IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML.

Mutations in the nicotinamide adenine dinucleotide phosphate ؉ -dependent isocitrate dehydrogenase gene 2 (IDH2) have recently been found in patients with acute myeloid leukemia (AML) as well as in patients with leukemic transformation of myeloproliferative neoplasms. We analyzed 272 adult patients with cytogenetically normal AML (CN-AML) for the presence of IDH2 mutations in codons R140 and R172. IDH2 mutations of amino acid 140 or 172 could be identified in 12.1% of CN-AML patients, with the majority of mutations (90%) occurring at position R140. The incidence of IDH2 mutations in AML patients with aberrant karyotypes (n ‫؍‬ 130) was significantly lower (3.8%, P ‫؍‬ .006). IDH2 mutations were mutually exclusive with mutations in IDH1. IDH2 mutation status alone or in combination with IDH1 mutations had no impact on response to therapy, overall survival, and relapse-free survival in patients with CN-AML. In conclusion, IDH2 mutations are frequently found in CN-AML, but in our analysis these mutations did not influence treatment outcome. This study was registered at www.clinicaltrials.gov as #NCT00209833. (Blood. 2010;116(4): 614-616) IntroductionIn an attempt to discover unknown molecular alterations in patients with acute myeloid leukemia (AML), whole genome sequencing was performed on AML patients. 1 With this approach, a novel mutation in nicotinamide adenine dinucleotide phosphate ϩ -dependent isocitrate dehydrogenase gene (IDH1) at codon R132 has been identified 2 previously described in gliomas. 3 Since this first description of IDH1 mutations in AML, several reports have confirmed that IDH1 mutations occur in patients with cytogenetically normal AML (CN-AML), with a frequency of 5.5% to 11%. [4][5][6][7] A strong association between IDH1 mutations and the intermediaterisk karyotypes and concurrent NPM1 mutations has been described. [4][5][6][7] The prognostic impact of IDH1 mutations in AML is currently being investigated. 4-7 A recent study also found mutations in IDH2 in codon R172 at a low frequency in AML patients. 6 In addition, a novel mutation in IDH2 in codon R140 could be identified in 2 patients with leukemic transformation of myeloproliferative neoplasm as well as in patients with AML. 8,9 IDH2 has the same enzymatic activity as IDH1 but is located in the mitochondrial matrix.In the present study, we performed a comprehensive analysis of mutations occurring in exon 4 of IDH2 (including both codons R140 and R172) in 272 patients with CN-AML in the context of other known prognostic markers. These patients were intensively treated with a uniform protocol in 2 consecutive multicenter trials.Overall, our data indicate that IDH2 mutations in codons R140 and R172 are frequent but have no prognostic implications in patients with CN-AML when considered alone or in combination with IDH1 mutations and treated with these intensive protocols. Methods PatientsWe examined 272 patients with CN-AML and 130 AML patients with aberrant karyotypes for mutations in IDH2. Of the latter, 45 had a core-binding factor ...

WT1 SNP rs16754 may be a novel independent favorable-risk marker in CN-AML patients that might improve risk and treatment stratification.