Enhanced prognosis of acute myeloid leukaemia patients with dmCEBPAbZIP -inf mutations: Insights from a multicentre Chinese cohort study.

The 2022 European LeukemiaNet (ELN) recommendation redefined favourable-risk CCAAT/enhancer binding protein alpha (CEBPA)-mutated acute myeloid leukaemia (AML) by in-frame C-terminal basic leucine zipper domain (bZIP) mutations rather than double CEBPA mutations. We analysed 411 CEBPA-mutated AML patients from six Chinese centres, classified as single-mutant CEBPAbZIP-other (smCEBPAbZIP-other; n = 38), smCEBPAbZIP-inf (n = 39), double-mutant CEBPAother (dmCEBPAother; n = 37) and dmCEBPAbZIP-inf (n = 297). DmCEBPAbZIP-inf patients were younger, had more de novo AML and showed distinct co-mutation profiles, with more GATA binding protein 2 (GATA2) and fewer nucleophosmin 1 (NPM1)/DNA methyltransferase 3 alpha (DNMT3A) mutations. Additionally, dmCEBPAbZIP-inf patients had a higher composite complete remission (CRc) rate (94.6% vs. 84.2%-89.2%, p = 0.025) and better survival than the other three groups (3-year overall survival [OS]: 80.0% vs. 57.4%-70.6%, p < 0.001; 3-year disease-free survival [DFS]: 74.5% vs. 45.4%-67.9%, p = 0.002). Multivariable Cox regression analysis showed that dmCEBPAbZIP-inf and smCEBPAbZIP-inf had comparable survival, whereas dmCEBPAbZIP-inf had better survival than smCEBPAbZIP-other and dmCEBPAother. However, among intensively treated patients, dmCEBPAbZIP-inf was associated with superior survival compared with smCEBPAbZIP-inf (OS, hazard ratio [HR] = 1.542, p = 0.017; DFS, HR = 1.618, p = 0.014) and other two CEBPA groups in multivariable models. Among dmCEBPAbZIP-inf patients, intensive chemotherapy (HR = 0.51, p = 0.012), adverse karyotype (HR = 1.52, p = 0.037), age ≥50 years (HR = 1.74, p = 0.044), neuroblastoma RAS viral oncogene homolog (NRAS) (HR = 1.64, p = 0.014) and colony-stimulating factor 3 receptor (CSF3R) mutation (HR = 1.78, p = 0.049) were independent factors for OS. No significant difference in survival was observed between patients with CEBPAbZIP-indel and CEBPbZIP-ms mutations. In conclusion, the dmCEBPAbZIP-inf subgroup displayed unique co-mutation gene spectra and had better prognoses among the intensive treated cohort.