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Date publication
février 2014
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CAILLOT Denis
Tous les auteurs :
Janin M, Mylonas E, Saada V, Micol JB, Renneville A, Quivoron C, Koscielny S, Scourzic L, Forget S, Pautas C, Caillot D, Preudhomme C, Dombret H, Berthon C, Barouki R, Rabier D, Auger N, Griscelli F, Chachaty E, Leclercq E, Courtier MH, Bennaceur-Griscelli A, Solary E, Bernard OA, Penard-Lacronique V, Ottolenghi C, de Botton S
Lien Pubmed
Résumé
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 mumol/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 mumol/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.
Référence
J Clin Oncol. 2014 Feb 1;32(4):297-305
