Neuro-Oncology Outlook: IDH-Mutant Glioma—Clinical Insights and Emerging Directions

Diffuse glioma is the most common malignant primary CNS tumor in adults.1 Mutations in isocitrate dehydrogenase (IDH1 or IDH2) define IDH-mutant glioma and distinguish it from IDH–wild-type glioblastoma. With an incidence rate of 0.80 per 100,000, approximately 2700 new cases of IDH-mutant glioma are diagnosed annually in the United States.² Compared with glioblastoma, IDH-mutant glioma typically arises in younger individuals, often being diagnosed in the third and fourth decades of life³; has a prognosis measured in years to decades rather than months to years^3,4; and is managed with distinct treatment strategies.^2,3 This review synthesizes key advances in the diagnosis, prognosis, and management of IDH-mutant glioma; examines areas of uncertainty in the field; and highlights emerging research poised to shape clinical practice.

Diagnostic Classification

The World Health Organization (WHO) classification of CNS tumors has shifted from a primarily histology-based framework to one that emphasizes molecular classification (Table). According to the most recent WHO classification of CNS tumors,⁵ IDH-mutant gliomas include oligodendroglioma (grades 2 or 3) and astrocytoma (grades 2–4).^5,6 Codeletion of 1p/19q defines oligodendroglioma, distinguishing it from 1p/19q-intact astrocytoma.⁵ Homozygous deletion of CDKN2A/B confers a grade 4 designation in astrocytoma, irrespective of histology.^5,7

Controversial Molecular Markers

Several molecular markers have been found to affect prognosis but have not yet been formally incorporated into guidelines. Although less prognostically impactful than in astrocytoma, CDKN2A/B homozygous deletion has been shown to negatively affect prognosis in oligodendroglioma.^7-9 However, unlike in astrocytoma, this deletion is merely supportive rather than diagnostic of a higher grade for oligodendroglioma. CDKN2A/B hemizygous deletion is controversial, with some studies not demonstrating a survival difference between hemizygous deletion and intact CDKN2A/B¹⁰ and others observing an intermediate phenotype falling between those with intact CDKN2A/B and those with homozygous deletion.^11,12 Whereas MGMT promoter methylation influences prognosis and response to alkylating chemotherapy in glioblastoma, several notable studies have not demonstrated prognostic or predictive significance of MGMT status in IDH-mutant glioma,¹³ so it is not routinely used to guide treatment decisions.^14,15 Other molecular markers, such as PDGFRA, CDK4/6, and MET alterations, have been associated with worse outcomes, but in part due to their rarity in IDH-mutant glioma, they have not been adopted into diagnostic classification.^11,15-17

Emerging Diagnostic and Monitoring Modalities

Novel, less-invasive diagnostic modalities are currently being evaluated. Next-generation sequencing assessing circulating tumor DNA can detect IDH mutations, representing an alternative diagnostic approach to surgically inaccessible tumors, such as brainstem-based lesions.^18-20 Magnetic resonance spectroscopy can be used to focally detect 2-hydroxyglutarate (2-HG) enrichment, which may assist both in diagnosing these tumors and noninvasively differentiating tumor from treatment effects.^20,21 Traditional [¹⁸F]fluorodeoxyglucose–based PET imaging has limited utility in IDH-mutant glioma due to high physiologic uptake in brain tissue and limited uptake in lower-grade tumors. However, novel amino acid–based PET tracers, such as [¹⁸F]fluoroethyltyrosine PET and [¹¹C]methionine PET, provide greater specificity and superior resolution and may play a role in delineating tumors more accurately than MRI for surgical purposes and distinguishing progression from treatment effects.^22,23

Response Assessment in Neuro-Oncology 2.0 is the current standardized criteria for defining progression and treatment response in IDH-mutant glioma based on MRI tumor measurements.²⁴ Although 2-dimensional measurements are standard, there has been interest in using 3-dimensional volumetric measurements to more accurately define tumor size and growth trajectory. However, there is no current standardized approach to volumetric assessment or method of automation, and this approach has yet to be validated on a large scale.^25,26

Management

Treatment decisions in IDH-mutant glioma must balance quality of evidence, expected prognosis, short- and long-term toxicities, and patient preferences. Maximal safe resection has remained a cornerstone for diagnosing and treating these individuals. Following surgery, individuals were historically dichotomized into low-risk groups (age <40 years, grade 2 pathology, and/or gross total resection [GTR]) versus high-risk groups (deviations from any of the low-risk factors), with observation typically recommended for low-risk individuals and radiation or chemotherapy for high-risk individuals.^27,28 However, the conception of these criteria, designed to predict early progression, predated molecular classification, and their impact on overall survival in molecularly defined gliomas has been questioned.²⁹ In real-world practice, treatment decisions are more nuanced than this simple framework suggests.²⁸

Regarding systemic treatment, adjuvant chemotherapy with temozolomide (TMZ) for astrocytoma and procarbazine, lomustine, and vincristine (PCV) for oligodendroglioma are often pursued after completion of radiation therapy.^3,30 Unlike in glioblastoma, there is no robust evidence to support the use of concurrent chemotherapy with radiation therapy in IDH-mutant glioma, although concurrent TMZ is still sometimes used in grade 4 IDH-mutant astrocytoma, extrapolated from the glioblastoma literature.^15,31,32

In the search for more tolerable and targeted treatment options, IDH inhibitors (IDHi) were developed to block mutant IDH from producing 2-HG, an oncometabolite, thereby stunting tumor proliferation.³³ TIBSOVO (ivosidenib; Servier Pharmaceuticals LLC, Boston, MA) and Voranigo (vorasidenib; Servier Pharmaceuticals LLC, Boston, MA) were the first IDHi used in IDH-mutant glioma. On the basis of results from a perioperative trial and the fact that vorasidenib inhibits both mutant IDH1 and IDH2 (whereas ivosidenib only inhibits IDH1), vorasidenib was selected for evaluation in the phase 3 Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO; NCT04164901).^34,35 In this trial of grade 2 IDH-mutant glioma, participants treated with vorasidenib had significantly reduced tumor growth rates and improved PFS and time to next intervention compared with placebo-treated participants, ultimately leading to the 2024 US Food and Drug Administration approval of vorasidenib for grade 2 IDH-mutant glioma.^26,34

Controversies in Management

Integration of IDHi

Whereas the decision to pursue IDHi is sometimes clear (for instance, if the individual closely matches the inclusion criteria used in the INDIGO trial), many clinical real-world situations remain uncertain.²⁹ For instance, modern molecular classification has reduced, though not eliminated, the prognostic distinction between grades 2 and 3 IDH-mutant glioma in some cohorts.^29,36-38 Therefore, although the INDIGO trial included only participants with a grade 2 classification, some suggest that IDHi could be considered in appropriately selected individuals with grade 3 IDH-mutant glioma.³⁹ Whether IDHi should be used in individuals who underwent GTR and have no residual radiographic disease to guide treatment or monitoring also remains unclear.²⁹

Evidence from early clinical trials suggested that individuals with contrast-enhancing tumors do not respond well to ivosidenib or vorasidenib, although it is uncertain whether small, subtle, patchy enhancement actually obviates therapeutic benefit from IDHi, especially if the enhancing region is entirely resected.^39-41 Exploratory analysis from INDIGO showed no negative effect on quality of life or neurocognition in participants treated with vorasidenib, and this medication appears to be relatively well-tolerated in the short term. However, the impact of long-term vorasidenib treatment on toxicity, overall survival, and potential changes to underlying tumor biology remains unexplored.²⁶ Given uncertain effects on fertility and potential teratogenicity, clinicians should discuss reproductive implications with individuals of childbearing potential (both men and women) before IDHi initiation.⁴² Emerging evidence suggests that IDHi does not appear to detrimentally affect response to radiotherapy.⁴³

Choice of Chemotherapy Regimen

The landmark Radiation Therapy Oncology Group (RTOG) 9802 (Observation or Radiation Therapy With or Without Combination Chemotherapy in Treating Patients With Low-Grade Glioma; NCT00003375), European Organisation for Research and Treatment of Cancer (EORTC) 26951 (Radiation Therapy With and Without Combination Chemotherapy in Patients With Resected Anaplastic Oligodendroglioma; NCT00002840), and RTOG 9402 (Radiation Therapy With or Without Chemotherapy in Treating Patients With Anaplastic Oligodendroglioma; NCT00002569) trials collectively demonstrated a survival benefit of adding PCV to radiotherapy in IDH-mutant gliomas, including both astrocytoma and oligodendroglioma.^13,44-46

The Phase III Trial of Anaplastic Glioma Without 1p/19q Loss of Heterozygosity (CATNON; NCT00626990) subsequently demonstrated a survival benefit of adding TMZ to radiotherapy in grade 3 astrocytoma, and due to better tolerability compared with PCV, TMZ has been widely adopted for the treatment of astrocytoma.¹⁵ Emerging retrospective data from the French Prise en Charge des Oligodendrogliomes Anaplasiques (POLA) group suggest that PCV may have improved PFS efficacy compared with TMZ in both grade 3 astrocytoma (4-year PFS 70.8% with RT + PCV versus 53.5% for RT + TMZ; P=.0074)⁴⁷ and oligodendroglioma (5-year PFS 75% with RT + PCV versus 51% with RT + TMZ; P<.0001).⁴⁸ These studies reported that this improved PFS came at the cost of increased grade 3 toxicity (46.7% in the PCV arm vs 8.6% in the TMZ arm; P<.0001).⁴⁷ Until results from the ongoing Radiation Therapy With Concomitant and Adjuvant Temozolomide Versus Radiation Therapy With Adjuvant PCV Chemotherapy in Patients With Anaplastic Glioma or Low Grade Glioma trial (NCT00887146) become available, prospective randomized trial data directly comparing the 2 agents in this setting are lacking.

Role of Extent of Resection

The traditional surgical approach has been maximal safe resection (ie, removing as much tumor as possible without causing debilitating neurologic symptoms). However, some studies suggest that the extent of resection (EOR) is less important for oligodendroglioma than astrocytoma. One study showed that survival curves based on EOR split within 3 years for astrocytoma but not until 6 to 8 years for oligodendroglioma.⁴ Another evaluated the impact of GTR on enhancing versus nonenhancing tumor portions, finding that GTR of enhancing and nonenhancing regions improved survival in astrocytoma, but only GTR of enhancing regions improved survival in oligodendroglioma.⁴⁹ Other groups have explored the utility of supramaximal resection (ie, extending resection beyond the nonenhancing borders until functional boundaries are encountered).^4,50 Despite potential benefits, this approach must be balanced against the risk of neurologic deficits.

Management of Grade 4 Astrocytoma

Whereas grade 4 astrocytoma was previously grouped with glioblastoma in clinical trials, the most recent WHO classification of CNS tumors⁵ categorized it as a distinct entity. As such, robust evidence to guide treatment decisions for individuals with grade 4 astrocytomas is lacking.^31,32 Whether these tumors should be treated more like lower-grade IDH-mutant astrocytomas, with radiotherapy followed by 12 cycles of TMZ, or more like glioblastomas, with concurrent radiotherapy/TMZ followed by 6 cycles of TMZ, or with an aggressive combination approach (concurrent TMZ/radiotherapy followed by 12 cycles of TMZ), is unclear.

Management of Recurrent Disease

Treatment recommendations for recurrent IDH-mutant glioma are even less well defined than those for newly diagnosed tumors. In the absence of a standardized algorithm, treatment decisions must be highly individualized and depend on multiple factors, including age, functional status, recurrence patterns, and previous therapies. 

Resection may be considered when the recurrence is surgically accessible; this approach can be both diagnostic (ie, distinguishing tumor progression from gliosis and treatment effects) and therapeutic (ie, providing cytoreduction). 

Radiotherapy can be considered in radio-naive individuals. Reirradiation can sometimes be considered, depending on the overlap of recurrence with the original radiation field and time since previous radiation.¹ 

Systemic options include repeating TMZ (especially if it initially led to a robust and long-lasting response) or switching to lomustine (CCNU) or PCV, depending on previous chemotherapy tolerability. 

Optune (Novocure; Portsmouth, NH), a device that produces alternating electrical fields called tumor-treating fields, is approved for use in glioblastoma. Although Optune has not been rigorously evaluated for the treatment of IDH-mutant glioma, it is sometimes used off-label, especially given its lack of systemic side effects and drug–drug interactions.^51,52

Tumor tissue sequencing occasionally identifies potentially actionable sequence mutations, such as in NTRK, BRAF, or PDGFRA, for which targeted, tissue-agnostic agents have been developed.^53-55

Bevacizumab is sometimes considered, particularly for individuals with debilitating neurologic symptoms, although this treatment has inherent risks and has not been shown to improve overall survival.⁵⁶

Emerging Therapeutic Strategies

Ongoing efforts to identify and optimize safe and effective treatments for IDH-mutant glioma are underway.³³ Two novel IDHi—safusidenib (an investigational IDHi developed by Nuvation Bio, New York, NY) and Rezlidhia (olutasidenib; Rigel Pharmaceuticals, South San Francisco, CA)—have preliminarily demonstrated responses in contrast-enhancing IDH-mutant glioma and are now being evaluated in larger trials for this indication. Peptide vaccines targeting mutant IDH have been developed and are being tested.^57-59 Because 2-HG promotes a local immunosuppressive effect, IDHi are hypothesized to reverse this immunosuppression, and ongoing trials (Vorasidenib in Combination With Tumor Specific Peptide Vaccine for Recurrent IDH1 Mutant Lower Grade Gliomas [ViCToRy; NCT05609994] and Study of Vorasidenib and Pembrolizumab Combination in Recurrent or Progressive IDH-1 Mutant Glioma [NCT05484622]) are evaluating the combination of IDHi with immunotherapy.⁶⁰ Additional modalities being explored for the treatment of IDH-mutant glioma include PARP inhibitors,^61,62 glutaminase inhibitors,⁶³ demethylating agents,^64,65 and CDK4/6 inhibitors.^66,67

Prognosis

Prognostication is particularly important for individuals with IDH-mutant glioma. Because diagnosis often occurs in young adulthood, these individuals must integrate their prognosis into decisions regarding employment, family planning,⁴² financial stability, and long-term risks vs benefits of treatment strategies. However, precise prognostication is hampered by several factors.⁶⁸ Clinical trials are prospective, but their strict inclusion criteria introduce selection bias, limiting generalizability. Studies examining real-world outcomes are typically retrospective in nature and therefore have inherent limitations, including survivorship bias, institutional bias, limited sample sizes, and confounding by indication, among others. Furthermore, studies using large databases, such as Surveillance, Epidemiology, and End Results, often lack sufficient clinical detail for rigorous analysis. 

A key limitation across all these types of studies is the rapidly evolving diagnostic and therapeutic landscape of IDH-mutant glioma. Because prognoses can be measured in decades rather than months or years, and disease trajectories may be nonlinear,⁶⁹ many landmark studies reporting prognosis rely on outdated diagnostic classification schemas (ie, not fully accounting for IDH, 1p/19q, or CDKN2A/B). A few studies have reported outcomes using the most contemporary diagnostic classification; however, these analyses are typically limited to short-term outcomes (eg, 1- to 5-year survival) because their data in lower-grade IDH-mutant glioma have not yet matured sufficiently to estimate end points such as median overall survival.^70,71 How the use of IDHi and other emerging therapies will affect overall survival also remains unclear.

Prognostic information based on tumor type and grade is provided in the Table. Given the numerous prognostic caveats, patients should be counseled that overall survival statistics do not necessarily reflect their specific situation and should be interpreted with caution. There are generally wide ranges of survival within a specific tumor type and grade, with some long-term survivors living for multiple decades after their diagnosis. Many factors affect an individual’s prognosis (Figure). Demographic factors include age,^72,73 functional status,⁷⁴ preexisting comorbidities,⁷⁵ and social support.⁷⁶ Clinical factors include tumor size,⁷³ location,⁷⁴ EOR,^50,73 presence of specific molecular alterations,¹⁶ response to and tolerability to treatment,⁷¹ and tumor growth kinetics.⁶⁹

Figure. Prognostic factors in IDH-mutant glioma. Abbreviations: WHO, World Health Organization.

Conclusion

Understanding the evolving molecular landscape of IDH-mutant glioma is essential for homogeneous classification, accurate prognostication, and appropriate management. Novel diagnostic modalities hold promise for less-invasive tumor characterization and serial disease monitoring. The recent introduction of IDHi caused a paradigm shift in the management of these tumors, although further investigation is required to delineate their optimal use and how to incorporate them with other treatments. Prognostication for individuals with IDH-mutant glioma remains challenging. Clinicians must advise their patients that published survival estimates may not reflect their individual circumstances and that numerous demographic and clinical factors can influence their outcome. 

Looking forward, the field is poised for continued progress. Further diagnostic refinement is likely in coming years. Emerging therapeutic strategies offer hope for better outcomes. The challenge for clinicians will be to carefully integrate these advances into practice while always striving to promote the highest quality of life and patient-centered care.