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K H. Metzeler et al. investigated the spectrum of recurrent driver gene mutations in 664 previously untreated AML patients who received intensive induction chemotherapy and were included in two consecutive phase III trials of the AMLCG. This is one of the largest patient cohorts with an extensive set of known driver mutations including patients ≥60 y who are fit for intensive therapy. This research, i.e. sequencing of 37 genes and recurrently mutated regions (in 31 genes), is of special interest as the clinical and prognostic implications of these gene mutations in adult acute myeloid leukemia (AML) is still not clearly characterized and may provide data to help to identify important targets for new treatment approaches. The results were published in Blood in 2016.
In conclusion these results represent one of the largest datasets to provide useful insights on the correlations between genetic mutations, prognosis and clinical characteristics stratified by age. These data also serve as evidence to support the inclusion of AML with RUNX1 or biallelic CEBPA mutations as separate entities in the imminent amendments of the WHO classification.
The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.
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