Homozygous CEBPA Mutations Predict Favorable Outcomes in AML Patients
Authors: PAN Lili , Lin Shenglong , Zheng Yi , Ma Yixin , Li Yining , Xie Yuwei , Cai Yuanhua , Li Xiaofan , Wang Shaoyuan 
Published: December 2023

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 ( CEBPAhomo). However, its clinical significance has been underappreciated.
Methods: We retrospectively analyzed the prognostic impact of CEBPAhomo in 1223 adult AML patients, where CEBPA mutations were detected using whole exome sequencing (n=296) or targeted sequencing (n=927) technology. CEBPAhomo is defined as the variant allele frequency (VAF) of a CEBPA mutation over 50%, and CEBPAheter 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 ( CEBPAbZIP). Compared to patients with other CEBPA mutations ( CEBPAothers), patients carrying CEBPAbZIP were significantly younger (40.38±14.80 vs. 52.05±17.44 years, P&lt;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) 10 9/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. CEBPAbZIP 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). CEBPAbZIP 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 CEBPAothers. These data are consistent with previous reports, suggesting the representative of this cohort. We further evaluated the clinical significance of CEBPAhomo in this cohort and found that patients with CEBPAhomo had higher white blood cell counts [29.37 (9.16, 76.11) vs. 10.37 (3.38, 43.43) 10 9/L, P=0.048] than those with CEBPAheter. Although CEBPAhomo 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 CEBPAheter. CEBPAhomo 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 CEBPAheter. There is no difference in CEBPA VAF between patients carrying CEBPAbZIP and CEBPAother, suggesting similar distribution of CEBPAhomo between these two groups.
Conclusions: The clinical significance of CEBPAhomo is different from CEBPAbZIP, 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 CEBPAhomo and CEBPAbZIP.