CEBPA double‐mutated acute myeloid leukaemia harbours concomitant molecular mutations in 76·8% of cases with TET 2 and GATA 2 alterations impacting prognosis

Summary Acute myeloid leukaemia ( AML ) with CEBPA mutations is listed as a provisional entity in the current World Health Organization classification. A difference in clinical outcome between single‐ (sm) and double‐mutated (dm) cases has been reported, whereupon CEBPA dm cases were shown to be associated with better overall survival ( OS ). The occurrence and prognostic impact of concomitant molecular mutations in addition to CEBPA dm has not been assessed until now with exception of GATA 2 mutations. Here, we investigated a cohort of 95 AML CEBPA dm cases for concomitant mutations. TET 2 was found to be most frequently mutated (34·0%) gene, followed by GATA 2 (21·0%), WT 1 (13·7%), DNMT 3A (9·6%), ASXL 1 (9·5%), NRAS (8·4%), KRAS (3·2%), IDH 1/2 (6·3%), FLT 3 ‐internal tandem duplication (6·3%), FLT 3 ‐tyrosine kinase domain (2·1%), NPM 1 (2·1%), and RUNX 1 (1/94). Patients harbouring additional mutations in the TET 2 gene showed significantly worse OS than TET 2 wild‐type cases ( P  =   0·035), whereas GATA 2 ‐mutated patients showed improved OS ( P  =   0·032). Serial analyses were performed for 39 CEBPA dm cases with concomitant mutations. Here, we observed that CEBPA mutations present the primary pathogenetic event in the majority of cases (76·9%). Further, a distinct gene expression profile ( GEP ) was confirmed for CEBPA dm versus CEBPA sm or CEBPA wild‐type cases while no significant changes in GEP were observed related to additional mutations within the CEBPA dm AML .