Ivosidenib and Vorasidenib decrease intratumoral 2-hydroxyglutarate and total choline levels in patients with lower-grade glioma: an in vivo MR Spectroscopy study

Purpose: IDH-mutant (mIDH) gliomas are slow-growing infiltrating tumors of astrocytic or oligodendroglial origin. Mutated metabolic enzymes IDH1 or IDH2 lead to production of 2-hydroxyglutarate (2HG) that can be measured with optimized in-vivo magnetic resonance spectroscopy (MRS). Since the 2HG oncometabolite plays a key role in the molecular pathogenesis of mIDH tumor, direct suppression of 2HG production has proven to be a viable intervention strategy; for example, with the small-molecule inhibitors ivosidenib (mIDH1) and vorasidenib (mIDH1/mIDH2). The aim of this study was to explore whether MRS measurements of 2HG can be used to non-invasively monitor response to treatment with mIDH inhibitors and to relate this response to changes in MRI assessed tumor volume. Experimental Design: 18 patients with diagnosed IDH-mutated glioma were enrolled and received ivosidenib or vorasidenib therapy. MRI/MRS scans with 2HG-optimized single-voxel PRESS were performed before treatment and repeated (follow-up) with a median on-drug follow-up of 4.3 months. Results: In the 14 patients that passed spectroscopy quality control (median follow-up 3.9 months) we observed a substantial and significant decrease of 2HG levels (p < 0.001) regardless of tumor and treatment type (astrocytoma/oligodendroglioma, ivosidenib/vorasidenib), while total choline (tCho) and glutamine, metabolites characteristically increased in glioma, also showed a significant decrease (p < 0.01). Volumetric assessment revealed a modest decrease on average, indicating tumor growth arrest. Conclusions: The striking reductions in tumor 2HG and tCho levels early following initiation of targeted therapy using an IDH inhibitor suggest that MRS may provide an important tool for monitoring treatment response of lower-grade gliomas.