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. Access through your institution Buy or

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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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * The Ohio

State University Comprehensive Cancer Center, Columbus, OH, USA Ann-Kathrin Eisfeld, Jessica Kohlschmidt, Krzysztof Mrózek, Christopher J. Walker, Deedra Nicolet, Sophia E. Maharry, Albert

de la Chapelle & Clara D. Bloomfield * Alliance Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA Jessica Kohlschmidt & Deedra

Nicolet * Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Division of Hematology, Columbus, OH, USA James S. Blachly, Shelley Orwick & John C.

Byrd * Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA Andrew J. Carroll * Dana-Farber/Partners CancerCare, Boston, MA, USA Richard M. Stone * Roswell Park

Cancer Institute, Buffalo, NY, USA Eunice S. Wang * Monter Cancer Center, Hofstra Northwell School of Medicine, Lake Success, NY, USA Jonathan E. Kolitz * Comprehensive Cancer Center of Wake

Forest University, Winston-Salem, NC, USA Bayard L. Powell Authors * Ann-Kathrin Eisfeld View author publications You can also search for this author inPubMed Google Scholar * Jessica

Kohlschmidt View author publications You can also search for this author inPubMed Google Scholar * Krzysztof Mrózek View author publications You can also search for this author inPubMed 

Google Scholar * James S. Blachly View author publications You can also search for this author inPubMed Google Scholar * Christopher J. Walker View author publications You can also search

for this author inPubMed Google Scholar * Deedra Nicolet View author publications You can also search for this author inPubMed Google Scholar * Shelley Orwick View author publications You

can also search for this author inPubMed Google Scholar * Sophia E. Maharry View author publications You can also search for this author inPubMed Google Scholar * Andrew J. Carroll View

author publications You can also search for this author inPubMed Google Scholar * Richard M. Stone View author publications You can also search for this author inPubMed Google Scholar *

Albert de la Chapelle View author publications You can also search for this author inPubMed Google Scholar * Eunice S. Wang View author publications You can also search for this author

inPubMed Google Scholar * Jonathan E. Kolitz View author publications You can also search for this author inPubMed Google Scholar * Bayard L. Powell View author publications You can also

search for this author inPubMed Google Scholar * John C. Byrd View author publications You can also search for this author inPubMed Google Scholar * Clara D. Bloomfield View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Ann-Kathrin Eisfeld, Krzysztof Mrózek or Clara D. Bloomfield. ETHICS

DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ELECTRONIC SUPPLEMENTARY MATERIAL SUPPLEMENTARY MATERIAL RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Eisfeld, AK., Kohlschmidt, J., Mrózek, K. _et al._ 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. _Leukemia_ 32, 1338–1348 (2018). https://doi.org/10.1038/s41375-018-0068-2 Download citation *

Received: 25 September 2017 * Revised: 23 January 2018 * Accepted: 29 January 2018 * Published: 25 February 2018 * Issue Date: June 2018 * DOI: https://doi.org/10.1038/s41375-018-0068-2

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