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

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.

journal_name

Blood

journal_title

Blood

authors

Metzeler KH,Herold T,Rothenberg-Thurley M,Amler S,Sauerland MC,Görlich D,Schneider S,Konstandin NP,Dufour A,Bräundl K,Ksienzyk B,Zellmeier E,Hartmann L,Greif PA,Fiegl M,Subklewe M,Bohlander SK,Krug U,Faldum A,Berdel

doi

10.1182/blood-2016-01-693879

subject

Has Abstract

pub_date

2016-08-04 00:00:00

pages

686-98

issue

eissn

0006-4971

issn

1528-0020

pii

blood-2016-01-693879

journal_volume

128

pub_type

杂志文章,多中心研究,随机对照试验

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