Isocitrate Dehydrogenase-Mutant Astrocytomas: Risk Stratification and Therapeutic Advance

Abstract

Isocitrate dehydrogenase (IDH)–mutant astrocytomas are recognized as a single molecular entity spanning CNS WHO Grades 2–4, and clinical behavior is shaped by early lineage-defining alterations (IDH1/2, ATRX, TP53) and by later events linked to malignant transformation (e.g., CDKN2A/B homozygous deletion). Despite integrated grading, substantial prognostic heterogeneity is observed, and treatment decisions are increasingly informed by multidomain risk stratification rather than grade alone. In this review, contemporary molecular classification and diagnostic principles are summarized, and pragmatic risk models integrating clinical factors, histomolecular features, and imaging/radiomics markers are synthesized. Standard therapies (maximal safe resection, involved-field radiotherapy, and alkylating chemotherapy) are reviewed in a grade-spanning, risk-adapted framework. Therapeutic advances are highlighted, with particular emphasis on brain-penetrant IDH inhibition (vorasidenib) and on emerging strategies including vaccines, checkpoint combinations, epigenetic modulation, metabolic and microenvironment targeting, and novel delivery platforms. Mechanisms of resistance and recurrence, including therapy-driven hypermutation and clonal evolution, are discussed alongside practical salvage considerations. Finally, future directions in trial design, survivorship-oriented endpoints, and biomarker-driven monitoring are outlined. A trajectory-based paradigm is emphasized in which neurocognitive preservation, time to radiotherapy or chemotherapy, and patient-reported outcomes are prioritized while durable disease control is pursued across decades-long survivorship.

Keywords

isocitrate dehydrogenase-mutant astrocytomas / molecular diagnostics / radiation therapy / surgical resection / vorasidenib

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