Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia

Metzeler Klaus H, Herold Tobias, Rothenberg-Thurley Maja, Amler Susanne , Sauerland Maria C, Görlich Dennis, Schneider Stephanie, Konstandin Nikola P, Dufour Annika, Bräundl Kathrin, Ksienzyk Bianka, Zellmeier Evelyn, Hartmann Luise, Greif Philipp A, Fiegl Michael, Subklewe Marion, Bohlander Stefan K, Krug Utz, Faldum Andreas, Berdel Wolfgang E, Wörmann Bernhard, Büchner Thomas, Hiddemann Wolfgang, Braess Jan, Spiekermann Karsten

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 18-86 years treated on two phase III trials of the German AML Cooperative Group. 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 co-mutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually non-overlapping 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 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.