood cell count was associated with early death, higher white blood cell count and lower platelet count with serious hemorrhage, and leukocytosis during induction therapy and higher body surface area with differentiation syndrome. In conclusion, these results indicate that patients with such high-risk features may benefit from more intensive supportive care. The hemorrhagic risk was not relieved by the introduction of new anticoagulants. Further studies are required to establish the predictive impact of body surface area on differentiation syndrome. This trial is registered with UMIN-CTR as C000000154 on September 13, 2005.

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Acknowledgments

The authors thank Yumi Satou, Yuka Komatsu, Ryoko Fujiyoshi, Shinya Satou, and Shuichi Miyawaki for their contribution on data management; Tomoya Maeda and Maho Ishikawa for data confirmation; Mio Kurata for her support of statistical analysis; and Gareth A. Roberts for English editing the manuscript. We thank all the patients and caregivers, the centers, and participating JALSG members for their support and commitment in this study. We wish to express our sincere gratitude to the late Katsuji Shinagawa for initiating this study as principal investigator.

Funding

The trial was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor, and Welfare of Japan (Clinical Cancer Research Grant No. 23–004), the National Cancer Centre Research and Development Fund (Grant No. 23-A-23, 26-A-24), and the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development, AMED (17ck0106251).

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Authors and Affiliations

  1. Division of Hematology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan

    Hitoshi Minamiguchi

  2. Hematology, Saiseikai Yokohama Nanbu Hospital, Yokohama, Japan

    Hiroyuki Fujita

  3. The Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Yoshiko Atsuta

  4. Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta

  5. International Medical Center, Saitama Medical University, Hidaka, Japan

    Norio Asou

  6. Hematology, Saiseikai Maebashi Hospital, Maebashi, Japan

    Toru Sakura

  7. Hematology/Oncology, Kurashiki Central Hospital, Kurashiki, Japan

    Yasunori Ueda

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

    Masashi Sawa

  9. Clinical Oncology and Hematology, The Jikei University School of Medicine, Tokyo, Japan

    Nobuaki Dobashi & Noriko Usui

  10. Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan

    Yasuhiro Taniguchi & Itaru Matsumura

  11. Hematology and Oncology, Tokai University Faculty of Medicine, Isahara, Japan

    Rikio Suzuki

  12. Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan

    Yoshihito Uchino

  13. Hematology, Fujita Health University School of Medicine, Toyoake, Japan

    Akihiro Tomita

  14. Hematology, Japanese Red Cross Ise Hospital, Ise, Japan

    Shigehisa Tamaki

  15. Hematology and Clinical Immunology, Yokohama City University School of Medicine, Yokohama, Japan

    Maki Hagihara

  16. Hematology, Fujisawa City Hospital, Fujisawa, Japan

    Katsumichi Fujimaki

  17. Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan

    Masamitsu Yanada

  18. Hematology, Oncology and Respiratory Medicine, Okayama University Medical School, Okayama, Japan

    Yoshinobu Maeda

  19. Clinical Epidemiology, Nagasaki University School of Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Masako Iwanaga

  20. Hematology, National Cancer Center Hospital, Tokyo, Japan

    Yukio Kobayashi

  21. Hematology, International University of Health and Welfare, Mita Hospital, Tokyo, Japan

    Yukio Kobayashi

  22. Kanazawa University, Kanazawa, Japan

    Shigeki Ohtake

  23. Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hitoshi Kiyoi

  24. Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan

    Yasushi Miyazaki

  25. National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Tomoki Naoe

  26. Transfusion and Cell Therapy, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Akihiro Takeshita

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  1. Hitoshi Minamiguchi
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  2. Hiroyuki Fujita
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on behalf of the Japan Adult Leukemia Study Group

Contributions

H.M., H.F., A.T., N.A., M.Y., Y.M., N.U., Y.K., H.K., I.M., and T.N. jointly developed the study design. T.S., Y.U., M.S., N.D., Y.T., R.S., Y.U., A.T., S.T., M.H., and K.F. recruited patients and collected data. S.O. and Y.M. were involved in data acquisition and interpretation. M.I. planned the statistical methods, and Y.A. did the statistical analysis. The first draft of the manuscript was written by H.M. and all authors interpreted the data, drafted and reviewed the report, gave their final approval for publication, and agreed to be accounted for all aspects of the work.

Corresponding author

Correspondence to Hitoshi Minamiguchi.

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Ethical approval

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

Informed consent was obtained from all individual participants included in the trial.

Conflict of interest

Y.A. has received honoraria from Chugai Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Meiji Seika Pharma Co. Ltd., and Kyowa Hakko Kirin Co., Ltd. N.A. has received honoraria from SRL, Inc. and Nippon-Shinyaku Co., Ltd., and research funds from Chugai Pharmaceutical Co., Ltd. N.D. has received research funds from Fujimoto Pharmaceutical Co. and scholarship endowments from Pfizer Japan Inc. A.T. has received honoraria and research funds from Chugai Pharmaceutical Co., Ltd., and research funds from Kyowa Hakko Kirin Co., Ltd., and Taiho Pharmaceutical Co., Ltd. Y.K. has received honoraria from Astellas Pharma Inc. H.K. has received honoraria from Bristol-Myers Squibb, Astellas Pharma Inc., and Novartis Pharma K.K., and consulting fees from Astellas Pharma Inc., Amgen Astellas BioPharma K.K., and Daiichi Sankyo Co., Ltd., and research funds from Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Zenyaku Kogyo Co., Ltd., FUJIFILM Corporation, Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., Otsuka Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Eisai Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co., Ltd., Sanofi K.K., and Celgene Corporation. I.M. has received honoraria from Pfizer Japan Inc., research funds from Chugai Pharmaceutical Co., Ltd., and scholarship endowments from Chugai Pharmaceutical Co., Ltd. and Nippon Shinyaku Co., Ltd. Y.M. has honoraria from Novartis Pharma K.K., Sumitomo Dainippon Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Nippon Shinyaku Co., Ltd., and scholarship endowments from Chugai Pharmaceutical Co., Ltd. The other authors have no conflict of interest.

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Minamiguchi, H., Fujita, H., Atsuta, Y. et al. Predictors of early death, serious hemorrhage, and differentiation syndrome in Japanese patients with acute promyelocytic leukemia. Ann Hematol 99, 2787–2800 (2020). https://doi.org/10.1007/s00277-020-04245-6

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