Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia

By Jay P. Patel, M. Gönen, Maria E. Figueroa, H. Fernandez, Zhuoxin Sun, J. Racevskis, P. Van Vlierberghe, Igor Dolgalev, S. Thomas, Olga S. Aminova and 21 more. New England Journal of Medicine, 2012

1,928 citations recorded by the source corpus.

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 standard-dose 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.)

Subfields: Cancer Research, Hematology

View Paper: https://www.semanticscholar.org/paper/7acb1fc16b8ae6ed107c09162dcf5ba31ea4982f

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In Cancer Research

1. Chuan He
2. Benjamin L. Ebert
3. Tony Kouzarides
4. Moritz Gerstung
5. Peter J. Campbell

In Hematology

1. M. Dawson
2. Benjamin L. Ebert
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4. M. Greaves
5. James E. Bradner

Citations in the corpus

• Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. (2017, methodology): “Likewise, ASXL1 mutations are more common in older patients and associated with inferior survival.(36,37,62-65,69,70) TP53 mutations are associated with complex karyotype, monosomal karyotype, and specific chromosomal aneuploidies (eg, 25/5q2, 27/7q2), and predict for very poor outcome.”
• R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling (2017, background): “…that leukemia patients with IDH mutations tend to be more sensitive to treatment with hypomethylating agents (AZA and decitabine) (Emadi et al., 2015), ATRA (Boutzen et al., 2016), or standard chemotherapy (daunorubicin and others) (Chou et al., 2011; Patel et al., 2012), than those without.”
• WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation (2015, neutral): “In addition to IDH1, IDH2 and TET2, wilm’s tumor gene, WT1, is also frequently mutated in AML (2013; Fernandez-Mercado et al., 2012; Liang et al., 2013; Patel et al., 2012; Rocquain et al., 2010; Welch et al., 2012).”
• Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. (2014, neutral): “Neutrophils (10(9)/L) average (range) 9 (2-36) 6 (3-16) 8 (3-21)”
• The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “IDH1/2 and TET2 mutations in patients tend to be mutually exclusive (3, 51), and share unique DNA methylation and gene expression patterns (59).”
• Cancer epigenetics: from mechanism to therapy. (2012, background): “The clinical implications of TET2 mutations have largely been inconclusive; however, in some subsets of AML patients, TET2 mutations appear to confer a poor prognosis (Patel et al., 2012).”
• Genomic Classification and Prognosis in Acute Myeloid Leukemia (2016, background): “AML meeting criteria for ≥2 genomic subgroups 56 (4)”