Correlation between IDH2 mutations and disease status in acute myeloid leukemia

The IDH1 and IDH2 genes encode NADPH (reduced nicotinamide adenine dinucleotide phosphate)-dependent isocitrate dehydrogenases, enzymes involved in protecting cells from oxidative damage. Idh1 and Idh2 proteins are structurally similar, but Idh1 is located in the cytoplasm and Idh2 in the mitochondria. Idh1 and Idh2 proteins are also functionally similar, and mutation of either gene increases 2-hydroxygluterate- and α-ketogluterate-dependent NADPH consumption [1]. Mutation of the IDH1 gene was first identified in association with colon cancer and gliomas [2,3], while mutations in IDH2 were described in gliomas (referred to as IDH2 R172) [4]. IDH2 R172 mutation was mutually exclusive with IDH1 mutation in gliomas [4]. Given the role of reactive oxygen species in carcinogenesis, identification of these mutations was of interest to understanding the pathogenesis of these diseases.

It was therefore of interest that mutation in IDH1 was identified in a ‘massively parallel’ sequencing study of an acute myeloid leukemia (AML) genome [5]. In this study, IDH1 was one of the mutations that was identified by sequencing of the single AML genome, but was subsequently found in other AML bone marrow samples [5]. Additional studies also identified recurring mutations in IDH1 and IDH2 in AML. A Cancer and Leukemia Group B (CALGB) study of 358 subjects with cytogenetically normal (CN) AML identified IDH mutations in 33% of these patients (14% IDH1 mutations and 19% IDH2 mutations) [6]. Two different IDH2 mutations were identified in this study: R140 and R172 (79% and 21% of IDH2 mutations, respectively) [6]. This study determined that IDH2 R172 was mutually exclusive with IDH1 mutation, and subjects with this mutation experienced a lower complete remission rate and poorer outcomes in comparison to subjects with IDH1/IDH2 Wt [6]. Thol et al. reported the results of a similar size study in which 12% of 272 adult subjects with CN-AML were found to have IDH2 mutation [7]. The distribution between IDH2 R140 vs. R172 was similar in this study (90% and 10%, respectively) [7]. This study also investigated the frequency of IDH2 mutation in subjects with cytogenetically abnormal AML, and found it to be significantly lower (3.8%). Unlike the CALGB study, this study found that the mutations of IDH1 and IDH2 were mutually exclusive and did not correlate with prognosis.

Two larger studies also investigated the relationship between IDH mutations and outcomes in CN-AML. A study from the German-Austrian AML Study Group (AMLSG) investigated 805 samples of adult AML and identified IDH2 mutations in 8.7% of CN-AML (68.5% R140 and 31.5% R172) [8]. This study identified two patients with coincident IDH2 R140 and IDH1 mutation [8]. This study was of importance because the prognostic relevance of IDH mutation was studied in the context of other leukemia-associated recurrent mutations. Importantly, outcomes were significantly poorer in subjects with IDH2 mutation in the presence of NPM1 mutation and Wt FLT [8]. A study of 893 patients from The Netherlands found an incidence of IDH1 mutation of 6% and IDH2 mutation of 11% [9]. This group found that IDH mutations were most common in CN-AML, AML with intermediate-prognosis cytogenetic abnormalities, and with NPM1 mutation [9]. Although the impact of IDH mutation on prognosis in the presence of NPM1 mutation was not specifically investigated, the authors established that IDH1 mutation was an adverse prognostic factor [9].

Although a number of studies have approached the question of the prognostic significance of IDH mutation in AML, there are no prior reports of the utility of these mutations as an indicator of minimal residual disease or relapse. In the current issue of Leukemia and Lymphoma, Jeziskova et al. report for the first time that IDH2 mutations in CN-AML are abolished in remission and recur with relapse [10]. These authors compared 46 normal and 54 samples of AML to determine the frequency of IDH2 mutation. They found no IDH2 mutation in normal subjects, but IDH2 mutation was present in 7.6% of samples of CN-AML [10]. The ratio of IDH R140 to R172 in this small study was comparable to that which has been reported with larger samples (75% vs. 25%, respectively) [10]. Remission was obtained in all four of these subjects, and it was associated with disappearance of the IDH2 mutation [10]. Of even greater significance, the same IDH2 mutation emerged with recurrent disease [10]. These findings suggest the potential utility of these mutations as an indicator of minimal residual disease and early relapse, assuming that a sensitive, specific, and feasible assay can be developed for use in clinical laboratories. The findings of Jeziskova et al. also suggest the possibility that mutation of IDH is a leukemia-initiating event, and not a later mutation acquired by the malignant clone. Additional, larger studies will be required to confirm these findings and definitively establish the relevance of IDH mutation detection for personalized approaches to the treatment of AML.