Blood Journal
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ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category

  1. Klaus H. Metzeler1,*,
  2. Heiko Becker1,*,
  3. Kati Maharry1,2,
  4. Michael D. Radmacher1,2,
  5. Jessica Kohlschmidt1,2,
  6. Krzysztof Mrózek1,
  7. Deedra Nicolet1,2,
  8. Susan P. Whitman1,
  9. Yue-Zhong Wu1,
  10. Sebastian Schwind1,
  11. Bayard L. Powell3,
  12. Thomas H. Carter4,
  13. Meir Wetzler5,
  14. Joseph O. Moore6,
  15. Jonathan E. Kolitz7,
  16. Maria R. Baer8,
  17. Andrew J. Carroll9,
  18. Richard A. Larson10,
  19. Michael A. Caligiuri1,
  20. Guido Marcucci1,, and
  21. Clara D. Bloomfield1,
  1. 1Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH;
  2. 2Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN;
  3. 3Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC;
  4. 4University of Iowa, Iowa City, IA;
  5. 5Roswell Park Cancer Institute, Buffalo, NY;
  6. 6Duke University Medical Center, Durham, NC;
  7. 7Monter Cancer Center, Hofstra North Shore–Long Island Jewish School of Medicine, Lake Success, NY;
  8. 8Greenebaum Cancer Center, University of Maryland, Baltimore, MD;
  9. 9Department of Genetics, University of Alabama at Birmingham, Birmingham, AL; and
  10. 10University of Chicago Medical Center, Chicago, IL


The associations of mutations in the enhancer of trithorax and polycomb family gene ASXL1 with pretreatment patient characteristics, outcomes, and gene-/microRNA-expression profiles in primary cytogenetically normal acute myeloid leukemia (CN-AML) are unknown. We analyzed 423 adult patients for ASXL1 mutations, other prognostic gene mutations, and gene-/microRNA-expression profiles. ASXL1 mutations were 5 times more common in older (≥ 60 years) patients (16.2%) than those younger than 60 years (3.2%; P < .001). Among older patients, ASXL1 mutations associated with wild-type NPM1 (P < .001), absence of FLT3-internal tandem duplications (P = .002), mutated CEBPA (P = .01), and with inferior complete remission (CR) rate (P = .04), disease-free survival (DFS; P = .03), overall survival (OS; P = .006), and event-free survival (EFS; P = .002). Within the European LeukemiaNet (ELN) genetic categories of older CN-AML, ASXL1 mutations associated with inferior CR rate (P = .02), OS (P < .001), and EFS (P < .001) among ELN Favorable, but not among ELN Intermediate-I patients. Multivariable analyses confirmed associations of ASXL1 mutations with unfavorable CR rate (P = .03), DFS (P < .001), OS (P < .001), and EFS (P < .001) among ELN Favorable patients. We identified an ASXL1 mutation-associated gene-expression signature, but no microRNA-expression signature. This first study of ASXL1 mutations in primary CN-AML demonstrates that ASXL1mutated older patients, particularly within the ELN Favorable group, have unfavorable outcomes and may be candidates for experimental treatment approaches.

  • Submitted August 23, 2011.
  • Accepted October 5, 2011.
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