CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group

Abstract

Biallelic CEBPA mutations are associated with favorable outcomes in acute myeloid leukemia (AML). We evaluated the clinical and biologic implications of CEBPA-basic leucine zipper (CEBPA-bZip) mutations in children and young adults with newly diagnosed AML. CEBPA-bZip mutation status was determined in 2958 patients with AML enrolled on Children's Oncology Group trials (NCT00003790, NCT0007174, NCT00372593, NCT01379181). Next-generation sequencing (NGS) was performed in 1863 patients (107 with CEBPA mutations) to characterize the co-occurring mutations. CEBPA mutational status was correlated with disease characteristics and clinical outcomes. CEBPA-bZip mutations were identified in 160 (5.4%) of 2958 patients, with 132 (82.5%) harboring a second CEBPA mutation (CEBPA-double-mutated [CEBPA-dm]) and 28 (17.5%) had a single CEBPA-bZip only mutation. The clinical and laboratory features of the 2 CEBPA cohorts were very similar. Patients with CEBPA-dm and CEBPA-bZip experienced identical event-free survival (EFS) of 64% and similar overall survival (OS) of 81% and 89%, respectively (P = .259); this compared favorably to EFS of 46% and OS of 61% in patients with CEBPA-wild-type (CEBPA-WT) (both P < .001). Transcriptome analysis demonstrated similar expression profiles for patients with CEBPA-bZip and CEBPA-dm. Comprehensive NGS of patients with CEBPA mutations identified co-occurring CSF3R mutations in 13.1% of patients and GATA2 mutations in 21.5% of patients. Patients with dual CEBPA and CSF3R mutations had an EFS of 17% vs 63% for patients with CEBPA-mutant or CSF3R-WT (P < .001) with a corresponding relapse rate (RR) of 83% vs 22%, respectively (P < .001); GATA2 co-occurrence did not have an impact on outcome. CEBPA-bZip domain mutations are associated with favorable clinical outcomes, regardless of monoallelic or biallelic status. Co-occurring CSF3R and CEBPA mutations are associated with a high RR that nullifies the favorable prognostic impact of CEBPA mutations.

Graphical abstract

Figure 1.

Cytogenetic and molecular characteristics according to CEBPA mutational status. (A) Cytogenetic profile according CEBPA-WT compared with CEBPA-bZip or CEBPA-dm status. *P < .001 for CEBPA-WT compared with CEBPA-bZip and CEBPA-dm. (B) Molecular profile according to CEBPA-WT compared with CEBPA-bZip or CEBPA-dm status. Abn 11, chromosome 11 abnormalities.

Figure 2.

Molecular profiles of patients with CEBPA mutations as determine by NGS. (A) Cyto-molecular status and co-occurring mutational profile of patients with CEBPA double and CEBPA-bZip mutations. (B) Comparison of common co-occurring mutations in patients with CEBPA mutations compared with patients with CEBPA-WT. *P < .0001.

Figure 3.

Correlation of CEBPA mutational status with clinical outcome. (A) EFS among the cohort according to CEBPA-WT vs CEBPA-dm vs CEBPA-bZip status; (B) RR according to CEBPA-WT vs CEBPA-dm vs CEBPA-bZip status; (C) OS for the cohort according CEBPA-WT vs CEBPA-dm vs CEBPA-bZip status.

Figure 4.

Transcriptome profiling according to CEBPA mutational status. (A) Gene expression clustering according to mutational status with CEBPA-mutant samples compared with other molecular alterations that have prognostic implications in pediatric AML. (B-C) Unsupervised hierarchical clustering of patients according to CEBPA mutational status (B) and with CEBPA-bZip and double mutations (C). (D) CEBPA mutational status and association with CEBPA transcript expression. mut, mutation; TPM, transcripts per million.

Figure 5.

Outcomes of CEBPA-mutant patients according to co-occurring CSF3R and GATA2 mutational status. (A) EFS of dual CEBPA⁺/CSF3R⁺ mutant patients compared to those with dual CEBPA⁺/GATA2⁺ and those with a CEBPA⁺ mutation and neither CSF3R nor GATA2; (B) RR of dual CEBPA⁺/CSF3R⁺ mutant patients compared to dual CEBPA⁺/GATA2⁺ and patients with a CEBPA⁺ mutation and neither CSF3R nor GATA2; (C) OS of dual CEBPA⁺/CSF3R⁺ mutant patients compared to dual CEBPA⁺/GATA2⁺ and patients with a CEBPA⁺ mutation and neither CSF3R nor GATA2.