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

Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2013-12-18)
Maxime Janin, Elena Mylonas, Véronique Saada, Jean-Baptiste Micol, Aline Renneville, Cyril Quivoron, Serge Koscielny, Laurianne Scourzic, Sébastien Forget, Cécile Pautas, Denis Caillot, Claude Preudhomme, Hervé Dombret, Céline Berthon, Robert Barouki, Daniel Rabier, Nathalie Auger, Frank Griscelli, Elisabeth Chachaty, Edwige Leclercq, Marie-Hélène Courtier, Annelise Bennaceur-Griscelli, Eric Solary, Olivier Adrien Bernard, Virginie Penard-Lacronique, Chris Ottolenghi, Stéphane de Botton
ABSTRACT

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). 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. 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). 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
L-α-Hydroxyglutaric acid disodium salt, ≥98.0% (GC)
Sigma-Aldrich
Isocitric Dehydrogenase (NADP) from porcine heart, Type IV, buffered aqueous glycerol solution, 3-20 units/mg protein
Sigma-Aldrich
Isocitric Dehydrogenase (NADP) from porcine heart, Type I, 0.5-3.0 unit/mg solid (plus numerous enzyme activities associated with porcine heart)
Sigma-Aldrich
Isocitrate Dehydrogenase 1 (NADP+) human, recombinant, expressed in E. coli, lyophilized powder, ≥80 units/mg protein
Sigma-Aldrich
Isocitrate Dehydrogenase 1 (NADP+) human, recombinant, expressed in Sf9 cells, ≥90% (SDS-PAGE)

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