Prognostic relevance of integrated genetic profiling in acute myeloid leukemia Journal Article


Authors: Patel, J. P.; Gonen, M.; Figueroa, M. E.; Fernandez, H.; Sun, Z.; Racevskis, J.; Van Vlierberghe, P.; Dolgalev, I.; Thomas, S.; Aminova, O.; Huberman, K.; Cheng, J.; Viale, A.; Socci, N. D.; Heguy, A.; Cherry, A.; Vance, G.; Higgins, R. R.; Ketterling, R. P.; Gallagher, R. E.; Litzow, M.; van den Brink, M. R. M.; Lazarus, H. M.; Rowe, J. M.; Luger, S.; Ferrando, A.; Paietta, E.; Tallman, M. S.; Melnick, A.; Abdel-Wahab, O.; Levine, R. L.
Article Title: Prognostic relevance of integrated genetic profiling in acute myeloid leukemia
Abstract: BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. METHODS: We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. RESULTS: We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P = 0.001 for FLT3-ITD, P = 0.009 for MLL-PTD, P = 0.05 for ASXL1, and P = 0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P = 0.05 for CEBPA and P = 0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standarddose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P = 0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P = 0.67). CONCLUSIONS: We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.) Copyright © 2012 Massachusetts Medical Society.
Keywords: adolescent; adult; cancer chemotherapy; cancer survival; controlled study; treatment outcome; middle aged; young adult; acute granulocytic leukemia; gene mutation; gene translocation; major clinical study; overall survival; mutation; leukemia, myeloid, acute; dose response; cytarabine; drug megadose; gene expression profiling; genetic association; mutational analysis; age; risk assessment; daunorubicin; gene duplication; dna fingerprinting; translocation, genetic; leukocyte count; dna mutational analysis; genetic risk; antibiotics, antineoplastic; tumor gene; induction chemotherapy; leukemia remission; asxl1 gene; kaplan-meier estimate; idh1 gene; idh2 gene; cebpa gene; cancer prognosis; dnmt3a gene; npm1 gene; flt3 gene; mll gene; phf6 gene
Journal Title: New England Journal of Medicine
Volume: 366
Issue: 12
ISSN: 0028-4793
Publisher: Massachusetts Medical Society  
Date Published: 2012-03-22
Start Page: 1079
End Page: 1089
Language: English
DOI: 10.1056/NEJMoa1112304
PROVIDER: scopus
PUBMED: 22417203
PMCID: PMC3545649
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 2 April 2012" - "CODEN: NEJMA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Adriana Heguy
    85 Heguy
  2. Mithat Gonen
    701 Gonen
  3. Martin Stuart Tallman
    408 Tallman
  4. Ross Levine
    469 Levine
  5. Agnes Viale
    205 Viale
  6. Nicholas D Socci
    182 Socci
  7. Jay Prakash Patel
    52 Patel
  8. Sabrena Antonette Thomas
    3 Thomas
  9. Janice Cheng
    2 Cheng