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Ivosidenib and Vorasidenib Decrease Intratumoral 2-Hydroxyglutarate and Total Choline Levels in Patients with
Dunja Simicic1, Seyma Alcicek1,2, Lindsay Blair3,4
1Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Purpose:
Isocitrate dehydrogenase (IDH)-mutant (mIDH) gliomas are slow-growing infiltrating tumors of astrocytic or oligodendroglial origin. Mutated metabolic enzymes IDH1 or IDH2 lead to the production of 2-hydroxyglutarate (2HG) that can be measured with optimized in vivo magnetic resonance spectroscopy (MRS). As 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 noninvasively monitor response to treatment with mIDH inhibitors and to relate this response to changes in MRI-assessed tumor volume.
Experimental Design:
Eighteen 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 in 2HG levels (P < 0.001) regardless of tumor and treatment type (astrocytoma/oligodendroglioma and ivosidenib/vorasidenib), whereas 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.
Conclusion:
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.
Insights
Magnetic resonance spectroscopy (MRS) can non-invasively monitor IDH-mutant glioma treatment response by tracking 2-hydroxyglutarate (2HG) levels. Significant reductions in 2HG and other metabolites indicate treatment efficacy and potential tumor growth arrest.
Area of Science:
- Neuro-oncology
- Molecular Diagnostics
- Medical Imaging
Background:
- IDH-mutant gliomas are characterized by the oncometabolite 2-hydroxyglutarate (2HG), a potential therapeutic target.
- Targeted therapies like ivosidenib and vorasidenib aim to suppress 2HG production in IDH-mutant gliomas.
- Non-invasive monitoring of treatment response is crucial for managing these slow-growing tumors.
Purpose of the Study:
- To evaluate the utility of in-vivo magnetic resonance spectroscopy (MRS) for monitoring treatment response in IDH-mutant gliomas.
- To assess if MRS-measured 2-hydroxyglutarate (2HG) levels correlate with treatment efficacy of IDH inhibitors.
- To relate changes in 2HG levels to alterations in tumor volume assessed by MRI.
Main Methods:
- 18 patients with IDH-mutated gliomas received ivosidenib or vorasidenib therapy.
- Pre-treatment and follow-up MRI/MRS scans using 2HG-optimized PRESS were performed.
- Median on-drug follow-up was 4.3 months, with 14 patients passing quality control.
Main Results:
- A significant decrease in 2HG levels was observed across all patients (p < 0.001).
- Levels of total choline (tCho) and glutamine also significantly decreased (p < 0.01).
- Volumetric MRI indicated tumor growth arrest, with a modest average decrease in tumor size.
Conclusions:
- MRS detection of 2HG reduction is a promising non-invasive method for monitoring IDH inhibitor therapy.
- Early decreases in tumor 2HG and tCho levels suggest treatment effectiveness.
- MRS may serve as a valuable tool for assessing treatment response in lower-grade gliomas.
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