Prevalence and Clinical Implications of IDH2 R140 and R172 Mutations in Older Adults with AML: A Report From SWOG,

Missense mutations in specific arginine residues of the isocitrate dehydrogenase genes (IDH1 and IDH2) lead to the production of 2-hydroxyglutarate, a potentially oncogenic metabolite, and have also been implicated in aberrant DNA methylation. We and others previously reported recurrent IDH1 R132 mutations in adult AML; recently, several groups have reported the prevalence in AML of IDH2 R172 mutations, originally described in gliomas, and IDH2 R140 mutations, which are specific to leukemia. The prognostic significance of IDH2 mutations is unclear; conflicting associations (or lack of association) with outcome have been reported in the context of other cooperative group AML clinical trials.

We examined the prevalence and clinical associations of IDH2 mutations in diagnostic specimens obtained from patients treated on three historical SWOG trials: SWOG-9031, SWOG-9333, and SWOG-9500. Patients ranged in age from 18 to 88 years, although patients in our study cohort were predominantly older (median age 63 years). Specimens were analyzed for mutations via direct sequencing of IDH2 exon 4. Mutation status was correlated with disease characteristics and outcome.

IDH2 mutations were present in 49 / 274 (18%) patients; R140 mutations occurred in 40 patients (39 R140Q, 1 R140L), while R172 mutations occurred in 9 patients (8 R172K, 1 R172M). R140 and R172 mutations were mutually exclusive from each other, and did not occur in the 12 patients with IDH1 mutations. There was significant heterogeneity in median diagnostic WBC count (IDH1 R132: 59,000; IDH2 R140: 25,000; and IDH2 R172: 5,000; compared to 30,000 for IDH wild-type patients, p=0.02). IDH mutations were also more common in elderly patients, occurring in 26% of patients age greater than 60 years, compared to 14% of patients age 60 or younger (p=0.013). IDH2 mutations occurred most commonly in those with a normal karyotype, and did not occur in patients with favorable cytogenetics. IDH2 mutations were significantly more common in NPM+ patients (27% prevalence in NPM+ patients vs. 13% prevalence in NPM - patients, p=0.01), although this association was restricted to R140 patients, while only 2 R172 patients had NPM mutations. IDH2 mutations were also somewhat more common in FLT3/ITD+ patients (31% prevalence in ITD+ patients vs. 17% prevalence in ITD- patients, p=0.20). There was no association between IDH2 mutations and either CEBPA or DNMT3A mutations. However, among FLT3/ ITD+ patients, DNMT3A and IDH mutations were almost mutually exclusive (only a single patient was FLT3+/IDH2+/DNMT3A+). Response to induction varied between the IDH genotypes, with complete remission (CR) rates of 75% for IDH1 R132, 52% for IDH2 R140, and 44% for IDH2 R172, as compared to 50% for IDH wild-type, (p=0.40). When all patients were considered, there was no difference in any outcome parameters between IDH mutated and IDH wild-type patients; further, IDH2 R140 and IDH2 R172 patients did not differ significantly from each other. We performed explorative subset analysis to determine whether IDH mutations predicted outcome in specific risk groups. Survival outcomes did not differ among IDH genotypes in FLT3/ ITD+ patients. Within the FLT3-/NPM- group, IDH mutated patients had numerically worse 5-year overall survival (OS, 5% vs. 16%) and relapse-free survival (RFS, 0% vs. 22%) than their wild-type counterparts, although these differences did not reach statistical significance (p=0.58 for OS, p=0.67 for RFS). Within the favorable FLT3 -/NPM+ subset, however, IDH mutated patients had a 5-year OS of 42% vs. 26% for wild-type patients (p=0.53), but had nearly identical 5-year RFS of 38% vs. 42%. There were no significant outcome differences when analysis was restricted to patients with normal karyotype.

IDH2 mutations were not significantly associated with outcome. The predominance of older patients in our study and resultant poor survival parameters may have hindered our ability to detect outcome differences. Subset analysis suggests that the prognostic impact of IDH2 mutations may vary between different risk groups as defined by FLT3 and NPM. R172 mutations had lower diagnostic WBC, lower CR rates, and a lack of association with NPMc, suggesting that their biology may be distinct from R140 mutations.

No relevant conflicts of interest to declare.