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Acute myeloid leukemia

Mutation patterns identify adult patients with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies

Abstract

Thus far, only 5–15% of AML patients aged ≥60 years are cured with chemotherapy. Identification of patients who are less (more) likely to respond to standard chemotherapy might enable early risk stratification toward alternative treatment regimens. We used a next-generation sequencing panel of 80 cancer- and/or leukemia-associated genes to profile molecularly 423 older patients with de novo AML. Using variables identified in multivariable models and co-occurring mutations in NPM1-mutated AML, we classified the patients into good-, intermediate-, and poor-risk groups for complete remission (CR) attainment, disease-free (DFS), and overall survival (OS). Whereas 81% of good-risk patients (comprising NPM1-mutated patients harboring mutations in chromatin remodeling, cohesin complex, methylation-related, spliceosome, and/or RAS pathway genes, FLT3-TKD, and/or patients without FLT3-ITD) achieved a CR, only 32% of poor-risk patients (with U2AF1, WT1 mutations and/or complex karyotype) did. Intermediate-risk patients had a 50% CR rate. Similarly, using NPM1 co-mutation patterns and SF1 mutation status, we identified patients with favorable DFS and OS 3-year rates of 46% and 45%, respectively. Patients with adverse genetic features had DFS and OS rates of only 2% and 4%. We show that application of our proposed criteria may refine the 2017 European LeukemiaNet classification for older patients treated with chemotherapy.

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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 the CALGB/Alliance Leukemia Tissue Bank at The Ohio State University Comprehensive Cancer Center, Columbus, OH, for sample processing and storage services; and to Lisa J. Sterling and Christine Finks for data management. Research reported in this publication was supported by an allocation of computing resources from The Ohio Supercomputer Center. This study was supported in part 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), U10CA003927, U10CA047545, U10CA101140, U10CA140158, U10CA180850, U10CA180861, U10CA180866, U10CA180867, U24CA196171, R35CA197734 (JCB), UG1CA189850, and 5P30CA016058; the Coleman Leukemia Research Foundation; the National Comprehensive Cancer Network Foundation Young Investigator Award; the Alliance for Clinical Trials in Oncology Scholar Award (JSB); The D Warren Brown Foundation, and the Pelotonia Fellowship Program (A-KE).

Author contributions:

A-KE, KM, and CDB contributed to the study design; A-KE, KM, AdlC, and CDB contributed to the data interpretation, A-KE, KM, JK, and CDB wrote the manuscript; A-KE, SEM, and SO performed laboratory-based research; JSB performed the data processing; JK and DN performed statistical analysis; and RMS, AJC, KM, JEK, BLP, ESW, 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.

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Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Ann-Kathrin Eisfeld or Krzysztof Mrózek or Clara D. Bloomfield.

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