Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: a study by the Acute Leukemia French Association group

J Clin Oncol. 2014 Feb 1;32(4):297-305. doi: 10.1200/JCO.2013.50.2047. Epub 2013 Dec 16.

Abstract

Purpose: Mutated isocitrate dehydrogenases (IDHs) 1 and 2 produce high levels of 2-hydroxyglutarate (2-HG). We investigated whether, in acute myeloid leukemia (AML), serum 2-HG would predict the presence of IDH1/2 mutations at diagnosis and provide a marker of minimal residual disease (MRD).

Patients and methods: Serum samples from 82 patients at diagnosis of de novo AML (IDH1/2 mutated, n = 53) and 68 patients without AML were analyzed for total 2-HG and its ratio of D to L stereoisomers by mass spectrometry. We measured 2-HG levels and molecular markers of MRD (WT1 and NPM1) in serial samples of 36 patients with IDH1/2 mutations after induction therapy.

Results: In patients with AML with IDH1/2 mutations, 2-HG serum levels were significantly higher than in patients with IDH1/2 wild type (P < .001). Area under the receiver operating characteristic curve was 99%. The optimum diagnostic cutoff between IDH1/2 mutated and normal was 2 μmol/L (sensitivity, 100%; specificity, 79%). Quantification of the D/L stereoisomers increased specificity (100%; 95% CI, 83% to 100%) compared with total 2-HG (P = .031). In patients with IDH2 R172 mutations, 2-HG levels were higher relative to those with other IDH1/2 mutations (P < .05). During follow-up, serum 2-HG levels showed strong positive correlation with WT1 and NPM1 (P < .001). After induction therapy, total 2-HG serum levels < 2 μmol/L were associated with better overall (P = .008) and disease-free survival (P = .005).

Conclusion: Serum 2-HG is a predictor of the presence of IDH1/2 mutations and outcome in these patients. Discrimination between D/L stereoisomers improved specificity.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Area Under Curve
  • Biomarkers, Tumor / blood*
  • Female
  • France
  • Glutarates / blood*
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Kaplan-Meier Estimate
  • Leukemia, Myeloid, Acute / blood*
  • Leukemia, Myeloid, Acute / diagnosis*
  • Leukemia, Myeloid, Acute / genetics
  • Male
  • Mass Spectrometry
  • Middle Aged
  • Mutation*
  • Neoplasm, Residual / blood
  • Nuclear Proteins / blood
  • Predictive Value of Tests
  • Prognosis
  • ROC Curve
  • Sensitivity and Specificity
  • Stereoisomerism
  • WT1 Proteins / blood

Substances

  • Biomarkers, Tumor
  • Glutarates
  • Nuclear Proteins
  • WT1 Proteins
  • WT1 protein, human
  • nucleophosmin
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human