FLT3|NPM1|TP53|DNMT3A|General AML|Chromatin Regulation|Spliceosome|RUNX1

Spectrum and prognostic relevance of driver gene mutations in Acute Myeloid Leukemia

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.

General findings
  • Association of driver gene mutations with clinical characteristics and cytogenetics
    • NPM1 and DNMT3A mutations were more common and mutations in RUNX1, SRSF2, ASXL1, STAG2 and BCOR less common in women compared with men
    • FLT3-ITD and NPM1 mutations were associated with higher leukocyte counts and higher BM blasts percentages
    • 8 genetically defined sub-groups with nonoverlapping mutations were identified, with widely divergent outcomes
  • Driver mutations and survival
    • Patients with mutated NPM1, especially in the absence of FLT3-ITD, and those with double CEBPA mutations had relatively favorable OS
    • Patients with DNMT3A, RUNX1, ASXL1, SRSF2, TP53, BCOR, U2AF1, or SF3B1 mutations had significantly shorter survival
    • In multivariate analysis, age <60y, favorable cytogenetics, mutated NPM1 in the absence of FLT3-ITD, were associated with longer OS
    • The prognostic impact of DNMT3A and RUNX1 mutations differed significantly according to age (inferior OS in younger but not older patients)
    • Thrapy-related AML, decreased PS, higher leukocyte counts, adverse cytogenetics changes and TP53 mutations were associated with shorter OS regardless of age
  •  Prognostic impact of gene mutations in defined age groups and cytogenetic subsets
    • NPM1, DNMT3A, and FLT3-ITD mutations occurred in 47% (212/452), 40% (181/452), and 39% (175/452) of MRC intermediate-risk patients
    • 97% of NPM1-mutated patients, 88% of DNMT3A-mutated patients, and 92% of FLT3-ITD–positive patients had intermediate-risk cytogenetics
    • DNMT3A mutations was a negative prognostic factor in younger patients
    • NPM1 mutations were correlated with favorable OS in older patients (see figure 1)
    • Patients with mutated NPM1 and wild-type DNMT3A had the most favorable outcomes in both age groups
    • Patients with mutated NPM1 in the absence of FLT3-ITD had favorable outcomes
    • In MRC intermediate-risk patients, OS was shorter, among younger patients only, if DNMT3A mutations were combined with NPM1/FLT3-ITD genotype

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.

Abstract

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.

References
  1. Metzeler K.H. et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016; 128:686-698; DOI:10.1182/blood-2016-01-693879.