Clinical Significance of bZIP In-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia

PURPOSE: We evaluated the characteristics of CCAAT/enhancer-binding protein α (CEBPA) mutations and the significance of a basic leucine zipper in-frame mutation (bZIP(in-f)) of CEBPA in patients with acute myeloid leukemia with a normal karyotype. MATERIALS AND METHODS: Based on updated knowledge of CEBPA mutations, we conducted next-generation sequencing analyses in a previously established real-world cohort. RESULTS: Among 78 of a total of 395 patients (19.7%), 50 had bZIP(in-f) CEBPA, and 28 had non-bZIP(in-f) CEBPA. In the multivariate analysis, patients with NPM1(mut), those with bZIP(in-f) CEBPA, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but FLT3-ITD(mut) was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIP(in-f) CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITD(pos) was associated with worse outcomes. In the CEBPA double-mutated group (CEBPA(dm)), bZIP(in-f) CEBPA was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIP(in-f) CEBPA. Of 50 patients with bZIP(in-f) CEBPA, 36 patients had at least one mutation. When grouped by the presence of mutations in chromatic/DNA modifiers (C), cohesion complex (C), and splicing genes (S) (CCS mutations), CCS-mutated bZIP(in-f) CEBPA was associated with poor OS (p=0.044; hazard ratio [HR], 2.419) and a trend in inferior RFS (p=0.186; HR, 1.838). CONCLUSION: Only bZIP(in-f) CEBPA was associated with favorable outcomes in patients with CEBPA(dm). However, some mutations accompanying bZIP(in-f) CEBPA showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIP(in-f) CEBPA.