D-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). Here, we investigated the clinical, radiological, 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; p=0.02), voxel coverage (> 75%; p=0.002) and expansive presentation (defined by equal size of T₁ and FLAIR abnormalities, p=0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p=0.03) and total choline levels (p<0.001) and were higher in IDH2-mutant compared to IDH1 ^R132H-mutant and non-R132H IDH1-mutant patients (p=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 two entities.

MEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared to oligodendrogliomas.