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

Abstract

Purpose We evaluated the characteristics of CCAAT/enhancer-binding protein α (<i>CEBPA</i>) mutations and the significance of a basic leucine zipper in-frame mutation (bZIP^in-f) of <i>CEBPA</i> in patients with acute myeloid leukemia with a normal karyotype.Materials and Methods Based on updated knowledge of <i>CEBPA</i> 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 <i>CEBPA</i>, and 28 had non-bZIP^in-f <i>CEBPA</i>. In the multivariate analysis, patients with <i>NPM1</i>^mut, those with bZIP^in-f <i>CEBPA</i>, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but <i>FLT3</i>-ITD^mut was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIP^in-f <i>CEBPA</i>, and allo-HCT were associated with favorable outcomes; <i>FLT3</i>-ITD^pos was associated with worse outcomes. In the <i>CEBPA</i> double-mutated group (<i>CEBPA</i>^dm), bZIP^in-f <i>CEBPA</i> was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIP^in-f <i>CEBPA</i>. Of 50 patients with bZIP^in-f <i>CEBPA</i>, 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 <i>CEBPA</i> 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 <i>CEBPA</i> was associated with favorable outcomes in patients with <i>CEBPA</i>^dm. However, some mutations accompanying bZIP^in-f <i>CEBPA</i> showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIP^in-f <i>CEBPA<i>.