IDH2 Mutations Have An Unfavorable Impact in Elderly Patients with Acute Myeloid Leukemia

Recurrent mutations in the genes coding the isocitrate dehydrogenases, IDH1 and IDH2, have recently been demonstrated in patients with acute myeloid leukemia (AML). However, it remains to be determined how frequently IDH1 and IDH2 mutations occur in Asian AML patients and whether IDH1 and IDH2 mutations are associated with clinical profiles and outcome. In this study, we examined the incidence and prognostic impacts of IDH1 and IDH2 mutations in Japanese adults with AML.

A total of 190 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 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 16 patients (8.4%). IDH2 mutations were found in 18 patients (9.5%; 17 with R140 and one with R172). IDH1 and IDH2 mutations had mutually exclusively occurred. IDH1 mutation was associated with higher platelet counts and was more frequent with M1 in FAB classification. IDH2 mutation was associated with ages, lower leukocyte counts and was more frequent with M0. Median age of patients with IDH2 mutation was 63.5 years, while that with wild type was 55.5 years (P=0.036). No IDH2 mutation was observed in patients aged 39 or less. Both IDH1 and IDH2 mutations were most frequent in cytogenetically normal AML and cytogenetic intermediate-risk group. Although IDH1 mutations were not significantly associated with mutations in NPM1 and FLT3, IDH2 mutations were associated with NPM1 mutations. Of 15 IDH2 mutations, 8 (53%) had NPM1 mutation, whereas 26 of 121 (21%) lacking IDH2 mutation had NPM1 mutation (P=0.012). Interestingly, both IDH1 and IDH2 mutations were mutually exclusive with CEBPA mutations. There was no significant difference in 5-year overall survival (OS) between patients with and without IDH1 mutation (32.6% vs. 26.7%, P=0.7377). In contrast, 5-year OS rates were 6.6% for patients harboring IDH2 mutation and 34.5% for patients lacking IDH2 mutation in the entire cohort of AML (P=0.0020). This unfavorable effect was also found in cytogenetically normal AML (P=0.0383). Of patients aged 59 or less, there was no significant difference in 5-year OS between IDH2 mutations (14.3%) and wild-type (43.3%) (P=0.1440). On the other hand, among patients aged 60 or older, 5-year OS rates were 0% for patients carrying IDH2 mutation and 21.6% for patients lacking IDH2 mutation (P=0.0100).

Frequent mutations in IDH1 and IDH2 are also found in Japanese adults with AML. Our study indicates that IDH2 mutation has an unfavorable impact on the treatment outcome in adult patients with AML, especially in older (age ≥60 years) patients. These data suggest that IDH2 mutation confer a significant adverse impact on elderly patients with AML.

No relevant conflicts of interest to declare.