Maxime Janin1, 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. 1. Maxime Janin, Robert Barouki, Daniel Rabier, and Chris Ottolenghi, Biochimie Métabolique, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Necker-Enfants Malades; Maxime Janin, Robert Barouki, and Chris Ottolenghi, Institut National de la Santé et de la Recherche Médicale (INSERM) U747, Université Paris Descartes; Hervé Dombret, Hôpital Saint-Louis, Paris; Elena Mylonas, Cyril Quivoron, Laurianne Scourzic, Olivier Adrien Bernard, Virginie Penard-Lacronique, and Stéphane de Botton, INSERM U985, Institut Gustave Roussy; Elena Mylonas, Cyril Quivoron, Laurianne Scourzic, Eric Solary, Olivier Adrien Bernard, and Virginie Penard-Lacronique, Institut Fédératif de Recherche 54, Institut Gustave Roussy; Véronique Saada, Sébastien Forget, Nathalie Auger, Frank Griscelli, Elisabeth Chachaty, Edwige Leclercq, Marie-Hélène Courtier, and Annelise Bennaceur-Griscelli, Institut Gustave Roussy; Jean-Baptiste Micol and Stéphane de Botton, Hématologie Clinique, Institut Gustave Roussy; Serge Koscielny, Service de Biostatistique et d'Epidémiologie, Institut Gustave Roussy, Villejuif; Elena Mylonas, Cyril Quivoron, Laurianne Scourzic, Olivier Adrien Bernard, Virginie Penard-Lacronique, Chris Ottolenghi, and Stéphane de Botton, Université Paris Sud-11, Orsay; Aline Renneville and Claude Preudhomme, Hématologie Biologique, Centre Hospitalier Régional Universitaire (CHRU) Lille; Céline Berthon, Hématologie Clinique, CHRU Lille, Lille; Cécile Pautas, Hématologie Clinique, Centre Hospitalier Henri Mondor, Créteil; and Denis Caillot, Hématologie Clinique, Centre Hospitalier Universitaire Dijon, Dijon, France.
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.
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.
Authors: D H Wiseman; E A Struys; D P Wilks; C I Clark; M W Dennis; E E W Jansen; G S Salomons; T C P Somervaille Journal: Leukemia Date: 2015-06-19 Impact factor: 11.528
Authors: Chen Yuan; Clary B Clish; Chen Wu; Jared R Mayers; Peter Kraft; Mary K Townsend; Mingfeng Zhang; Shelley S Tworoger; Ying Bao; Zhi Rong Qian; Douglas A Rubinson; Kimmie Ng; Edward L Giovannucci; Shuji Ogino; Meir J Stampfer; John Michael Gaziano; Jing Ma; Howard D Sesso; Garnet L Anderson; Barbara B Cochrane; JoAnn E Manson; Margaret E Torrence; Alec C Kimmelman; Laufey T Amundadottir; Matthew G Vander Heiden; Charles S Fuchs; Brian M Wolpin Journal: J Natl Cancer Inst Date: 2016-01-11 Impact factor: 13.506
Authors: Anja Karlstaedt; Xiaotian Zhang; Heidi Vitrac; Romain Harmancey; Hernan Vasquez; Jing Han Wang; Margaret A Goodell; Heinrich Taegtmeyer Journal: Proc Natl Acad Sci U S A Date: 2016-08-31 Impact factor: 11.205