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Cytogenetics and molecular genetics

Additional gene mutations may refine the 2017 European LeukemiaNet classification in adult patients with de novo acute myeloid leukemia aged <60 years

Leukemia volume 34, pages 3215–3227 (2020)Cite this article

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Abstract

The European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) have become an important tool to assess patients’ prognosis and guide treatment. We tested the prognostic impact of the 2017 ELN classification in a large cohort of 863 AML patients aged <60 years similarly treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology studies. Based on multivariable models within each ELN genetic-risk group, we identified additional gene mutations that may refine the 2017 ELN risk classification. BCOR- or SETBP1-mutated favorable-risk patients with non-core-binding factor AML and IDH-mutated adverse-risk patients had intermediate-risk outcomes. Outcomes of NPM1/WT1 co-mutated patients and those of ZRSR2-mutated patients resembled outcome of adverse-risk patients. Moreover, FLT3-ITDhigh allelic ratio conferred adverse rather than intermediate-risk irrespective of the NPM1 mutation status, and DNMT3A mutations associated with very poor survival. Application of these refinements reclassified 9% of current favorable-risk patients and 53% of current intermediate-risk patients to the adverse-risk group, with similar poor survival as current adverse-risk patients. Furthermore, 4% of current favorable-risk patients and 9% of adverse-risk patients were reclassified to the intermediate-risk group.

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Fig. 1: Oncoprint of genes most frequently mutated in younger acute myeloid leukemia patients categorized into genetic-risk groups according to the 2017 European LeukemiaNet (ELN) classification (green color, favorable-risk; yellow, intermediate-risk; red, adverse-risk).
Fig. 2: Line graphs showing the impact of gene mutations found to be prognostically significant in multivariable models for 2017 European LeukemiaNet (ELN) genetic-risk groups.
Fig. 3: Outcomes of patients with AML according to FLT3-ITD allelic ratio and NPM1 mutation status.
Fig. 4: Outcomes of patients with AML according to NPM1 and WT1 mutation status.
Fig. 5: A comparison of treatment outcomes between younger (aged <60 years) adult patients with acute myeloid leukemia classified into European LeukemiaNet (ELN) genetic-risk groups after the proposed refinement of the 2017 ELN classification with outcomes of patients classified into the original 2017 ELN genetic-risk groups.

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Acknowledgements

The authors are grateful to the patients who consented to participate in these clinical trials and the families who supported them; to Donna Bucci and Christopher Manring, and the CALGB/Alliance Leukemia Tissue Bank at The Ohio State University Comprehensive Cancer Center, Columbus, OH, for sample processing and storage services, Lisa J. Sterling and Christine Finks for data management and Jason Hsu for his statistical input. This paper is dedicated to the memory of the senior author (CDB) who unexpectedly died during final completion of this manuscript.

Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), https://acknowledgments.alliancefound.org; UG1CA233338, U24CA196171, UG1CA233180, UG1CA189824, UG1CA189850, P30CA016058, the Coleman Leukemia Research Foundation, Pelotonia (A-KE), American Society of Hematology Scholar Award (AK-E), NIH R35 CA197734 (JCB) and by an allocation of computing resources from The Ohio Supercomputer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Ann-Kathrin Eisfeld, Alice Mims, James S. Blachly, Dimitrios Papaioannou & John C. Byrd

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

    Jessica Kohlschmidt, Deedra Nicolet, Christopher J. Walker, James S. Blachly, Albert de la Chapelle, John C. Byrd, Krzysztof Mrózek & Clara D. Bloomfield

  3. Alliance Statistics and Data Center, The Ohio State University, Columbus, OH, USA

    Jessica Kohlschmidt & Deedra Nicolet

  4. University of Alabama at Birmingham, Birmingham, AL, USA

    Andrew J. Carroll

  5. Monter Cancer Center, Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY, USA

    Jonathan E. Kolitz

  6. Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA

    Bayard E. Powell

  7. Dana-Farber/Partners CancerCare, Boston, MA, USA

    Richard M. Stone

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  1. Ann-Kathrin Eisfeld
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Contributions

A-KE, JK, KM, and CDB contributed to the study design and wrote the manuscript; A-KE, JK, KM, AdlC, JCB, and CDB contributed to the data interpretation; A-KE, AM, and DP performed laboratory-based research; JSB and CJW performed the data processing; JK and DN performed statistical analysis; RMS, AJC, BEP, JEK, JCB, and CDB were involved directly or indirectly in the care of patients and/or sample procurement. All authors read and agreed on the final version of the manuscript. Modifications of the revision were made after the death of CDB.

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Correspondence to Ann-Kathrin Eisfeld or Krzysztof Mrózek.

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Eisfeld, AK., Kohlschmidt, J., Mims, A. et al. Additional gene mutations may refine the 2017 European LeukemiaNet classification in adult patients with de novo acute myeloid leukemia aged <60 years. Leukemia 34, 3215–3227 (2020). https://doi.org/10.1038/s41375-020-0872-3

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