Prevalence and Clinical Effect of TET2 Mutations in Cytogenetically Normal Acute Myeloid Leukemia (CN-AML)

Abstract 1448

Mutations in the TET2 gene were recently identified in a variety of myeloid neoplasms including acute myeloid leukemia (AML). To investigate the frequency and clinical relevance of TET2 mutations in cytogenetically normal AML (CN-AML), the largest cytogenetic subgroup of adult AML, the total coding region of TET2 was analyzed by direct sequencing in 215 adult CN-AML patients younger than 60 years. All patients were uniformly treated on the AML SHG 0295 or AML SHG 0199 treatment protocols, both including double induction and intensive consolidation regimes. To test the prognostic value of TET2 mutations in the context of other prognostic molecular markers, mutational analyses for CEBPA, DNMT3A, FLT3-ITD, IDH1/2, MLL-PTD, ND4, NPM1, NRAS and WT1 and expression analyses for BAALC, ERG, EVI-1, IDH1, MLL5, MN1 and WT1 were performed. At least 1 sequence variation in TET2 was found in 16 out of 215 patients (7.4%). In 3 of these patients the somatic origin of the mutation could not be validated, so these patients were considered wildtype in all subsequent analyses. Mutations were detected throughout the entire gene with the highest frequency found in exon 3 (n=6). Patients harboring TET2 mutations showed higher platelet counts (P=.041), a higher frequency of concomitant NPM1 (11 of 13, P=.047) and DNMT3A (10 of 13, P=.001) mutations and tended to be older (P=.078) when compared to TET2 wildtype patients. The recently reported mutational exclusiveness of IDH1/2 and TET2 was validated in the present cohort (P=.042). No differences for complete remission (CR) rate (P=.76), relapse-free survival (RFS; P=.63) or overall survival (OS; P=.59) was observed based on the TET2 mutation status. When restricting the analyses to CN-AML patients assigned to the European LeukemiaNet (ELN) favorable-risk or intermediate1-risk groups (ELN-favorable risk-group: CN-AML patients with mutated CEBPA and/or mutated NPM1 without FLT3 -ITD, n=96; ELN-intermediate-1-risk group CN-AML with wild-type CEBPA and wild-type NPM1 and/or FLT3-ITD; n=106), the TET2 mutation status again did not impact on CR rate, RFS or OS. We conclude that in younger CN-AML patients, TET2 mutations occur with a lower prevalence compared to other myeloid malignancies such as MDS or CMML, and have no prognostic effect. Therefore, TET2 mutation analysis at present is not required for risk-stratified protocols in AML.