David Olayinka Kamson

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.

Supplementary tables and figures for manuscript “Ivosidenib and Vorasidenib decrease intratumoral 2-hydroxyglutarate and total choline levels in lower-grade glioma: an in vivo MR Spectroscopy study”.

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.

Leptomeningeal disease (LMD) is a devastating complication of cancer, and its incidence is rising. The inaugural LMD Think Tank Meeting took place in 2023 during the Society for Neuro-Oncology (SNO) and American Society of Clinical Oncology (ASCO) Central Nervous System (CNS) annual meeting, convening an international group of clinicians and scientists dedicated to understanding and treating LMD in a multidisciplinary fashion. While this meeting laid the foundation for a SNO/ASCO consensus review on the clinical management of LMD, the frequent exclusion of LMD patients from trials was identified as a clear and pervasive challenge. To address this gap, a follow-up assembly convened in 2024 with a goal of developing an SNO/ASCO consensus on best practices for clinical research; this included addressing the role of industry and basic scientists in clinical trials, providing guidance for improved clinical trial design, and accelerating the enrollment of LMD patients into clinical trials. Academic-industry partnerships and multi-institutional collaborations are crucial to advance our understanding of LMD, expand treatment access, and ultimately, improve survival and quality of life for our patients.

Current assessments of brain permeability rely predominantly on drug delivery to contrast-enhancing tumor regions. However, substantial portions of central nervous system (CNS) tumors reside within non-enhancing brain (NEB), where drug concentrations frequently remain subtherapeutic. This collaborative Adult Brain Tumor Consortium and Food and Drug Administration workshop aimed to identify criteria for defining NEB permeability to accomplish two critical objectives: 1) allocate clinical trial resources toward agents achieving therapeutic NEB concentrations and 2) minimize systemic toxicity when CNS benefit is improbable. The workshop systematically evaluated permeability assessment modalities, including drug physicochemical properties, in vitro blood-brain barrier models, and penetration into cerebrospinal fluid and normal rodent brain. Methodological approaches to determine requisite NEB drug concentrations and approaches to measuring NEB pharmacokinetics and pharmacodynamics were examined. This culminated in developing the Non-Enhancing Brain Permeability Index (NEBPI), which assigns therapeutic agents to three categories: sufficiently permeable, insufficiently permeable, or impermeable. The NEBPI provides a standardized framework to assist investigators and regulatory agencies to evaluate NEB penetration before human efficacy studies are initiated for agents that require direct tumor contact. Assessing NEB drug penetration is critical to improving outcomes in CNS tumors and reducing the incidence of brain metastases in systemic malignancies.

Supplementary Table 1 - Detailed volumetric data for each patient.

Supplementary Table 2 - Raw data for growth modeling.

Purpose:Isocitrate dehydrogenase (IDH)-mutant gliomas are usually treated with radiotherapy and chemotherapy, which increases the risk for neurocognitive sequelae during patients’ most productive years. We report our experience using off-label first-in-class mutant IDH1 inhibitor ivosidenib and its impact on tumor volume in IDH-mutant gliomas.Experimental Design:We retrospectively analyzed patients ages ≥18 years with radiation/chemotherapy-naïve, mutant IDH1, nonenhancing, radiographically active, grade 2/3 gliomas, and ≥2 pretreatment and ≥2 on-treatment ivosidenib MRIs. T2/FLAIR-based tumor volumes, growth rates, and progression-free survival (PFS) were analyzed. log-linear mixed-effect modeling of growth curves adjusted for grade, histology, and age was performed.Results:We analyzed 116 MRIs of 12 patients [10 males, median age 46 years (range: 26–60)]: 8 astrocytomas (50% grade 3) and 4 grade 2 oligodendrogliomas. Median on-drug follow-up was 13.2 months [interquartile range (IQR): 9.7–22.2]. Tolerability was 100%. A total of 50% of patients experienced ≥20% tumor volume reduction on-treatment and absolute growth rate was lower during treatment (−1.2 ± 10.6 cc/year) than before treatment (8.0 ± 7.7 cc/year; P ≤ 0.05). log-linear models in the Stable group (n = 9) showed significant growth before treatment (53%/year; P = 0.013), and volume reduction (−34%/year; P = 0.037) after 5 months on treatment. After treatment, volume curves were significantly lower than before treatment (after/before treatment ratio 0.5; P < 0.01). Median time-to-best response was 11.2 (IQR: 1.7–33.4) months, and 16.8 (IQR: 2.6–33.5) months in patients on drug for ≥1 year. PFS at 9 months was 75%.Conclusions:Ivosidenib was well tolerated and induced a high volumetric response rate. Responders had significant reduction in tumor growth rates and volume reductions observed after a 5-month delay. Thus, ivosidenib appears useful to control tumor growth and delay more toxic therapies in IDH-mutant nonenhancing indolently growing gliomas.See related commentary by Lukas and Horbinski, p. 4709