Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL

IDH1 and IDH2 mutations (IDH1/2(Mut)) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2(Mut) inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2(Mut). Mutational patterns of IDH1/2(Mut) in T-ALL present some specific features compared to AML. Whereas IDH2(R140Q) mutation was frequent in T-ALL (25 of 51 mutations), the IDH2(R172) AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2(Mut) were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.

Automated summary

IDH2 mutations in T-ALL are associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations, and epigenetic regulator loss-of-function alterations. Conversely, IDH1 mutations appeared to be an independent prognostic factor in multivariate analysis.