Prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group

Abstract

CCAAT/enhancer-binding protein alpha (CEBPA) mutations are a favorable prognostic factor in adult acute myeloid leukemia (AML) patients; however, few studies have examined their significance in pediatric AML patients. Here we examined the CEBPA mutation status and clinical outcomes of pediatric AML patients treated in the AML-05 study. We found that 47 (14.9%) of the 315 evaluable patients harbored mutations in CEBPA; 26 cases (8.3%) harbored a single mutation (CEBPA-single) and 21 (6.7%) harbored double or triple mutations (CEBPA-double). After excluding core-binding factor-AML cases, patients harboring CEBPA mutations showed better overall survival (OS; P=0.048), but not event-free survival (EFS; P=0.051), than wild-type patients. Multivariate analysis identified CEBPA-single and CEBPA-double as independent favorable prognostic factors for EFS in the total cohort (hazard ratio (HR): 0.47 and 0.33; P=0.02 and 0.01, respectively). CEBPA-double was also an independent favorable prognostic factor for OS (HR: 0.30; P=0.04). CEBPA-double remained an independent favorable factor for EFS (HR: 0.28; P=0.04) in the normal karyotype cohort. These results suggest that CEBPA mutations, particularly CEBPA-double, are an independent favorable prognostic factor in pediatric AML patients, which will have important implications for risk-stratified therapy.

Figure 1

Location and type of the mutations detected in pediatric AML patients enrolled in the AML-05 study. AA, amino acid; BZIP, basic leucine zipper; TAD, transactivation domain.

Figure 2

Kaplan–Meier survival curves showing EFS and OS from the time of diagnosis according to CEBPA mutation status. (a) EFS and (b) OS of patients harboring CEBPA mutations, patients harboring WT CEBPA (excluding core-binding factor-acute myeloid leukemia (CBF-AML) cases (WT non-CBF)) and patients with CBF-AML. (c) EFS and (d) OS of patients harboring a single CEBPA mutation (CEBPA-single), patients harboring double or triple CEBPA mutations (CEBPA-double), WT patients (excluding CBF-AML cases (WT non-CBF)) and patients with CBF-AML. P-values were determined using the log-rank test.

Figure 3

Kaplan–Meier survival curves showing EFS and OS in acute myeloid leukemia patients with a normal karyotype. (a) EFS and (b) OS of patients harboring a single CEBPA mutation (CEBPA-single), patients harboring double or triple CEBPA mutations (CEBPA-double) and WT patients. P-values were determined using the log-rank test.

Figure 4

Kaplan–Meier survival curves showing EFS and OS according to the location and number of CEBPA mutations. Only patients with hotspot mutations predicted to cause p30 isoform translation and/or disruption or loss of the C-terminal bZIP domain were included in the analysis. (a) EFS and (b) OS in patients harboring a single N-terminal mutation (CEBPA-single N-term), patients harboring a single C-terminal mutation (CEBPA-single C-term), patients harboring both N and C-terminal mutations (CEBPA-double N+C-term), WT patients (excluding core-binding factor-acute myeloid leukemia (CBF-AML) cases (WT non-CBF)) and patients with CBF-AML. (c) EFS and (d) OS of AML patients with a normal karyotype. P-values were determined using the log-rank test.