In Vivo 2-Hydroxyglutarate Monitoring With Edited MR Spectroscopy for the Follow-up of <i>IDH</i> -Mutant Diffuse Gliomas
Anna Luisa Di Stefano, Lucia Nichelli, Giulia Berzero, Romain Valabrègue, Mehdi Touat, Laurent Capelle, Clément Pontoizeau, Franck Bielle, Julie Lerond, Marine Giry, Chiara Villa, Bertrand Baussart, Caroline Dehais, Damien Galanaud, Capucine Baldini, Julien Savatovsky, F. Dhermain, Dinesh K. Deelchand, Chris Ottolenghi, Stéphane Lehéricy, Małgorzata Marjańska, Francesca Branzoli, Marc Sanson
Abstract
<h3>Background and Objectives</h3> D-2-hydroxyglutarate (2HG) characterizes <i>IDH</i>-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels. <h3>Methods</h3> MEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS). <h3>Results</h3> MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm<sup>3</sup>; <i>p</i> = 0.02), voxel coverage (>75%; <i>p</i> = 0.002), and expansive presentation (defined by equal size of T<sub>1</sub> and FLAIR abnormalities, <i>p</i> = 0.04). 2HG levels were positively correlated with <i>IDH</i>-mutant allelic fraction (<i>p</i> = 0.03) and total choline levels (<i>p</i> < 0.001) and were higher in <i>IDH2</i>-mutant compared with <i>IDH1</i><sup>R132H</sup>-mutant and non–R132H <i>IDH1</i>-mutant patients (<i>p</i> = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities. <h3>Discussion</h3> MEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of <i>IDH</i> inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.