bZIP-Domain Variant Allele Frequency Helps to Refine Risk Stratification in CEBPA-Mutated AML

<b>Objectives</b>: To investigate the prognostic value of CEBPA (CCAAT/enhancer-binding protein α) molecular features, such as variant allele frequency (VAF), in patients with de novo acute myeloid leukemia (AML). <b>Methods</b>: Next-generation sequencing (NGS) was used to detect CEBPA mutations in 162 patients with newly diagnosed AML (except acute promyelocytic leukemia). <b>Results</b>: We established 44.2% as the optimal threshold for both maximum VAF and bZIP-domain VAF. The high-VAF group showed higher leukemia burden and inferior event-free survival (EFS). bZIP-domain VAF demonstrated superior prognostic value over maximum VAF (HR: 3.174 vs. 2.460) and was validated across subgroups, namely cytogenetically normal acute myeloid leukemia (CN-AML), chemotherapy-only, and low/intermediate-risk subgroups. Multivariate analysis confirmed high bZIP-domain VAF and DNMT3A mutation as independent risk factors. <b>Conclusions</b>: Our results confirm that the bZIP-domain VAF of CEBPA mutations is a more effective predictor of relapse than the maximum VAF, offering a valuable tool for the early identification of patients at high risk of relapse.