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Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity

2010; Elsevier BV; Volume: 117; Issue: 8 Linguagem: Inglês

10.1182/blood-2010-09-307280

1528-0020

Erdogan Taskesen, Lars Bullinger, Andrea Corbacioglu, Mathijs A. Sanders, Claudia Erpelinck, Bas J. Wouters, Sonja C. van der Poel-van de Luytgaarde, Frédérik Damm, Jürgen Krauter, Arnold Ganser, Richard F. Schlenk, Bob Löwenberg, Ruud Delwel, Hartmut Döhner, Peter J.M. Valk, Konstanze Döhner,

Chronic Myeloid Leukemia Treatments

Abstract We evaluated concurrent gene mutations, clinical outcome, and gene expression signatures of CCAAT/enhancer binding protein alpha (CEBPA) double mutations (CEBPAdm) versus single mutations (CEBPAsm) in 1182 cytogenetically normal acute myeloid leukemia (AML) patients (16-60 years of age). We identified 151 (12.8%) patients with CEBPA mutations (91 CEBPAdm and 60 CEBPAsm). The incidence of germline mutations was 7% (5 of 71), including 3 C-terminal mutations. CEBPAdm patients had a lower frequency of concurrent mutations than CEBPAsm patients (P < .0001). Both, groups were associated with a favorable outcome compared with CEBPAwt (5-year overall survival [OS] 63% and 56% vs 39%; P < .0001 and P = .05, respectively). However, in multivariable analysis only CEBPAdm was a prognostic factor for favorable OS outcome (hazard ratio [HR] 0.36, P < .0001; event-free survival, HR 0.41, P < .0001; relapse-free survival, HR 0.55, P = .001). Outcome in CEBPAsm is dominated by concurrent NPM1 and/or FLT3 internal tandem duplication mutations. Unsupervised and supervised GEP analyses showed that CEBPAdm AML (n = 42), but not CEBPAsm AML (n = 18), expressed a unique gene signature. A 25-probe set prediction signature for CEBPAdm AML showed 100% sensitivity and specificity. Based on these findings, we propose that CEBPAdm should be clearly defined from CEBPAsm AML and considered as a separate entity in the classification of AML.