IDH-Mutant Astrocytoma

IDH-mutant astrocytoma is a diffuse astrocytic glioma that carries a mutation in IDH1 or IDH2, lacks 1p/19q co-deletion, and is graded 2, 3 or 4 on histology and CDKN2A/B status. It is the group of astrocytomas with the best outlook, with a median survival of about 10 years overall and about 3 to 5 years in grade 4 disease.

It forms about 20% to 25% of diffuse gliomas in adults, with a median age of 35 to 40. Tumours begin in the frontal or insular regions and progress to higher grade over years.

Associations are germline TP53 variants (Li-Fraumeni syndrome), constitutional mismatch repair deficiency and prior cranial radiotherapy, but most cases are sporadic.

Pathophysiology. The mutant IDH enzyme (IDH1 R132H in about 90%) produces 2-hydroxyglutarate, which inhibits demethylases and causes a hypermethylated phenotype. TP53 mutation and ATRX loss are almost universal. Loss of CDKN2A/B is the strongest marker of progression.

Grading. Grade 2: no mitotic activity or anaplasia. Grade 3: mitoses and anaplasia. Grade 4: necrosis or microvascular proliferation, or homozygous CDKN2A/B deletion, whatever the histology.

Imaging features. T2-FLAIR mismatch (T2 hyperintense lesion with relatively low FLAIR signal) is specific for the IDH-mutant astrocytoma. MR spectroscopy shows a 2-hydroxyglutarate peak.

• Seizures at presentation in about 70% (grade 2) and fewer in higher grades.
• Headache, cognitive change, personality change, language disturbance and focal deficits.
• Signs of raised intracranial pressure in grade 3 and 4 tumours.
• Long preclinical course, with sudden worsening at progression.

Red flags.

• Rapid neurological decline or new contrast enhancement on MRI, suggesting higher grade.
• Status epilepticus and signs of herniation.

• MRI brain with gadolinium, perfusion and diffusion: non-enhancing infiltrating lesion in grade 2, with enhancement, necrosis and raised perfusion in higher grades. Look for the T2-FLAIR mismatch sign.
• Tissue is needed. Integrated diagnosis tests IDH1 R132H immunohistochemistry (with sequencing if negative in patients under 55), ATRX and p53, 1p/19q status, CDKN2A/B deletion, MGMT promoter methylation and Ki-67.
• Perfusion imaging and PET help choose biopsy targets in heterogeneous tumours.
• Baseline neuropsychological testing, FBC, liver tests and creatinine.
• Germline testing in young patients and when there is a family history.

Differential diagnosis.

• Oligodendroglioma (IDH-mutant and 1p/19q co-deleted)
• Glioblastoma, IDH-wildtype
• Diffuse hemispheric glioma, H3 G34-mutant
• Pleomorphic xanthoastrocytoma and ganglioglioma
• Dysembryoplastic neuroepithelial tumour and focal cortical dysplasia
• Encephalitis, demyelination and infarction

Treatment depends on the molecular grade. Tumours with CDKN2A/B deletion are classed as grade 4 and given grade 4 treatment.

Surgery. Maximal safe resection for all grades.

Grade 2 with no high risk features. Observation after gross total resection, or targeted therapy for residual or recurrent non-enhancing disease.

• Vorasidenib: vorasidenib 40 mg orally once daily at the same time each day, at least 2 hours after or 1 hour before food (20 mg once daily when body weight is under 40 kg), until progression or unacceptable toxicity; maximum 40 mg daily; monitoring: ALT, AST and bilirubin before starting, every 2 weeks for the first 2 months, monthly for the first 2 years, then as indicated; adjustment: reduce stepwise to 20 mg then 10 mg for toxicity, withhold for ALT or AST over 3 times the upper limit and resume at the next lower dose when 3 times or less, stop permanently for recurrence at 10 mg or for ALT or AST over 3 times the upper limit with bilirubin over 2 times, avoid strong and moderate CYP1A2 inhibitors and avoid smoking, use non-hormonal contraception because hormonal methods may fail, avoid in pregnancy

Grade 3 and grade 4 disease, and high risk grade 2 disease. Radiotherapy 59.4 Gy in 33 fractions (54 Gy for grade 2 disease), then chemotherapy.

• Temozolomide: temozolomide 150 mg/m2 orally once daily on days 1 to 5 of a 28-day cycle for cycle 1, increased to 200 mg/m2 on days 1 to 5 from cycle 2 when neutrophils and platelets allow, for 12 cycles starting 4 weeks after radiotherapy (some centres add 75 mg/m2 daily during radiotherapy); maximum 200 mg/m2 daily; monitoring: FBC on day 22 of each cycle, liver tests, antiemetic cover; adjustment: reduce by 50 mg/m2 for neutrophils under 1.0 x 10^9/L or platelets under 50 x 10^9/L and stop if 100 mg/m2 is not tolerated, no change when creatinine clearance is 36 mL/min or more and caution when it is lower, caution in severe hepatic impairment
• Procarbazine, lomustine and vincristine (alternative for grade 2 and 3): procarbazine 60 mg/m2 orally daily on days 8 to 21, lomustine 110 mg/m2 orally on day 1 and vincristine 1.4 mg/m2 IV on days 8 and 29, every 6 to 8 weeks for up to 6 cycles; maximum procarbazine 100 mg daily, lomustine 200 mg each cycle and vincristine 2 mg each dose; monitoring: FBC on day 1 and at the nadir, liver tests, neuropathy and constipation, lung function, avoidance of alcohol and tyramine rich foods during procarbazine; adjustment: reduce procarbazine and lomustine by 25% for grade 3 to 4 haematological toxicity, reduce vincristine by 50% when bilirubin is 26 to 51 micromol/L and avoid it over 51 micromol/L, avoid strong CYP3A inhibitors, avoid lomustine when creatinine clearance is under 30 mL/min
• Pneumocystis prophylaxis during concurrent temozolomide and while corticosteroids continue: co-trimoxazole 960 mg orally three times weekly (for example Monday, Wednesday and Friday) throughout concurrent temozolomide and radiotherapy, continued while corticosteroids are used and until lymphocytes recover above 0.5 x 10^9/L; maximum 960 mg daily; monitoring: FBC, potassium, creatinine, rash; adjustment: halve the dose when creatinine clearance is 15 to 30 mL/min and avoid under 15 mL/min, stop for rash or severe cytopenia and use a non-sulfonamide agent

Seizure and oedema control.

• Antiseizure therapy: levetiracetam 500 mg orally twice daily, increased by 500 mg twice daily every 1 to 2 weeks to a usual 1000 to 1500 mg twice daily after a seizure (it is not continued as prophylaxis in seizure free patients after the early postoperative period); maximum 3000 mg daily; monitoring: mood, irritability, somnolence, renal function; adjustment: creatinine clearance 50 to 79 mL/min 500 to 1000 mg twice daily, 30 to 49 mL/min 250 to 750 mg twice daily, under 30 mL/min 250 to 500 mg twice daily; avoid enzyme inducing antiseizure drugs because they lower temozolomide and lomustine exposure
• Corticosteroid for symptomatic oedema: dexamethasone 4 mg orally or IV once or twice daily for mild symptoms and up to 4 mg four times daily for marked oedema or raised intracranial pressure, for the shortest period, tapered over 1 to 2 weeks once symptoms settle; maximum 16 mg daily; monitoring: glucose, blood pressure, mood and sleep, gastric symptoms (gastric protection when combined with other risk factors), opportunistic infection, myopathy; adjustment: use the lowest effective dose, avoid prolonged courses because of myopathy, osteoporosis and infection, use lower doses in hepatic impairment

Recurrence. Re-resection, re-irradiation, or chemotherapy.

• Lomustine: lomustine 110 mg/m2 orally as a single dose on day 1 of a 6-week cycle, on an empty stomach at bedtime with an antiemetic, for up to 6 cycles; maximum 110 mg/m2 each cycle and cumulative 1000 mg/m2; monitoring: FBC before each cycle and weekly for 6 weeks after each dose, liver tests, lung function (pulmonary fibrosis rises with cumulative dose); adjustment: reduce to 90 mg/m2 then 70 mg/m2 for neutrophil nadir under 1.0 x 10^9/L or platelets under 50 x 10^9/L, delay until neutrophils reach 1.5 x 10^9/L and platelets 100 x 10^9/L, avoid when creatinine clearance is under 30 mL/min, caution in hepatic impairment, prescribe one dose each cycle only to avoid overdose

Monitoring. MRI every 3 to 6 months. Review of molecular grade at progression. Neurocognitive and endocrine assessment, and monitoring of liver tests for patients on vorasidenib.

Referral and escalation.

• Neuro oncology multidisciplinary referral at diagnosis.
• Urgent assessment for neurological decline, seizures that do not stop, or new enhancement.

Special groups.

• Young adults: fertility preservation counselling before chemotherapy, and vorasidenib may weaken hormonal contraception.
• Pregnancy: surgery in the second trimester, and deferral of radiotherapy and chemotherapy.
• Older adults: shorter radiotherapy courses and single agent temozolomide in selected patients.
• Li-Fraumeni carriers: avoid radiotherapy where possible.