Homozygous CEBPA Mutations Predict Favorable Outcomes in AML Patients

Background: Loss of heterozygosity (LOH) of CEBPA has been sporadically reported in acute myeloid leukemia (AML), resulting in a complete or nearly complete homozygosity of CEBPA mutations (CEBPA^homo). However, its clinical significance has been underappreciated.

Methods: We retrospectively analyzed the prognostic impact of CEBPA^homo in 1223 adult AML patients, where CEBPA mutations were detected using whole exome sequencing (n=296) or targeted sequencing (n=927) technology. CEBPA^homo is defined as the variant allele frequency (VAF) of a CEBPA mutation over 50%, and CEBPA^heter is the opposite. Propensity score matching was used to reduce selection bias when comparing the survival difference between two groups.

Results: CEBPA mutations were identified in 106 patients (8.7%), 47(44.3%) of which carried the C-terminal DNA-binding or basic leucine zipper region (CEBPA^bZIP). Compared to patients with other CEBPA mutations (CEBPA^others), patients carrying CEBPA^bZIP were significantly younger (40.38±14.80 vs. 52.05±17.44 years, P<0.001) and had higher hemoglobin [89(65.5, 98) vs 70(58, 81) g/dL, P=0.001], lower platelet counts [35(17.5, 43) vs. 44(24, 78.5) 10⁹/L, P=0.019) and higher proportion of peripheral blast cells [80(52.5, 90.5) vs. 51(14, 86.5) %, P=0.001] at diagnosis. CEBPA^bZIP was associated with a higher complete remission rate (CR; 85% vs. 61%, P=0.012) in AML patients but did not reduce the relapse rate (32% vs. 39%, P=0.582). CEBPA^bZIP significantly improved 4-year overall survival (OS; 0.70±0.09 vs. 0.30±0.13, P=0.013), 2-year event-free survival (EFS; 0.47±0.09 vs. 0.2±0.09, P=0.01), and 3-year pre-transplantation survival (PTS; 0.54±0.09 vs. 0.38±0.09, P=0.003) in AML patients compared to those with CEBPA^others. These data are consistent with previous reports, suggesting the representative of this cohort. We further evaluated the clinical significance of CEBPA^homo in this cohort and found that patients with CEBPA^homo had higher white blood cell counts [29.37 (9.16, 76.11) vs. 10.37 (3.38, 43.43) 10⁹/L, P=0.048] than those with CEBPA^heter. Although CEBPA^homo was not associated with CR rate (65% vs. 80%, P=0.145), it did reduce relapse rate (26% vs. 47%, P=0.045) in AML patients compared to those with CEBPA^heter. CEBPA^homo was significantly associated with improved 5-year OS (0.68±0.10 vs. 0.29±0.10, P=0.006), 5-year EFS (0.30±0.09 vs. 0.10±0.08, P=0.018), and 5-year PTS (0.40±0.10 vs. 0.14±0.07, P=0.046) compared to CEBPA^heter. There is no difference in CEBPA VAF between patients carrying CEBPA^bZIP and CEBPA^other, suggesting similar distribution of CEBPA^homo between these two groups.

Conclusions: The clinical significance of CEBPA^homo is different from CEBPA^bZIP, which suggests a distinct biological meaning. Our study would add one new layer to the current stratification of CEBPA-mutated AML based on the prognosis. More cases are needed to further examine the clinical significance of the concurrency of CEBPA^homo and CEBPA^bZIP.