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We have investigated the prognostic significance of isocitrate dehydrogenase 2 (IDH2) mutations in 1473 younger adult acute myeloid leukemia patients treated in 2 United Kingdom Medical Research Council trials. An IDH2 mutation was present in 148 cases (10%), 80% at R140 and 20% at R172. Patient characteristics and outcome differed markedly between the 2 mutations. IDH2 R140 significantly correlated with nucleophosmin mutations (NPM1 MUT ), whereas IDH2 R172 cases generally lacked other molecular mutations. An IDH2 R140 mutation was an independent favorable prognostic factor for relapse (P ‫؍‬ .004) and overall survival (P ‫؍‬ .008), and there was no significant heterogeneity with regard to NPM1 or FLT3 internal tandem duplication (FLT3/ITD) genotype. Relapse in FLT3/ITD WT NPM1 MUT IDH2 R140 patients was lower than in favorable-risk cytogenetics patients in the same cohort (20% and 38% at 5 years, respectively). IntroductionRecurrent mutations in the genes coding for isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) have recently been described in acute myeloid leukemia (AML) patients. 1-3 Both enzymes convert isocitrate to ␣-ketoglutarate in an NAD phosphate ϩ -dependent manner, but they have different subcellular locations: IDH1 in the cytoplasm and IDH2 in mitochondria. Heterozygous mutations at IDH1 R132 , the functionally equivalent IDH2 R172 , and also IDH2 R140 were found to cause loss of normal enzymatic function and accumulation of 2-hydroxyglutarate (2-HG) through neomorphic enzyme activity, with a substrate switch from isocitrate to ␣-ketoglutarate, which is then converted to 2-HG. 4 IDH2 mutations have been reported in 9% to 19% of AML cases, predominantly IDH2 R140 rather than IDH2 R172 alterations. [5][6][7][8] However, the prognostic significance of these mutations remains unclear with either no impact on outcome, [5][6][7] or an adverse effect when IDH1 and IDH2 mutant patients are analyzed together in the subgroup of normal karyotype patients with a nucleophosmin 1 mutation (NPM1 MUT ) but not an internal tandem duplication in the fms-like tyrosine kinase gene (FLT3/ITD WT ). 8 In addition, there is some evidence that IDH2 R172 mutations confer an extremely poor prognosis, although this is based on very small numbers of patients, many of them elderly. 5,9 We recently demonstrated that the prognostic impact of an IDH1 mutation is dependent on FLT3/ITD genotype. 10 To determine whether IDH2 mutations have a similar effect on outcome and to investigate whether IDH2 R140 and IDH2 R172 mutations differ in their impact, we analyzed IDH2 mutant status and clinical outcome in 1473 adult nonacute promyelocytic leukemia AML patients, mostly 60 years of age or younger, treated on the United Kingdom Medical Research Council AML10 and 12 trials. MethodsDetails of the study cohort and samples, patient therapy, clinical end points, and statistical methods are in supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Amplicons of I...

These results suggest that Th17 cells play a destructive role in the immune balance of periodontitis, and the effect of Th1 cells is not significant, while Th2 cells have a protective effect.

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