IDH1 和 IDH2 突变的初发急性髓系白血病中的血清 2-羟戊二酸产生：急性白血病法国协会组的一项研究。

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

机构信息

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.

出版信息

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

DOI:10.1200/JCO.2013.50.2047

PMID:24344214

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.

摘要

目的

突变的异柠檬酸脱氢酶（IDH）1 和 2 会产生高水平的 2-羟戊二酸（2-HG）。我们研究了急性髓系白血病（AML）患者中，血清 2-HG 是否可以预测诊断时 IDH1/2 突变的存在，并作为微小残留病（MRD）的标志物。

患者和方法

采用质谱法分析了 82 例初诊 AML 患者（IDH1/2 突变，n=53）和 68 例非 AML 患者的血清总 2-HG 及其 D/L 对映异构体的比例。我们在诱导治疗后对 36 例 IDH1/2 突变患者的连续样本中测量了 2-HG 水平和 MRD 的分子标志物（WT1 和 NPM1）。

结果

IDH1/2 突变的 AML 患者的血清 2-HG 水平明显高于 IDH1/2 野生型（P<0.001）。受试者工作特征曲线下面积为 99%。IDH1/2 突变与正常之间的最佳诊断截止值为 2μmol/L（灵敏度为 100%；特异性为 79%）。与总 2-HG 相比，D/L 对映异构体的定量增加了特异性（100%；95%CI，83%至 100%）（P=0.031）。在 IDH2 R172 突变的患者中，与其他 IDH1/2 突变相比，2-HG 水平更高（P<0.05）。在随访期间，血清 2-HG 水平与 WT1 和 NPM1 呈强正相关（P<0.001）。诱导治疗后，血清总 2-HG 水平<2μmol/L 与总生存（P=0.008）和无病生存（P=0.005）的改善相关。