IDH1 and IDH2 Mutations Confer An Adverse Effect In Patients With Acute Myeloid Leukemia Lacking The NPM1 Mutation

Recurrent mutations in the genes coding the isocitrate dehydrogenases IDH1 and IDH2 have recently been identified in patients with acute myeloid leukemia (AML). However, the prognostic importance of IDH1 and IDH2 mutations is not consistent among several studies.  In the present study, we examined the incidence and prognostic impacts of IDH1 and IDH2 mutations in Japanese adults with AML.

A total of 233 adults with AML were subjected to the study. Age ranged from 15 to 86 years, with a median of 57.0 years. Patients with aged 69 or less were treated with the protocols of Japan Adult Leukemia Study Group (JALSG). Patients with aged 70 or more were treated with low dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (G-CSF) (Suzushima et al. Leuk Res 2010). DNA was extracted from bone marrow or peripheral blood mononuclear cells of AML patients at diagnosis and subjected to PCR amplification and direct sequencing of the IDH1 and IDH2 genes. NPM1, FLT3 and CEBPA gene mutations were also analyzed. The study was approved by the Institutional Review Boards and informed consent was obtained from each patient according to guidelines based on the tenets of the revised Declaration of Helsinki.

IDH1 R132 mutations were detected in 20 (8.6%) patients with AML. IDH2 mutations were found in 19 (8.2%; 17 R140 and two R172) patients. IDH1 and IDH2 mutations were mutually exclusive and were most frequent in the cytogenetic intermediate-risk group. In addition, IDH1 and IDH2 mutations were mutually exclusive with the CEBPA mutation. Moreover, IDH1 and IDH2 mutations were associated with NPM1 mutations. Of 39 patients with IDH mutations, 17 (44%) had the NPM1 mutation, whereas 36 of 194 (19%) lacking an IDH mutation had an NPM1 mutation (P = 0.001). There was no significant correlation of the IDH mutation with FLT3-ITD. Of 226 patients evaluable for treatment outcome, there was no significant difference in 5-year overall survival (OS) between patients with and those without IDH1 mutations (25.1% vs. 29.9%, P = 0.3089). In contrast, 5-year OS rates were significantly lower (6.2%) in patients harboring the IDH2 mutation than in patients lacking the IDH2 mutation (31.5%) in the entire cohort of AML (P = 0.0026). Because IDH1 and IDH2 mutations were associated with NPM1 mutations, we compared OS in patients with and those without IDH1 or IDH2 mutations among patients with and those without NPM1 mutations. Of 51 patients with NPM1 mutations, there was no significant difference in 5-year OS between patients with and those without the IDH1 or IDH2 mutation. In contrast, among 175 patients lacking the NPM1 mutation, 5-year OS in patients with IDH1 or IDH2 mutations was significantly lower than in those without such mutations (0% vs. 32.4%, P = 0.0023 and 0% vs. 32.6%, P = 0.0001, respectively). Moreover, among patients with the wild-type of NPM1, 5-year OS in patients with IDH1 or IDH2 mutations was significantly lower than that in those with the CEBPA mutation, FLT3-ITD, or the wild-type of CEBPA, FLT3, IDH1 and IDH2 (P=0.0002).

Frequent mutations in IDH1 and IDH2 are also found in Japanese adults with AML. Our data strongly suggest that IDH1 and IDH2 mutations confer adverse prognostic effect in NPM1 wild-type AML. On the other hand, an adverse effect of IDH1 and IDH2 mutations may be negated among patients with NPM1 mutations, because NPM1 mutations generally have a higher complete remission rate and more favorable OS.

No relevant conflicts of interest to declare.