Serum levels of 2-hydroxyglutarate (2-HG) predict IDH1/2 status and outcome in patients with AML.
Major finding: Serum levels of 2-hydroxyglutarate (2-HG) predict IDH1/2 status and outcome in patients with AML.
Concept: The D-to-L stereoisomer ratio predicts IDH1/2 mutations with better specificity than total 2-HG.
Impact: Serum 2-HG may be an easily measurable biomarker of minimal residual disease in AML.
Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in 15% to 20% of patients with acute myeloid leukemia (AML). Unlike wild-type IDH enzymes, which convert isocitrate to α-ketoglutarate, mutant IDH enzymes reduce α-ketoglutarate to the D stereoisomer of 2-hydroxyglutarate (2-HG), raising the possibility that increased levels of this metabolite in the blood could be a biomarker of IDH1/2 mutations in patients with AML. Janin and colleagues measured total 2-HG and the ratio of the D and L stereoisomers in the serum of patients with and without AML or metabolic disorders that might affect IDH enzymatic function and found that both total 2-HG levels and the D-to-L ratio were significantly higher in patients with IDH-mutant AML. Moreover, high total 2-HG and D-to-L ratio values were both highly predictive of the presence of an IDH1/2 mutation, although the D-to-L ratio distinguished IDH-mutant and IDH–wild-type AML with greater specificity. Total 2-HG level and the D-to-L ratio were both positively correlated with WT1 overexpression and NPM1 mutation—known markers of minimal residual disease—in the blood and bone marrow of patients with IDH-mutant AML after induction therapy. Among patients with IDH-mutant AML who experienced complete responses (CR) after induction therapy, only a total 2-HG level lower than 2 μmol/L at CR, not the type of IDH1/2 mutation or the presence of a FLT3 internal tandem duplication or NPM1 mutation, was associated with significantly longer progression-free survival and overall survival durations. These results suggest that the total amount of 2-HG or the D-to-L stereoisomer ratio in serum could be predictive biomarkers of minimal residual disease and clinical outcome in IDH-mutant AML that may be easier to measure and more reliable than current molecular markers.