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Acute myeloid leukemia

Tamibarotene maintenance improved relapse-free survival of acute promyelocytic leukemia: a final result of prospective, randomized, JALSG-APL204 study

Leukemia volume 33, pages 358–370 (2019)Cite this article

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Abstract

Between April 2004 and December 2010, we conducted a prospective randomized controlled study comparing tamibarotene with all-trans retinoic acid (ATRA) in the maintenance therapy of newly diagnosed acute promyelocytic leukemia (APL), and here report the final results of this study with a median follow-up of 7.3 years. Of 344 eligible patients who had received ATRA and chemotherapy, 319 (93%) achieved complete remission (CR). After completion of three courses of consolidation chemotherapy, 269 patients in molecular remission underwent maintenance randomization, 135 to ATRA (45 mg/m2 daily), and 134 to tamibarotene (6 mg/m2 daily) for 14 days every 3 months for 2 years. The primary endpoint was relapse-free survival (RFS). The 7-year RFS was 84% in the ATRA arm and 93% in the tamibarotene arm (p = 0.027, HR = 0.44, 95% CI, 0.21 to 0.93). The difference was prominent in high-risk patients with initial leukocytes ≥ 10.0 × 109/L (62% vs. 89%; p = 0.034). Tamibarotene was significantly superior to ATRA by decreasing relapse in high-risk patients. Overall survival after randomization did not differ (96% vs. 97%; p = 0.520). Secondary hematopoietic disorders developed in nine patients, secondary malignancies in 11, and grade 3 or more late cardiac comorbidities in three. These late complications did not differ between the two arms.

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Acknowledgements

We thank Ms. Yumi Satou, Ms. Yuka Komatsu, Ms. Ryoko Fujiyoshi, Dr. Shinya Satou, and Dr. Shuichi Miyawaki for their contribution on data management, Dr. Tomoya Maeda and Dr. Maho Ishikawa for data confirmation, Ms. Mio Kurata for her support in statistical analysis, and Dr. 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 late Dr. Katsuji Shinagawa for initiating this study as a principal investigator, and Dr. Ryuzo Ohno, who is the Chairperson of JALSG, instigated this study, and greatly helped to improve the final manuscript.

Author contribution

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., M.N., S.T., M.H., K.F., and H.Fuj. recruited patients and collected data. S.O. and Y.M. were involved in data acquisition and interpretation. Y.A., H.Fur., and Y.O. did the statistical analysis. 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.

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. Transfusion and Cell Therapy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu, 431-3192, Japan

    Akihiro Takeshita, Hiroaki Furumaki & Yukako Obata

  2. International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, 350-1298, Japan

    Norio Asou

  3. The Japanese Data Center for Hematopoietic Cell Transplantation, 1-1-20 Taikou-minami, Higashiku, Nagoya, 461-0047, Japan

    Yoshiko Atsuta

  4. Hematology, Saiseikai Maebashi Hospital, 564-1 Kamishindenmachi, Maebashi, 371-0821, Japan

    Toru Sakura

  5. Hematology/Oncology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan

    Yasunori Ueda

  6. Hematology and Oncology, Anjo Kosei Hospital, 28 Higashikurokute, Anjochou, Anjo, 446-8602, Japan

    Masashi Sawa

  7. Clinical Oncology and Hematology, The Jikei University School of Medicine, 3-19-18 Nishisinbashi, Minatoku, Tokyo, 105-8471, Japan

    Nobuaki Dobashi & Noriko Usui

  8. Hematology and Rheumatology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Ohsakasayama, 589-8511, Japan

    Yasuhiro Taniguchi & Itaru Matsumura

  9. Hematology and Oncology, Tokai University School of Medicine, 143 Shimokasuya, Isahara, 259-1193, Japan

    Rikio Suzuki

  10. Hematology and Rheumatology, Nihon University School of Medicine, 30-1 Ohyaguchi Kamichou, Itabashiku, Tokyo, 173-8610, Japan

    Masaru Nakagawa

  11. Hematology, Japanese Red Cross Ise Hospital, 1-471-2 Funae, Ise, 516-8512, Japan

    Shigehisa Tamaki

  12. Hematology and Clinical Immunology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama, 236-0004, Japan

    Maki Hagihara

  13. Hematology, Fujisawa City Hospital, 2-6-1 Fujisawa, Fujisawa, 251-8550, Japan

    Katsumichi Fujimaki

  14. Hematology, Saiseikai Yokohama Nanbu Hospital, 3-2-10 Kounandai, Kounanku, Yokohama, 234-0054, Japan

    Hiroyuki Fujita

  15. Hematology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukakecho, Toyoake, 470-1192, Japan

    Masamitsu Yanada

  16. Hematology, Oncology and Respiratory Medicine, Okayama University Medical School, 2-5-1 Shikatachou, Kitaku, Okayama, 700-8558, Japan

    Yoshinobu Maeda

  17. National Cancer Center Hospital, 5-1-1 Tsukiji, Chuouku, Tokyo, 104-0045, Japan

    Yukio Kobayashi

  18. Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumaichou, Showaku, Nagoya, 466-8550, Japan

    Hitoshi Kiyoi

  19. Kanazawa University, Kakumamachi, Kanazawa, 920-1192, Japan

    Shigeki Ohtake

  20. National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Nakaku, Nagoya, 460-0001, Japan

    Tomoki Naoe

  21. Hematology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Yasushi Miyazaki

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  1. Akihiro Takeshita
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Takeshita, A., Asou, N., Atsuta, Y. et al. Tamibarotene maintenance improved relapse-free survival of acute promyelocytic leukemia: a final result of prospective, randomized, JALSG-APL204 study. Leukemia 33, 358–370 (2019). https://doi.org/10.1038/s41375-018-0233-7

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