P448: prognostic impact of somatic cebpa bzip domain mutations in acute myeloid leukemia

Background: Mutations of CEBPA (CEBPAmut) are present in ~5-10% of newly diagnosed adult acute myeloid leukemia (AML), and approximately half of the patients (pts) exhibit biallelic mutations (CEBPAbi). CEBPAbi defines a distinct entity within the 2016 WHO classification and is categorized as favorable in the 2017 risk stratification by the European LeukemiaNet. CEBPAmut can be divided into basic leucine zipper domain (bZIP) or transcription activation domains (TAD) mutations, respectively. Recent studies have demonstrated CEBPAbZIP mutations, in particular in-frame mutations (CEBPAbZIP-inf), to be associated with favorable outcome, regardless of mono- or biallelic status. Aims: To evaluate the prognostic impact of CEBPAbZIP, in particular CEBPAbZIP-inf mutations in AML. Methods: Investigating a cohort of 454 intensively treated CEBPA mutated AML pts entered into the AMLSG BiO Registry study (NCT01252485). Results: Of the 454 pts, 223 had CEBPAbi and 231 monoallelic CEBPA mutations (CEBPAsm) affecting bZIP in 78 pts or TAD in 153 pts. Genotypes differed significantly with regard to clinical and genetic features: CEBPAbi pts were younger than CEBPAsmbZIP and CEBPAsmTAD (median age in yrs: 52 vs 59 vs 60; P<.001), had a higher rate of de novo AML (97% vs 81% vs 84%; P<.001), lower platelet counts (median G/l 36 vs 57 vs 52; P<.001), higher peripheral blood (PB) blast counts (median 71% vs 60% vs 44%; P<.001), and showed an inverse correlation with FLT3 internal tandem duplication (FLT3-ITD) and NPM1 mutation (NPM1mut) (6% vs 21% vs 35% and 0% vs 26% vs 50%; P<.001 each). Outcome analysis revealed a significant improved overall (OS) and event-free survival (EFS) for CEBPAbi with no difference between CEBPAsmbZIP and CEBPAsmTAD (5-year OS: 62% vs 42% vs 51%; P<.001, 5-year EFS: 47% vs 27% vs 43%; P<.022). Subgroup specific analysis within CEBPAsmbZIP revealed an improved outcome for CEBPAbZIP-inf pts (n=46) (5-year OS: 52% vs 29%; P=.001, and 5-year EFS: 34% vs 18%; P=.018). To further address the impact of CEBPAbZIP-inf, pts were categorized as CEBPAbZIP-inf (n=250), irrespective of the allelic status, vs all others (CEBPAother) (n=204). CEBPAbZIP-inf pts were younger (median age in yrs: 52 vs 62; P<.001), had a higher rate of de novo AML (97% vs 81%; P<.001), lower platelet counts (median G/l 36 vs 53; P<.001), higher white blood cell (WBC) (median G/l 25.4 vs 16.1; P=.029), and higher PB blast counts (median 72% vs 46%; P<.001); FLT3-ITD and NPM1mut were less common in CEBPAbZIP-inf pts (9% vs 30% and 3% vs 44%; P<.001 each). CEBPAbZIP-inf exhibited a significant improved OS (5-year OS: 60% vs 48%; P<.001) and EFS (5-year EFS: 47% vs 37%; P=.007); in multivariate Cox models for OS and EFS, including allogeneic hematopoietic cell transplantation (HCT) in first complete remission as time-dependent covariate, age (HR: 1.50; P<.001), WBC (HR: 1.40; P=.018), and adverse cytogenetics (HR: 2.33; P=.010) were unfavorable factors for OS, whereas NPM1mut (HR: 0.63; P=.040), HCT (HR: 0.46; P=.010), and CEBPAbZIP-inf (HR: 0.59; P=.007) revealed as favorable. For EFS, age (HR: 1.19; P=.002), WBC (HR: 1.30; P=.028), and FLT3-ITD (HR: 1.83; P=.003) were unfavorable, whereas NPM1mut (HR: 0.65; P=.028) and HCT (HR: 0.33; P<.001) were favorable. Summary/Conclusion: In this cohort of 454 CEBPA mutated adult AML pts, CEBPAbZIP-inf was associated with specific clinical and genetic characteristics. Furthermore, CEBPAbZIP-inf pts had a significantly superior outcome irrespective of the allelic status. This study confirms recent findings suggesting a prognostic role of this mutation type. FGR and AC contributed equally