CEBPA Mutations Predict Favorable Prognosis in Pediatric AML

C/EBPα is a transcription factor that regulates terminal granulocytic differentiation. Although functional mutations in the CEBPA gene have been associated with improved outcome, they have not been well-characterized in pediatric AML. We evaluated the prevalence and prognostic significance of CEBPA mutations in 847 children with de novo AML treated on three consecutive pediatric AML trials (CCG-2941, CCG-2961, and COG-AAML03P1). Clinical characteristics and outcomes for patients with CEBPA mutations were compared to that of patients with wild-type CEBPA. Two types of CEBPA mutations—N-terminal truncating mutations and in-frame bZip domain mutations—were detected in 38/847 (4.5%) patients tested, and 31/38 (82%) patients with mutations harbored both mutation types. Polymorphisms were also identified in 7.8% of patients screened; patients with polymorphisms were analyzed in the CEBPA wild-type subgroup. The presence of functional mutations was correlated with laboratory and clinical characteristics, and clinical outcome. CEBPA mutations were significantly more common in older patients, patients with FAB M1 and M2, and patients with normal cytogenetics. These mutations did not occur in patients with either favorable or unfavorable risk cytogenetics. CEBPA mutations were found almost exclusively in the normal karyotype cohort, and patients with CEBPA mutations accounted for 17% of all patients with normal cytogenetics. Actuarial event-free survival at 5 years from study entry was 69% vs. 38% (p=0.017) with a cumulative incidence of relapse after complete remission of 13% vs. 44% (p=0.007) for those with and without CEBPA mutations. For patients with known diagnostic cytogenetic information, clinical outcome of those with CEBPA mutations was compared to that of those with favorable risk Core Binding Factor (CBF) AML. Patients with CEBPA mutations had an overall survival similar to those with CBF AML (78% vs. 74%, p=0.999). The presence of CEBPA mutations was an independent prognostic factor for improved outcome (hazard ratio 0.24, p=0.047). CEBPA mutations are associated with a lower relapse rate and improved survival in pediatric AML. CEBPA mutation analysis needs to be incorporated into initial screening for risk identification and therapy allocation at diagnosis.