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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LOMUSTINE IS BENEFICIAL TO OLDER AML WITH ELN2017 ADVERSE RISK PROFILE AND INTERMEDIATE KARYOTYPE: A FILO STUDY Article 18 September 2020 ADDITIONAL GENE MUTATIONS MAY REFINE THE 2017

EUROPEAN LEUKEMIANET CLASSIFICATION IN ADULT PATIENTS WITH DE NOVO ACUTE MYELOID LEUKEMIA AGED <60 YEARS Article 27 May 2020 CLINICAL IMPACT OF THE GENOMIC LANDSCAPE AND LEUKEMOGENIC

TRAJECTORIES IN NON-INTENSIVELY TREATED ELDERLY ACUTE MYELOID LEUKEMIA PATIENTS Article Open access 17 August 2023 REFERENCES * Dӧhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia.

N Engl J Med. 2015;373:1136–52. Article  CAS  Google Scholar  * Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization

classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405. Article  PubMed  CAS  Google Scholar  * Cancer Genome Atlas Research Network. Genomic and epigenomic

landscapes of adult de novo myeloid leukemia. N Engl J Med. 2013;368:2059–74. * Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and

prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21. Article  PubMed  PubMed Central  CAS  Google Scholar  * Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J,

et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–89. Article  PubMed  PubMed Central  CAS  Google Scholar  * Metzeler KH,

Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Görlich D, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128:686–98. Article

  PubMed  CAS  Google Scholar  * Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev. 2004;18:115–36. Article  PubMed  Google Scholar  * Grimwade D, Mrózek K.

Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia. Hematol Oncol Clin North Am. 2011;25:1135–61. Article  PubMed  Google Scholar  * Döhner H, Estey E, Grimwade D,

Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47. Article  PubMed 

PubMed Central  CAS  Google Scholar  * Marcucci G, Haferlach T, Döhner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol.

2011;29:475–86. Article  PubMed  CAS  Google Scholar  * Meyer SC, Levine RL. Translational implications of somatic genomics in acute myeloid leukaemia. Lancet Oncol. 2014;15:e382–94. Article

  PubMed  CAS  Google Scholar  * Grimwade D, Ivey A, Huntly BJP. Molecular landscape of acute myeloid leukemia in younger adults and its clinical significance. Blood. 2016;127:29–41. Article

  PubMed  PubMed Central  CAS  Google Scholar  * Metzeler KH, Becker H, Maharry K, Radmacher MD, Kohlschmidt J, Mrózek K, et al. _ASXL1_ mutations identify a high-risk subgroup of older

patients with primary cytogenetically normal AML within the ELN favorable genetic category. Blood. 2011;118:6920–29. Article  PubMed  PubMed Central  CAS  Google Scholar  * Gaidzik VI,

Bullinger L, Schlenk RF, Zimmermann AS, Röck J, Paschka P, et al. _RUNX1_ mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study

group. J Clin Oncol. 2011;29:1364–72. Article  PubMed  Google Scholar  * Mendler JH, Maharry K, Radmacher MD, Mrózek K, Becker H, Metzeler KH, et al. _RUNX1_ mutations are associated with

poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and microRNA expression signatures. J Clin Oncol. 2012;30:3109–18.

Article  PubMed  PubMed Central  Google Scholar  * Mrózek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP, et al. Prognostic significance of the European LeukemiaNet standardized

system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30:4515–23. Article  PubMed  PubMed Central  Google Scholar  * Mrózek K,

Carroll AJ, Maharry K, Rao KW, Patil SR, Pettenati MJ, et al. Central review of cytogenetics is necessary for cooperative group correlative and clinical studies of adult acute leukemia: the

Cancer and Leukemia Group B experience. Int J Oncol. 2008;33:239–44. PubMed  PubMed Central  Google Scholar  * Vittinghoff E, Glidden DV, Shiboski SC, McCulloch CE _Regression Methods in

Biostatistics: Linear, Logistic, Survival and Repeated Measures Models_. (Springer, New York, 2005) * Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat

Assoc. 1958;53:457–81. Article  Google Scholar  * Marcucci G, Maharry K, Radmacher MD, Mrózek K, Vukosavljevic T, Paschka P, et al. Prognostic significance of, and gene and microRNA

expression signatures associated with, _CEBPA_ mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B study. J Clin

Oncol. 2008;26:5078–87. Article  PubMed  PubMed Central  CAS  Google Scholar  * Patel JL, Schumacher JA, Frizzell K, Sorrells S, Shen W, Clayton A, et al. Coexisting and cooperating

mutations in _NPM1_-mutated acute myeloid leukemia. Leuk Res. 2017;56:7–12. Article  CAS  Google Scholar  * Mrózek K. Cytogenetic, molecular genetic, and clinical characteristics of acute

myeloid leukemia with a complex karyotype. Semin Oncol. 2008;35:365–77. Article  PubMed  PubMed Central  CAS  Google Scholar  * Eisfeld A-K, Mrózek K, Kohlschmidt J, Nicolet D, Orwick S,

Walker CJ, et al. The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia. Leukemia. 2017;31:2211–18. Article  PubMed  PubMed

Central  CAS  Google Scholar  * Becker H, Marcucci G, Maharry K, Radmacher MD, Mrózek K, Margeson D, et al. Favorable prognostic impact of _NPM1_ mutations in older patients with

cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28:596–604. Article 

PubMed  CAS  Google Scholar  * Ostronoff F, Othus M, Lazenby M, Estey E, Appelbaum FR, Evans A, et al. Prognostic significance of _NPM1_ mutations in the absence of _FLT3_-internal tandem

duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. J Clin Oncol. 2015;33:1157–64. Article  PubMed 

PubMed Central  Google Scholar  * Tsai C-H, Hou H-A, Tang J-L, Liu C-Y, Lin C-C, Chou W-C, et al. Genetic alterations and their clinical implications in older patients with acute myeloid

leukemia. Leukemia. 2016;30:1485–92. Article  PubMed  CAS  Google Scholar  * Mrózek K, Heinonen K, Lawrence D, Carroll AJ, Koduru PRK, Rao KW, et al. Adult patients with de novo acute

myeloid leukemia and t(9;11)(p22;q23) have a superior outcome to patients with other translocations involving band 11q23: a Cancer and Leukemia Group B study. Blood. 1997;90:4532–38. PubMed

  Google Scholar  * Krauter J, Wagner K, Schäfer I, Marschalek R, Meyer C, Heil G, et al. Prognostic factors in adult patients up to 60 years old with acute myeloid leukemia and

translocations of chromosome band 11q23: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2009;27:3000–06. Article  PubMed  Google

Scholar  * Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic

significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354–65. Article 

PubMed  CAS  Google Scholar  Download references 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. 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

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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

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