Mutations in the isocitrate dehydrogenase 2 gene and IDH1 SNP 105C > T have a prognostic value in acute myeloid leukemia

Abstract

Background: The isocitrate dehydrogenase (IDH1/IDH2) genes are metabolic enzymes, which are frequently mutated in acute myeloid leukemia (AML). The enzymes acquire neomorphic enzymatic activity when they mutated.

Methods: We have investigated the frequency and outcome of the acquired IDH1/IDH2 mutations and the IDH1 SNP 105C > T (rs11554137) in 189 unselected de novo AML patients by polymerase chain reaction amplification followed by direct sequencing. The survival are presented in Kaplan Meier curves with log rank test. Multivariable survival analysis was conducted using Cox regression method, taking age, risk group, treatment, IDH1/2 mutations and IDH1 SNP105 genotype into account.

Results: Overall, IDH1/2 mutations were found in 41/187 (21.7%) of the AML patients. IDH1 codon 132 mutations were present in 7.9%, whereas IDH2 mutations were more frequent and mutations were identified in codon 140 and 172 in a frequency of 11.1% and 2.6%, respectively. The SNP 105C > T was present in 10.5% of the patients, similar to the normal population. A significantly reduced overall survival (OS) for patients carrying IDH2 codon 140 mutation compared with patients carrying wild-type IDH2 gene (p < 0.001) was observed in the intermediate risk patient group. Neither in the entire patient group nor subdivided in different risk groups, IDH1 mutations had any significance on OS compared to the wild-type IDH1 patients. A significant difference in OS between the heterozygous SNP variant and the homozygous wild-type was observed in the intermediate risk FLT3 negative AML patients (p = 0.004).

Conclusions: Our results indicate that AML-patients with IDH2 mutations or the IDH1 SNP 105C > T variant can represent a new subgroup for risk stratification and may indicate new treatment options.

Keywords: AML; IDH1; IDH2; Prognostic markers; SNP.

Figure 1

Kaplan-Meier curves of OS, IDH2 codon 140. (A) Significant differences in OS between IDH2 codon 140 genotypes in intermediate risk AML patients. Median OS 6 vs. 18 months (p < 0.001) for IDH2 codon 140 mutated patients and wild-type patients, respectively. (B) OS for AML-patients with mutated or unmutated IDH2 codon 140 in the entire group, median OS 9 vs. 14 months, respectively (p = 0.278).

Figure 2

Kaplan-Meier curve of OS, IDH2 codon 172. The low frequency of AML-patients with mutated IDH2 codon 172 showed a tendency towards improved OS survival compared to wildtype IDH2, OS 30 vs. 12 months, p = 0.09.

Figure 3

Kaplan-Meier curve of OS, IDH1 codon 105 SNP. Significant differences in OS between codon 105 genotypes in FLT3-ITD negative intermediate risk patients; median OS 6 vs. 20 months (p = 0.004) for codon 105 variant allele and wild-type patients, respectively.