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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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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DOI: https://doi.org/10.1038/s41375-018-0233-7
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