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Prospective comparison of 5- and 7-day administration of azacitidine for myelodysplastic syndromes: a JALSG MDS212 trial

Abstract

The hypomethylating agent azacitidine (AZA) significantly extends overall survival (OS) in patients with higher risk myelodysplastic syndromes (MDS), when compared with other conventional care regimens, including supportive care and low-dose and intensive chemotherapy. However, the effects of 5- and 7-day treatment schedules of AZA (AZA-5 and AZA-7, respectively) on the OS of MDS patients had not been compared prospectively. We started a phase 3 trial comparing the effects of AZA-7 and AZA-5 on MDS patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T). However, this trial was prematurely terminated because of poor recruitment. Using all data, there was no significant difference in the OS of patients between AZA-7 (92 patients) and AZA-5 (95 patients), with the 2-year OS rates of AZA-7 and AZA-5 at 36.4% and 25.8%, respectively (P = 0.293). Adverse event profiles were similar between the two groups. Interestingly, data of the centrally diagnosed RAEB and RAEB-T cases showed that AZA-7 significantly prolonged the time to leukemia transformation compared with AZA-5 (P = 0.022), confirmed by multivariate analysis. Although this trial could not provide definite evidence, the results support the use of AZA-7 for RAEB and RAEB-T. (UMIN Clinical Trials Registry UMIN000009633).

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Acknowledgements

This work was supported in part by a research fund from the Ministry of Health, Labor and Welfare, Japan (H25-cancer, clinical-general-006). The authors would like to express their gratitude to the patients who participated in the study and all participating physicians and staff of the Japan Adult Leukemia Study Group (JALSG). The English language review was performed by Enago (http://www.enago.jp).

JALSG MDS212 study Committee: Yasushi Miyazaki, Kensuke Usuki, Ken Ishiyama, Yoshikazu Ito, Takahiro Suzuki, Jun Taguchi, Shigeru Chiba, Nobuaki Dobashi, Akihiro Tomita, Hironori Harada, Hiroshi Handa, Shigeo Horiike, Tomoya Maeda, Mitsuhiro Matsuda, Motoshi Ichikawa, and Sumihisa Honda

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The committee of the MDS212 study designed this study, and Y. Miyazaki was the primary investigator of the study. All data were collected and monitored by JALSG Data Center (SO). TK, SI, HS, YM, TK, and TY were major contributors for this study. TH and SS performed central review. YM wrote the manuscript with a biostatistician (KY) and the committee members of the MDS212 study. IM, HK, and TN operated JALSG. All authors participated in analyzing and interpreting the data, and checked the final version of the manuscript.

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Correspondence to Yasushi Miyazaki.

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Conflict of interest

Y. Miyazaki received grants from Sumitomo-Dainippon, honoraria from Astellas, SynBio, Nippon-Shinyaku, Novartis, Abbvie, Sumitomo-Dainippon, Chugai; K. Ushiki received grants from Astellas Pharma, AbbVie, Apellis, SymBio, Daiichi-Sankyo, Novartis, Janssen, Otsuka, Astellas-Amgen-Biopharma, Takeda, Nippon-Shinyaku, Bristol-Myers-Squibb, Amgen, Alexion, Incyte, Ono, Kyowa-Kirin, Celgene, Sumitomo-Dainippon, Chugai, Pfizer, Mundi, Yakult, MSD, Gilead, and Nippon-Boehringer-Ingelheim, honoraria from Novartis, Bristol-Myers-Squibb, Sanofi, Pfizer, Abbvie, Takeda, Ono, Kyowa-Kirin, Astellas, Alexion, Eisai, MSD, Otsuka, Celgene, Daiichi-Sankyo, Nippon-Shinyaku, PharmaEssentia, Yakult, SymBio, Alexion, Chugai, and participation in Data Safety Monitoring for Takeda; I. Matsumura received grants from ONO PHARMACEUTICAL CO., LTD., Janssen Pharmaceutical K.K., NIPPON SHINYAKU CO.,LTD., Kyowa Kirin Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Shionogi & Co., Ltd., TEIJIN PHARMA LIMITED., Boehringer Ingelheim, Sanofi, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., MSD K.K., ASAHI KASEI PHARMA CORPORATION. Astellas Pharma Inc., Takeda Pharmaceutical Company Limited., Japan Blood Products Organization., NIHON PHARMACEUTICAL CO., LTD, DAIICHI SANKYO COMPANY, LIMITED., AbbVie GK, TAIHO PHARMACEUTICAL CO., LTD., Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., CSL Behring, Mundipharma K.K., AYUMI Pharmaceutical Corporation, Eli Lilly Japan K.K., Actelion Pharmaceuticals Japan Ltd., Amgen BioPharma K.K., consulting fee from Otsuka Pharmaceutical Co., Ltd., honoraria from Bristol-Myers Squibb (Celgene), Novartis Pharmaceuticals, Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Janssen Pharmaceutical K.K., Astellas Pharma Inc., Takeda Pharmaceutical Company Limited., DAIICHI SANKYO COMPANY, LIMITED., AbbVie GK, Amgen BioPharma K.K.; T. Maeda received grants from Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd., Eisai Co., Ltd., Novartis Pharmaceuticals, Otsuka Pharmaceutical Co., Ltd., Alexion Pharmaceuticals, Inc., honoraria from Nippon Shinyaku Co., Ltd., Bayer Yakuhin, Ltd., Novartis Pharmaceuticals; A. Tomita received grants from Chugai Pharmaceutical, Ono Pharmaceutical, Kyowa Kiri, Taiho Pharmaceutical, and honoraria from Chugai Pharmaceutical, Takeda Pharmaceutical; H. Handa received grants from Nippon shinyaku, honoraria from Nippon Shinyaku; T. Yamiuchi received honoraria from Nippon Shinyaku; M. Ichikawa received consulting fee from Takeda Pharmaceuticals Co. Ltd.; T. Kiguchi received grants from Nippon Shinyaku Co., Ltd, honoraria from Nippon Shinyaku Co., Ltd; H. Kiyoi received grants from Nippon Shinyaku Co.; T. Naoe received support for the present manuscript from Astellas Pharma, Fuji Film, Daiichi Sankyo, honoraria from Sysmex, Bristol Myers Squibb, participation to Data Safety Monitoring for Nippon Shinyaku, Pfizer, Otsuka Pharma; T. Suzuki received grants from Abbie Inc, Kyowa Kirin Co.,Ltd, Nippon Shinyaku, honoraria from AbbVie Inc, Kyowa Kirin Co., Ltd., Nippon Shinyaku Co., Novartis Pharma K.K., Bristol-Myers Squibb, Ltd; S. Iyama received research funding from Sanofi, Alexion Pharmaceuticals, MSD, Otsuka, SynBio Pharmaceuticals, honoraria from Otsuka Pharmaceuticals Factory, Astellas Pharma, Alexion Pharmaceuticals, CSI Behring, Daiichi Sankyo, Meiji Pharma, Novartis, Nippon Shinyaku, Sanofi, SynBio Pharmaceuticals; S. Chiba received grants from Kyowa-Kirin, Chugai, Ono, Astellas, Eisai, Beyer. Other authors declared that there was no conflict of interest.

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The names of JALSG MDS212 commettee members are listed in Acknowledgement.

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Miyazaki, Y., Kiguchi, T., Sato, S. et al. Prospective comparison of 5- and 7-day administration of azacitidine for myelodysplastic syndromes: a JALSG MDS212 trial. Int J Hematol 116, 228–238 (2022). https://doi.org/10.1007/s12185-022-03347-3

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Keywords

  • Azacitidine
  • Myelodysplastic syndromes
  • Higher risk
  • Treatment schedule
  • Leukemia transformation