Advances in the management of patients with IDH-mutant glioma

Abstract

Background: Isocitrate dehydrogenase (IDH)-mutant gliomas represent a distinct category of diffuse gliomas with unique biological behavior and clinical course. Over the past decade, our understanding of these tumors has dramatically evolved, thanks to advances in molecular classification, imaging, and targeted therapies.

Method: This review provides a comprehensive overview of the current landscape in IDH-mutant glioma management.

Results: We highlight key molecular features and recent refinements in WHO tumor classification, along with novel diagnostic tools such as magnetic resonance spectroscopy and liquid biopsy. Surgical strategies have also shifted, with emphasis on maximal safe resection guided by functional mapping and advanced neuroimaging. Therapeutically, IDH inhibitors like vorasidenib are emerging as promising agents in selected patient populations, offering prolonged disease control. Additionally, radiotherapy and chemotherapy remain critical components, with ongoing trials evaluating their integration with targeted approaches. Finally, we explore future directions, including immunotherapy, PARP inhibitors, and CDK4/6 inhibitors especially in recurrent or treatment-resistant cases.

Conclusions: This review underscores the importance of a multidisciplinary, precision medicine approach in optimizing outcomes for patients with IDH-mutant gliomas.

Keywords: IDH inhibitors; IDH mutation; glioma; precision medicine; targeted therapy.

Figure 1.

Sustained clinical improvement and neuroradiological response to check-point inhibitors in advanced progressing IDH mutant astrocytoma. We show the case of a young 31-year-old patient suffering of a progressing IDH mutant astrocytoma treated with surgery, RT, chemotherapy (PCV) at the first line and second surgery, RT, carboplatin, bevacizumab in subsequent lines. Interestingly the recurrent glioma showed loss of IDH mutant allele detected with WES and ultra-hypermutation status with tumor mutational burden >150/Mb. Based on the very high tumor mutational burden, salvage therapy was proposed with ICI (pembrolizumab; A, B, C, D, E, F). After the start of pembrolizumab the patient showed a rapid and dramatic clinical improvement with KPS improving from 40 to 70 and a multisite radiological response two months (G, H, I, L, M, N) and four months (O, P, Q, R, S, T) after the start of ICI. The patient is still clinical able to carry normal activity after 12 months after the start of ICI. A, G, O, C, I, Q, E, M, S: Magnetic resonance imaging (MRI), axial T1 sequences after injection of gadolinium shows reduction of contrast enhancing area in corpus callosum and fourth ventricule from baseline before ICI (A, C, E) with, to 2 months (G, I, M) and 4 months after the start of ICI (O, Q, S). B, H, P, D, L, R, F, N, T: MRI axial T2 Flair sequences shoes reduction of hyperintense areas related to tumor burden from baseline before ICI (B, D, F) with contrast enhancing area in corpus callosum and fourth ventricule, to 2 months (H, L, N) and 4 months after the start of ICI (P, R, T). Abbreviations: RT, radiotherapy; IDH, isocitrate dehydrogenase; PCV, procarbazine; CCNU, vincristine; KPS, Karnofsky performance score; ICI, immune-checkpoint inhibitors; FLAIR, fluid-attenuated inversion recovery; WES, whole exome sequencing.

Figure 2.

Emerging targeted therapies and molecular alterations in IDH-mutant glioma. The central panel illustrates the neomorphic activity of mutant IDH1/2, leading to D-2-hydroxyglutarate (D-2HG) accumulation and epigenetic dysregulation via inhibition of α-KG–dependent enzymes (TET, KDM). Peripheral panels summarize therapeutic strategies under investigation: IDH inhibitors and peptide vaccines (NCT03893903, NCT02193347); checkpoint inhibitors (durvalumab, nivolumab; NCT04056910, NCT05484622); PARP inhibitors (olaparib, niraparib, pamiparib; NCT05188508, NCT03991832); CDK4/6 inhibitors (palbociclib, abemaciclib; NCT02530320, NCT03220646); MAT2A/PRMT inhibitors in MTAP-deleted gliomas (TNG908; NCT05275478).

Figure 3.

Tumor response to second line PCV regimens in recurrent grade 4 IDH mutant glioma. We show the case of a 48-year-old patient affected by left fronto-temporal IDH mutant grade 4 astrocytoma He was initially treated with surgery, concomitant radiotherapy and temozolomide and 12 cycles of adjuvant temozolomide (TMZ). After 24 months from TMZ discontinuation, MR imaging showed the appearance of contrast-enhancement area in the corpus callosum (A) with positive PET Tyr signal in favour of tumor recurrence (B). He started PCV-based chemotherapy. Subsequent MR imaging showed reduction of contrast-enhancement tumor subvolume from the baseline (C, D; Ce subvolume 10.9 cm³) to subsequent time points: 3 months (E; F; Ce subvolume 10.0 cm³), 6 months (G, H; Ce subvolume 3.9 cm³), 10 months after the start of chemotherapy with PCV (I; Ce subvolume 1.3 cm³) namely at the end of the sixth PCV cycle. Recent PET Tyr scan showed complete disappearance of the pathological uptake (L). Abbreviations: PCV, procarbazine; CCNU, vincristine; MR, magnetic resonance; PET Tyr, positron emission tomography with 18F-fluoroéthyl-L-tyrosine tracer. Tumor subvolumes were calculated with 3D slicer software are represented by green areas. A, C, D, E, F, G, H, I: MR imaging, axial T1 sequences after injection of gadolinium. B coregistered imaging of PET-Tyr scan with axial T1 gadolinium sequences at the same time point before the start of PCV regimen. L coregistered imaging of PET-Tyr scan with axial T1 gadolinium sequences 12 months after the start of chemotherapy with PCV.