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  • Clinical implications of su...
    Prochazka, Katharina T; Pregartner, Gudrun; Rücker, Frank G; Heitzer, Ellen; Pabst, Gabriel; Wölfler, Albert; Zebisch, Armin; Berghold, Andrea; Döhner, Konstanze; Sill, Heinz

    Haematologica (Roma), 03/2019, Letnik: 104, Številka: 3
    Journal Article

    The role of subclonal mutations, defined by a variant allele frequency of <20%, has not been addressed in acute myeloid leukemia yet. We, therefore, analyzed their prognostic value in a cohort of 1,537 patients with newly diagnosed disease, prospectively treated within three trials of the "German-Austrian Acute Myeloid Leukemia Study Group". Mutational analysis was performed by targeted deep sequencing and patients with mutations were categorized by their variant allele frequency into groups with frequencies >40%, 20%-40% and <20%. A total of 108 mutations were found in 98 patients (6.4%). Among these, 61 patients had variant allele frequencies >40%, 19 had variant allele frequencies between 20%-40% and 18 had frequencies <20%. Compared to specimens with clonal mutations, those with subclonal ones showed significantly fewer complex karyotypes and chromosomal losses. In either -mutated group, patients experienced significantly fewer complete responses ( <0.001) and had worse overall and event-free survival rates ( <0.0001). In Cox regression analyses adjusting for age, white blood cell count, cytogenetic risk and type of acute myeloid leukemia, the adverse prognostic effect of mutations remained significant for all -mutated subgroups. These data suggest that subclonal mutations are a novel prognostic parameter in acute myeloid leukemia and emphasize the usefulness of next-generation sequencing technologies for risk stratification in this disorder. The study was registered at ClinicalTrials.gov with number NCT00146120.