# Isocitrate Dehydrogenase‐Mutant Astrocytomas: Risk Stratification and Therapeutic Advance

## TL;DR

This review discusses how to classify and treat IDH-mutant astrocytomas using molecular markers and risk models, emphasizing personalized approaches to improve outcomes.

## Contribution

The paper introduces a multidomain risk stratification framework integrating molecular, clinical, and imaging data for IDH-mutant astrocytomas.

## Key findings

- IDH-mutant astrocytomas show prognostic heterogeneity despite unified grading, requiring multidimensional risk models.
- Therapeutic advances include brain-penetrant IDH inhibitors and strategies like vaccines and epigenetic modulation.
- Resistance mechanisms and recurrence involve therapy-driven hypermutation and clonal evolution.

## 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.

This graphical abstract synthesizes the core logic of our revised review by linking integrated diagnosis, risk stratification, and trajectory‐based management in IDH‐mutant astrocytomas across CNS WHO Grades 2–4. It highlights lineage‐defining molecular classification (IDH mutation with core co‐alterations), integrated histomolecular grading, and key adverse biomarkers (including CDKN2A/B homozygous deletion defining Grade 4), together with imaging and radiomics to quantify tumor burden and refine prognosis. These multidimensional variables converge into an integrated risk framework that informs initial and longitudinal decision‐making. The diagram maps risk strata to management trajectories—maximal safe resection as the cornerstone, followed by risk‐adapted chemoradiation for higher grade disease and IDH inhibition strategies that can defer chemoradiation in selected Grade 2 patients—while positioning emerging modalities (immunotherapy, epigenetic, and metabolic targeting) and novel delivery technologies as future directions. Overall, the schematic emphasizes personalized, trial‐minded care that balances durable tumor control with preservation of long‐term neurocognitive function.