Characteristics and prognostic impact of IDH mutations in AML: a COG, SWOG, ECOG analysis.

Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, co-occurring mutational profile, and prognostic significance of IDH mutations in AML across the age spectrum. Our cohort included 3,141 patients aged <1 month-88 years treated on CCG/COG (N=1872), SWOG (N=359), ECOG (N=397) trials and in Beat AML (N=333) and TCGA (N=180) genomic characterization cohorts. We retrospectively analyzed patients in four age groups (age range, N): pediatric (0-17, 1744), adolescent/young adult (AYA) (18-39, 444), intermediate-age (40-59, 640), older (≥ 60, 309). IDH mutations (IDHmut) were identified in 9.2% of the total cohort (N=288; IDH1 [N=123, 42.7%]; IDH2 [N=165, 57.3%]) and were strongly correlated with increased age: 3.4% pediatric vs 21% older, P<0.001. Outcomes were similar in IDHmut and IDH-wildtype (IDHWT) AML (event-free survival [EFS]: 35.6% vs 40.0%, P=0.368; overall survival [OS]: 50.3% vs 55.4%, P=0.196). IDH mutations frequently co-occurred with NPM1 (47.2%), DNMT3A (29.3%), and FLT3-ITD (22.4%) mutations. In patients with IDHmut AML, survival was significantly improved with co-occurring NPM1 mutation (IDHmut/NPM1mut) compared to the poor outcomes experienced by patients without (IDHmut/NPM1WT) (EFS: 55.1% vs 17.0%, P<0.001; OS: 66.5% vs 35.2%, P<0.001). Presence of DNTM3A or FLT3-ITD mutations in otherwise favorable IDHmut/NPM1mut AML led to inferior outcomes. Analysis according to age group demonstrated that IDH mutations did not abrogate the favorable prognostic impact of NPM1mut in patients younger than 60 years; older patients had poor outcomes regardless of NPM1 status. Clinical Trials: NCT00070174, NCT00372593, NCT01371981, NCT00049517, NCT00085709.