In Vivo 2-Hydroxyglutarate Monitoring With Edited MR Spectroscopy for the Follow-up of <i>IDH</i>-Mutant Diffuse Gliomas: The <i>IDASPE</i> Prospective Study.

Abstract

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. 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). MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm³; <i>p</i> = 0.02), voxel coverage (>75%; <i>p</i> = 0.002), and expansive presentation (defined by equal size of T₁ 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> ^R132H-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. 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.