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Integrated Genetic Profiling in Acute Myeloid Leukemia
A series of somatic mutations that affect the progression and development of acute myeloid leukemia (AML) has recently been discovered. The prognostic relevance of cytogenetic abnormalities has led to the widespread adoption of risk stratification, with patients divided into 3 cytogenetically defined risk groups with significant differences in overall survival. Although progress has been made in defining prognostic markers for AML, a substantial percentage of patients lack a specific abnormality of prognostic significance.
In addition, there is considerable heterogeneity in the outcome for individual patients in each risk group. The novel recurrent somatic mutations in patients with AML that have recently been identified include mutations in TET2, ASXL1, IDH1 or IDH2, DNMT3A, and PHF6. The prognostic value of these recently identified mutations had not been evaluated in a phase 3 trial of treatment for AML.
In this study [N Engl J Med. 2012;366(12):1079-1089], the investigators performed a mutational analysis of 18 genes in 398 patients from the ECOG (East Coast Oncology Group) E1900 trial. The test cohort included patients in that trial for whom viably frozen cells were available for DNA extraction and mutational profiling. A validation cohort of 104 patients comprised a separate set of patients for whom samples were banked in Trizol reagent, which was used to extract DNA for mutational studies.
All patients were <60 years of age who had AML and had been randomly assigned to receive induction therapy with high-dose (90 mg/m2) or standard-dose (45 mg/m2) daunorubicin. Median follow-up time for the patients included in the analysis, calculated from the time of randomization for induction therapy, was 47.4 months.
The source of extracted DNA was bone marrow in the case of 55.2% of the samples (277/502) and peripheral blood in the case of 44.8% (225/502). The investigators sequenced the entire coding regions of TET2, ASXL1, DNMT3A, CEBPA, PHF6, WT1, TP53, EZH2, RUNX1, and PTEN and the regions of previously described mutations for FLT3, NPM1, HRAS, KRAS, NRAS, KIT, IDH1, and IDH2.
Somatic alterations were identified in 97.3% of patients. Mutational heterogeneity was greater in patients with intermediate-risk AML than in patients with favorable-risk or unfavorable-risk AML (P=.01). On univariate analysis, FLT3 internal tandem duplication (FLT3-ITD) mutations and MLL partial tandem duplication (MLL-PTD) mutations were associated with reduced overall survival (P=.001 for FLT3-ITD and P=.009 for MLL-PTD), whereas CEBPA mutations and core-binding factor alterations t(8;21) and inv(16)/t(16;16) were associated with improved overall survival (P=.05 for CEBPA and P<.001 for the core-binding factor alterations).
In addition, PHF6 and ASXL1 mutations were associated with reduced overall survival (P=.006 for PHF6 and P=.05 for ASXL1). IDH2 mutations were associated with an improved rate of overall survival in the entire test cohort (3-year rate, 66%; P=.01).
DNMT3A mutational status had a significant effect on the outcome with dose-intensive chemotherapy (P=.02). When the effects of DNMT3A mutational status on outcome according to treatment group were assessed, high-dose daunorubicin was associated with an improved rate of survival among patients with mutant DNMT3A (P=.04), but not among patients with wild-type DNMT3A.
Dose-intensive induction therapy was associated with a marked improvement in the rate of survival among patients who were positive for DNMT3A or NPM1 mutations or MLL translocations (P=.001), but not among patients with wild type DNMT3A and NPM1 and no MLL translocations. This finding was independent of the clinical covariates of age, white-cell count, and status with respect to transplantation, treatment-related death, and response to chemotherapy, suggesting that high-dose anthracycline chemotherapy provides a benefit in genetically defined subgroups of patients with AML.
The investigators suggested that mutational profiling could potentially be used for risk stratification and to influence prognostic and therapeutic decisions regarding patients with AML.
