title: Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: a study by the Acute Leukemia French Association group.
abstract: OBJECTIVE
  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).
  
  
  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).
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Maxime
authors.initials: M
authors.lastname: Janin
authors.forename: Elena
authors.initials: E
authors.lastname: Mylonas
authors.forename: Véronique
authors.initials: V
authors.lastname: Saada
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Micol
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Cyril
authors.initials: C
authors.lastname: Quivoron
authors.forename: Serge
authors.initials: S
authors.lastname: Koscielny
authors.forename: Laurianne
authors.initials: L
authors.lastname: Scourzic
authors.forename: Sébastien
authors.initials: S
authors.lastname: Forget
authors.forename: Cécile
authors.initials: C
authors.lastname: Pautas
authors.forename: Denis
authors.initials: D
authors.lastname: Caillot
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Céline
authors.initials: C
authors.lastname: Berthon
authors.forename: Robert
authors.initials: R
authors.lastname: Barouki
authors.forename: Daniel
authors.initials: D
authors.lastname: Rabier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auger
authors.forename: Frank
authors.initials: F
authors.lastname: Griscelli
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Chachaty
authors.forename: Edwige
authors.initials: E
authors.lastname: Leclercq
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Courtier
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Olivier Adrien
authors.initials: OA
authors.lastname: Bernard
authors.forename: Virginie
authors.initials: V
authors.lastname: Penard-Lacronique
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D005260:Female; D005602:France; D005977:Glutarates / Q000097:blood*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009154:Mutation; D018365:Neoplasm, Residual / Q000097:blood; D009687:Nuclear Proteins / Q000097:blood; D000090243:Nucleophosmin; D011237:Predictive Value of Tests; D011379:Prognosis; D012372:ROC Curve; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D025721:WT1 Proteins / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; D005977:Glutarates; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D025721:WT1 Proteins; C583751:WT1 protein, human; D000090243:Nucleophosmin; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human