Abstract
Mutational analysis improves AML risk stratification and clinical management.
Major Finding: Mutational analysis improves AML risk stratification and clinical management.
Approach: The prognostic value of AML mutations was evaluated in a phase III trial.
Impact: High-dose chemotherapy is beneficial in genetically defined AML subtypes.
Characteristic cytogenetic abnormalities are used to classify patients with acute myeloid leukemia (AML) into favorable, intermediate, and poor outcome groups, but significant heterogeneity remains in the outcome for patients within each risk group. Patel and colleagues hypothesized that risk stratification could be improved by integrating cytogenetic data with mutational analysis of 18 genes known to be recurrently mutated in subsets of AML patients. To systemically analyze the prognostic relevance of these somatic mutations in a large, homogenously treated cohort, the authors analyzed samples from a recent phase III trial of high-dose induction chemotherapy in patients with AML. Somatic mutations in the genes tested were identified in 97.3% of the patients and appeared to fall into distinct complementation groups as evidenced by co-occurrence or mutual exclusivity of distinct mutations and cytogenetic abnormalities. Among the intermediate-risk subgroup, individual mutations were associated with significantly improved or reduced overall survival, even when adjusted for age, white cell count, and transplantation status. Based on this integration of cytogenetic and mutational analyses, the authors proposed a revised prognostic schema that redistributes some members of the intermediate-risk subgroup into the favorable- and poor-outcome subgroups. Furthermore, the authors were able to identify a specific population of patients—those with DNMT3A or NPM1 mutations or MLL translocations—who had an improved outcome in response to induction therapy with high-dose daunorubicin. Together, these findings indicate that integration of traditional cytogenetic profiling with comprehensive mutational analysis of AML genes has the potential to better stratify patients into prognostic groups and guide treatment decisions.
