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Phase II study of FLAGM (fludarabine + high-dose cytarabine + granulocyte colony-stimulating factor + mitoxantrone) for relapsed or refractory acute myeloid leukemia

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Abstract

Given the poor prognosis of patients with relapsed/refractory acute myeloid leukemia (AML), better therapy is needed. Fludarabine enhances the efficacy of Ara-C (cytarabine) by increasing intracellular Ara-C-triphosphate. The FLAG (fludarabine, high-dose Ara-C, supported with granulocyte colony-stimulating factor) regimen has been tested for use in AML patients by other investigators. In the phase II study reported here, we evaluated the efficacy and toxicity of FLAGM therapy (FLAG with mitoxantrone), further intensified by adding mitoxantrone, based on the results of a phase I study by our group. The major endpoints were complete remission (CR) rate and early death. From June 2004 to February 2008, 41 patients (median age 52 years; range 18–64 years) were enrolled. Thirty (73% 95% CI 58–84%) patients achieved CR, which met the primary endpoint; there was a single case of early death from pneumonia. Two-year overall survival was 39.4% (95% CI 25.2–55.6%). Of those who achieved CR, 27 underwent allogeneic stem cell transplantation (SCT), and 12 SCT recipients showed long-term survival. Grade 3/4 non-hematological adverse events included infection (59%), nausea/vomiting (15%), diarrhea (7%), and elevated liver enzymes (7%). In conclusion, FLAGM is an effective and safe salvage therapy for patients with relapsed/refractory AML, and facilitated SCT for a large proportion of patients.

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Acknowledgements

The authors would like to thank the patients for entering this study and the participating physicians from the 20 institutions who registered their patients and provided necessary data, which made this study possible. The authors would also like to thank Dr. Ryuzo Ohno for his advice and help during the entire study, as well as the preparation of the manuscript, Nihon Schering KK for providing fludarabine, and Kirin Brewery Company, Limited, for providing filgrastim. This study was supported in part by a grant from the Ministry of Health, Labor and Welfare of Japan.

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Author notes

  1. Yukihiro Arai: Deceased.

Authors and Affiliations

  1. Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan

    Nahoko Hatsumi & Shuichi Miyawaki

  2. Division of Hematology, Tokyo Metropolitan Ohtsuka Hospital, 2-8-1 Minamiohtsuka Toshima-ku, Tokyo, 170-8476, Japan

    Shuichi Miyawaki

  3. First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan

    Takahiro Yamauchi

  4. Department of Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Akihiro Takeshita

  5. Division of Hematology, Jichi Medical University, Shimotsuke, Japan

    Norio Komatsu

  6. Division of Clinical Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan

    Noriko Usui

  7. Department of Hematology, Dokkyo University School of Medicine, Mibu, Japan

    Yukihiro Arai

  8. Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan

    Fumihiro Ishida

  9. The Second Department of Internal Medicine, Nara Medical University, Nara, Japan

    Takeshi Morii

  10. Division of Hematology, Tochigi Cancer Center, Utsunomiya, Japan

    Yasuhiko Kano

  11. Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan

    Michinori Ogura

  12. Department of Hematology and Oncology, Kasugai Municipal Hospital, Kasugai, Japan

    Michinori Ogura

  13. Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan

    Shinichiro Machida

  14. Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan

    Kazuhiro Nishii

  15. Department of Public Health, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Sumihisa Honda

  16. Oncology Center, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Kazunori Ohnishi

  17. Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tomoki Naoe

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  1. Nahoko Hatsumi
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  2. Shuichi Miyawaki
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  3. Takahiro Yamauchi
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  4. Akihiro Takeshita
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  14. Sumihisa Honda
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The Japan Adult Leukemia Study Group (JALSG)

Corresponding author

Correspondence to Shuichi Miyawaki.

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Conflict of interest

SM received personal fees from Astelas, Ohtsuka Pharmaceutical and Novartis Pharma K. K, outside the submitted work; AT received grants from Chugai Pharmaceutical Co., Ltd., grants from Teijin Pharma K.K., grants from Pfizer Japan Inc., grants from Astellas Pharma Inc., grants from Takeda Pharmaceutical Co.,Ltd., grants from Nihon Pharmaceutical Co.,Ltd., grants from Bristol-Myers Squibb Co., grants from Kyowa Hakko Kirin Co.,Ltd., grants from Daiichi Sankyo Co.,Ltd., grants from Japan Blood Product Organization, outside the submitted work; MO received personal fees from MundiPharma, personal fees from MeijiSeika Pharma, grants and personal fees from Celltrion, personal fees from Takeda, grants and personal fees from SymBio, personal fees from Cellgene, personal fees from AstraZeneka, outside the submitted work; NU received personal fees from Celgene Co.,Ltd, personal fees from CIMIC Co.,Ltd., personal fees from Otsuka Pharmaceutical Co.,Ltd., grants and personal fees from Pfizer Co.,Ltd., personal fees from Takeda Bio Development Center Ltd., personal fees from Kyowa Hakko Kirin Co.,Ltd., personal fees from Chugai Pharmaceutical Co.,Ltd, outside the submitted work; TN received grants and personal fees from Astellas Pharma Inc., grants from Amgen Astellas BioPharma K.K., grants and personal fees from Dainippon Sumitomo Pharma Co.,LTD., grants from Fujifilm Corporation, personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants from Otsuka Pharmaceutical Co.,Ltd., grants from TOYAMA CHEMICAL CO.,LTD., outside the submitted work; In addition, TN has a patent Fujifilm Corporation issued, a patent Chugai Pharmaceutical Co.,LTD. issued, and a patent Kyowa-Hakko Kirin Co.,Ltd. issued. The other authors declare that they have no conflicts of interest.

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Hatsumi, N., Miyawaki, S., Yamauchi, T. et al. Phase II study of FLAGM (fludarabine + high-dose cytarabine + granulocyte colony-stimulating factor + mitoxantrone) for relapsed or refractory acute myeloid leukemia. Int J Hematol 109, 418–425 (2019). https://doi.org/10.1007/s12185-019-02606-0

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  • DOI: https://doi.org/10.1007/s12185-019-02606-0

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