LAUSR

Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis, however the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adult AML patients recruited into Study Alliance Leukemia trials to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%), 131 CEBPAbi and 109 CEBPAsm (60 affecting the amino-terminal transactivation domains (CEBPAsmTAD) and 49 the carboxy-terminal DNA-binding or basic leucine zipper region (CEBPAsmbZIP)). Interestingly, CEBPAbi and CEBPAsmbZIP patients shared several clinical factors, i.e. were significantly younger (median 46 years and 50 years) and had higher WBC counts at diagnosis (median 23.7 and 35.7 109/l) compared to CEBPAsmTAD patients (median age 63 yrs., median WBC 13.1 109/l; p<.001). Co-mutations were also similar in both groups, e.g. GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs. 6.7% CEBPAsmTAD; p<.001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs. 38.3% CEBPAsmTAD; p<.001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (median OS: 103 and 63 vs. 13 months) and event-free survival (median EFS: 20.7 and 17.1 vs. 5.7 months), in univariate and multivariable analyses. More detailed analysis revealed that the clinical and molecular features as well as the favorable survival were confined to patients showing in-frame mutations in bZIP (CEBPAbZIP-inf). When grouping patients into CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and other non-CEBPAbZIP-inf patients), only CEBPAbZIP-inf patients showed superior CR rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutations.