BIOM-108. MR SPECROSCOPY DETECTS SIGNIFICANT 2-HYDROXYGLUTARATE REDUCTIONS IN RESPONSE TO IDH-INHIBITOR THERAPY IN LOWER GRADE GLIOMA

Abstract BACKGROUND Small molecule IDH-inhibitors (IDHi) such as ivosidenib and vorasidenib reduce the oncometabolite 2-hydroxyglutarate (2- HG) produced by mutant IDH in gliomas. These drugs decrease glioma growth rates, but usually after a delay of several months and often preceded by significant growth. Therefore, an early response biomarker is highly desired. 2-HG is detectable on MR spectroscopy (MRS) at the 2.25 PPM peak. Here, we explored whether 2-HG measurements on MRS can be used to non-invasively monitor response to IDHi and compare this response to changes in tumor volume. METHODS Fourteen patients (aged ≥18y) with a histomolecularly confirmed IDH1 mutated, non-contrast-enhancing diffuse glioma (astrocytoma or oligodendroglioma) received ivosidenib (n=12) or vorasidenib (n=2) as part of routine clinical care. MRI was performed before treatment (baseline) and repeated (follow-up) with a median on-drug follow-up of 6 months [4, 12 IQR]. Tumors were segmented from FLAIR images in 3D Slicer and volumes were calculated in cm3. All MRS data were processed in Osprey with the built-in LCModel fitting module. Comparisons between baseline and follow-up measured metabolite levels were conducted using paired t-tests or non-parametric Wilcoxon tests (for non-normal distribution). RESULTS Eleven patients had adequate quality spectra from both baseline and follow-up sessions. All spectra exhibited characteristic tumor features: elevated total choline (tCho), lactate (Lac), myo-inositol (mI) and reduced total N-acetylaspartate (tNAA). The 2-HG peak at 2.25 ppm was visibly reduced after treatment. The decrease in 2-HG levels was highly significant (p<0.001) across all analyzed patients on IDHi, regardless of reference standard. A trend was noted towards tumor volume reduction that was not statistically significant. CONCLUSIONS This is the first in-vivo evidence using MRS confirming 2-HG reduction in response to IDHi in humans. 2HG reductions occurred before volumetric responses raising the possible use this method as an early response assessment method in IDHi therapy. Longitudinal volumetric and radiomic analyses in an expanded cohort are underway.