Characteristics and Prognostic Effects of IDH Mutations Across the Age Spectrum in AML: A Collaborative Analysis

In acute myeloid leukemia (AML), somatic mutations in the isocitrate dehydrogenase (IDH) genes are common and occur at active site arginine residues in the IDH1(R132) and IDH2 (R140, R172) enzymes. Ivosidenib (IDH1) and enasidenib (IDH2), IDH inhibitors, have demonstrated improved clinical outcomes in patients with relapsed/refractory IDH-mutated AML, and studies of these treatments in combination with chemotherapy in de novo AML are in progress. Based on the hypothesis that refining understanding of IDH-mutated AML will contribute to risk-adapted treatment strategies, including optimal use of IDH-targeting agents, the objective of this study was to identify characteristics that influence outcomes in de novo IDH-mutated AML across the age spectrum. For this analysis, a large cohort of patients enrolled in a number of pediatric and adult trials (CCG-2961, Children’s Oncology Group [COG] 03P1, COG 0531, COG 1031, SWOG S0106, Eastern Cooperative Oncology Group [ECOG] E1900, Beat AML, and The Cancer Genome Atlas [TCGA] AML Biology study) was utilized.

The total cohort (N = 3588) included patients with ages ranging from <1 month to 88 years. Patients were divided into 3 age-groups for analysis as follows: younger (aged 0-29 years [n = 2401]), intermediate (aged 30-59 years [n = 819]), and older (aged ≥60 years [n = 319]). Data regarding clinical characteristics and treatment outcomes were collected and evaluated based on the respective studies. Mutational profiling was performed by targeted sequencing for patient samples from the COG, Beat AML, ECOG, and SWOG trials; whole-genome or whole-exome sequencing was performed for the TCGA cohort. The prevalence of IDH mutations, co-occurring mutations, and outcomes (5-year event-free survival [EFS]) was analyzed across the defined age-groups.

In the entire cohort, the prevalence of IDH mutations was 8.6% (n = 276), with mutations detected in IDH2 in 158 cases (57%) and IDH1 in 118 cases (43%). There was a strong correlation between the prevalence of IDH mutations and increased age. Among the 3 age cohorts, the prevalence was 4.0% in younger, 15.2% in intermediate, and 20.3% in older patients (P <.001). IDH mutations were found to commonly co-occur with NPM1, DNMT3A, and FLT3-internal tandem duplication mutations based on the co-occurring mutational profile. Among patients with IDH mutations, 48% had dual mutations (IDHmut/NPM1mut) and 11.6% had triple mutations (IDH^mut /NPM1^mut/DNMT3A^mut). Triple mutations were more prevalent in intermediate-aged adults (85%). In the cohort with available outcomes data (n = 2824), analysis demonstrated that patients with IDH^mut and IDH-wild type (WT) experienced similar landmark 5-year EFS rates of 39% and 40%, respectively (P = .723). Based on the favorable prognostic significance of NPM1, outcomes of this dual-mutated group were subsequently analyzed, with the analysis showing that NPM1 mutations retained favorable prognostic impact in the setting of IDH-mutated patients (P <.001). Of note, this effect was age dependent. Patients withIDHmut^mut/NPM1^mut had a more favorable landmark 5-year EFS rate compared with IDH^mut /NPM1-WT for both younger patients (76% vs 29%; P <.001) and intermediate-aged patients (43% vs 15%; P = .001); however, this favorable effect was not found among older patients (24% vs 34%; P = .456). When further stratified by DNMT3A status and IDH^mut /NPM1^mut/DNMT3A^mut, intermediate-aged patients experienced a significantly inferior 5-year EFS rate of 25% versus 57% in IDH^mut /NPM^mut (P = .003).

In conclusion, this analysis, which was based on a large patient cohort, offers the most comprehensive description of the pathobiological effects of IDH mutations in AML across the age spectrum. The age-associated prevalence of IDH mutations and frequent co-occurrence with NPM1 mutations in all ages, and subsequently in combination with DNMT3A mutations in intermediate-aged adults, was confirmed. In addition, it was demonstrated that IDH-mutation status is not an independent prognostic determinant of outcome in any age-group. Among AML patients aged >60 years, the co-occurrence of NPM1 and IDH mutations favorably impacts outcome, particularly in the absence of a DNMT3A mutation. These data suggest that IDH inhibitors may be of particular interest in older adults and in patients aged >60 years, based on co-occurring NPM1 and DNMT3A mutations.

Reference

Zarnegar-Lumley S, Alonzo TA, Othus M, et al. Characteristics and Prognostic Effects of IDH Mutations Across the Age Spectrum in AML: A Collaborative Analysis from COG, SWOG, and ECOG. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition, December 5-8, 2020. Abstract 388.