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Acute myeloid leukemia

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial

Leukemia volume 35, pages 2539–2551 (2021)Cite this article

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Abstract

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54–0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

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Acknowledgements

We thank the patients who participated and their families, the clinical and laboratory research staff members of multiple international cooperative groups, CTEP of the NCI, and Novartis Pharmaceuticals. We acknowledge Dr. Francesco Lo-Coco’s and Dr. Clara D. Bloomfield’s key roles in the design and completion of this study. CALGB is now part of the Alliance for Clinical Trials in Oncology. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180821, U10CA180882, U24CA198171 (to the Alliance for Clinical Trials in Oncology), U10CA032291, U10CA041287, U10CA077651, U10CA077658, U10CA180791, U10CA180820 (ECOG-ACRIN), UG1CA233290, U10CA180836, U10CA180850, U10CA180863 (CCTG), U10CA180867, U10CA180888 (SWOG), and UG1CA233338 [https://acknowledgments.alliancefound.org]. This study was also supported in part by funds from Novartis. Clinicaltrials.gov Identifier number: NCT00651261.

Author information

Authors and Affiliations

  1. Department of Medicine and Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA

    Richard A. Larson

  2. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    Sumithra J. Mandrekar

  3. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

    Sumithra J. Mandrekar, Lucas J. Huebner, Kristina Laumann & Susan Geyer

  4. Alliance Statistics and Data Center, Duke University, Durham, NC, USA

    Ben L. Sanford

  5. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Clara D. Bloomfield & Thomas W. Prior

  6. Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany

    Christian Thiede & Gerhard Ehninger

  7. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    Konstanze Döhner, Richard F. Schlenk & Hartmut Döhner

  8. City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Guido Marcucci

  9. Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy

    Maria Teresa Voso & Sergio Amadori

  10. Emory University School of Medicine, Atlanta, GA, USA

    Rebecca B. Klisovic

  11. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Ilene Galinsky & Richard M. Stone

  12. Department of Clinical Haematology, The Alfred Hospital and Monash University, Melbourne, Australia

    Andrew H. Wei

  13. Hematology Department, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau and Jose Carreras Leukemia Research Institute, Autonomous University of Barcelona, Barcelona, Spain

    Jorge Sierra

  14. Department of Hematology, Hospital Universitario y Politécnico La Fe and Department of Medicine, University of Valencia, Valencia, Spain

    Miguel A. Sanz

  15. Department of Medicine, University of Alberta, Edmonton, AB, Canada

    Joseph M. Brandwein

  16. Radboud University Medical Centre, Nijmegen, Netherlands

    Theo de Witte

  17. Department of Hematology and Oncology, University of Leipzig, Leipzig, Germany

    Dietger Niederwieser

  18. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Frederick R. Appelbaum

  19. Division of Hematology, Stanford Comprehensive Cancer Center, Stanford University, Stanford, CA, USA

    Bruno C. Medeiros

  20. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Martin S. Tallman

  21. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    Jürgen Krauter & Arnold Ganser

  22. NCT Trial Center, National Center of Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany

    Richard F. Schlenk

  23. Department of Medicine II, Hematology/Oncology, Goethe University Hospital Frankfurt, Frankfurt/Main, Germany

    Hubert Serve

  24. Novartis Pharma AG, Basel, Switzerland

    Insa Gathmann

Authors
  1. Richard A. Larson
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  2. Sumithra J. Mandrekar
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  3. Lucas J. Huebner
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  32. Richard M. Stone
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Contributions

RAL and RMS designed the study, performed research, collected, assembled, analyzed, and interpreted data, and wrote the manuscript; SJM, LJH, BLS, KL, SG, and IGathmann performed statistical analyses; CDB, CT, TWP, KD, GM, MTV, RBK, IGallinsky, AHW, JS, MAS, JMB, TdW, DN, FRA, BCM, MST, JK, RFS, AG, HS, GE, SA, and HD collected, assembled, analyzed, and interpreted data, and edited the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Richard A. Larson.

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Conflict of interest

RAL has acted as a consultant or advisor to Novartis, Amgen, Ariad/Takeda, Astellas, Celgene/BMS, CVS/Caremark, Epizyme, and MorphoSys, and has received clinical research support from Novartis, Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty Seven, Rafael Pharmaceuticals, and royalties from UpToDate. SJM has acted as a consultant or advisor for Pfizer and Pique Therapeutics, and has another relationship with BeiGene. CT is the Chief Executive Officer and a co-owner of AgenDix, a company performing molecular diagnostics, and has acted as a consultant or advisor for Novartis and Astellas, and has received clinical research support from Bayer. KD has acted as a consultant or advisor for Astellas, Celgene, Daiichi Sankyo, Janssen, Novartis, and Roche and has received clinical research support from Astex, Celgene, and Novartis. GM, RBK, DN, and HS have acted as consultants or advisors for Novartis. AHW has acted as a consultant or advisor for Novartis, Astellas, Pfizer, MacroGenics, AbbVie, Genentech, Servier, Celgene, Amgen, Astra Zeneca, and Janssen, and is a member of the speakers bureau for AbbVie/Genentech and Novartis, and has received research funding from Novartis, Celgene, AbbVie, Servier, Astra Zeneca, and Amgen, and is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax. JS has acted as a consultant or advisor for Pfizer, Daiichi Sankyo, AbbVie, Novartis, Astellas, and Roche and is a member of the speakers bureau for Novartis, Pfizer, Daiichi Sankyo, and AbbVie. MAS has acted as a consultant or advisor for Teva Pharmaceutical Industries, Daiichi Sankyo, Orsenix, AbbVie, Novartis, and Pfizer. TdW has acted as a consultant or advisor for Novartis, Celgene, Johnson & Johnson, and Incyte and has received clinical research support from Novartis, Celgene, and Johnson & Johnson. BCM has acted as a consultant or advisor for Celgene, Novartis, and Astellas and is currently employed by Roche/Genentech. MST has acted as a consultant or advisor for AbbVie, BioLineRx, Daiichi Sankyo, Orsenix, KAHR Medical, Rigel Pharmaceuticals, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, and Jazz Pharmaceuticals, and has received clinical research funding from AbbVie, Cellerant Therapeutics, Orsenix, ADC Therapeutics, and BioSight, and has received royalties from UpToDate. JK has acted as a consultant or advisor for Amgen, Astellas, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. AG has received clinical research support from Novartis. RFS has acted as a consultant or advisor for Pfizer and Daiichi Sankyo, is a member of the speakers bureau for Novartis, Pfizer, and Daiichi Sankyo, and has received clinical research funding from Pfizer, Daiichi Sankyo, PharmaMar, Astra Zeneca, and Roche. SA has acted as a consultant or advisor for Novartis and Daiichi Sankyo. IGathmann is an employee of Novartis. HD has acted as a consultant or advisor for AbbVie, Agios, Amgen, Astellas, Astex Pharmaceuticals, Celgene, Helsinn, Janssen, Jazz Pharmaceuticals, Novartis, Oxford Biomedicals, and Roche, and has received institutional research support from Amgen, AROG Pharmaceuticals, Bristol-Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, Pfizer, and Sunesis. RMS has acted as a consultant or advisor for AbbVie, Actinium, and Agios, has received personal fees from Amgen, Argenx, AROG, Astellas, Astra Zeneca, BioLineRx, Celgene, Cornerstone, Daiichi Sankyo, Fujifilm, Jazz Pharmaceuticals, MacroGenics, Novartis, Ono/Theradex Oncology, Orsenix, Otsuka/Astex, Pfizer, Roche, Stemline Therapeutics, Takeda, and Trovagene, and has received institutional research support from AbbVie, Agios, AROG, and Novartis. The remaining authors declare no competing financial interests.

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Larson, R.A., Mandrekar, S.J., Huebner, L.J. et al. Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial. Leukemia 35, 2539–2551 (2021). https://doi.org/10.1038/s41375-021-01179-4

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