What is the management approach for a grade 3 Isocitrate Dehydrogenase (IDH) mutant glioma with Alpha-Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) retained and no 1p19q codeletion?

Management of Grade 3 IDH-Mutant Glioma with ATRX Retained and No 1p19q Codeletion

For grade 3 IDH-mutant glioma with ATRX retained and no 1p19q codeletion available, the standard of care is maximal safe surgical resection followed by radiotherapy (54-60 Gy in 1.8-2 Gy fractions) with adjuvant temozolomide. 1

Molecular Classification and Diagnosis

The molecular profile of this tumor is critical for proper classification and treatment planning:

• IDH mutation: Present (defining feature)
• ATRX status: Retained (unusual for IDH-mutant astrocytoma)
• 1p19q codeletion: Not available

This molecular profile creates a diagnostic challenge. Typically:

• IDH-mutant astrocytomas usually show ATRX loss and TP53 mutations
• IDH-mutant oligodendrogliomas show ATRX retention and 1p19q codeletion

Since 1p19q status is unavailable but ATRX is retained, additional molecular testing is recommended to confirm the tumor's lineage. 1

Step-by-Step Management Algorithm

1. Complete Molecular Profiling

• Confirm IDH mutation type (IDH1 R132H or other variants)
• Obtain 1p19q codeletion status if possible
• Test for TERT promoter mutations (common in oligodendrogliomas)
• Assess MGMT promoter methylation status (predictive of response to alkylating agents)
• Consider testing for homozygous CDKN2A/B deletion (marker of WHO grade 4 in IDH-mutant astrocytomas) 1

2. Initial Treatment

• Maximal safe surgical resection whenever feasible
• Radiotherapy: 54-60 Gy in 1.8-2 Gy fractions
• Adjuvant chemotherapy: Temozolomide (12 cycles) 1, 2

3. Follow-up

• Clinical and radiological follow-up every 3-6 months
• MRI is the preferred imaging modality
• Monitor for treatment-related toxicities 1

4. Treatment at Recurrence

• Consider re-resection if feasible
• Chemotherapy options:
  • Temozolomide rechallenge (if good initial response)
  • Nitrosourea-based regimens
  • Bevacizumab (for symptomatic relief) 1, 2

Important Considerations

Molecular Ambiguity

The retained ATRX with unknown 1p19q status creates diagnostic uncertainty. If 1p19q codeletion is present, this would be an oligodendroglioma, which would alter treatment recommendations to radiotherapy followed by PCV (procarbazine, lomustine, vincristine) chemotherapy. 1

Treatment Efficacy

Current treatments for IDH-mutant grade 3 astrocytomas can prolong overall survival up to 10 years, compared to 14 years for grade 3 IDH-mutant codeleted oligodendrogliomas. 2

Advanced Radiation Techniques

Consider advanced radiation techniques such as intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) to minimize long-term neurocognitive effects, especially in younger patients with longer expected survival. 3

Pitfalls to Avoid

1. Misclassification: Don't assume tumor lineage without complete molecular profiling
2. Undertreatment: Don't delay adjuvant therapy in grade 3 tumors
3. Overtreatment: Don't treat as glioblastoma without evidence of grade 4 features
4. Neglecting seizure management: Anti-epileptic drugs may be needed regardless of tumor control 4

Special Scenarios

Young Patient with Minimal Residual Disease

• Consider more aggressive resection if safe and feasible
• Standard adjuvant therapy still recommended due to grade 3 status 1, 5

Elderly Patient or Poor Performance Status

• Consider hypofractionated radiotherapy regimens
• Temozolomide monotherapy may be appropriate if MGMT promoter is methylated 1

The management of grade 3 IDH-mutant gliomas requires careful molecular characterization and a multidisciplinary approach. The current evidence strongly supports maximal safe resection followed by radiotherapy and adjuvant temozolomide for these tumors, with treatment modifications based on complete molecular profiling.