How are headaches managed in patients undergoing Chimeric Antigen Receptor T-cell (CAR-T) therapy?

Management of Headaches in CAR-T Therapy Patients

Headaches in CAR-T therapy patients should be managed with supportive care (antipyretics, IV hydration) as they are a common symptom of both cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but headache alone does not trigger specific interventions or determine ICANS grading. 1

Understanding Headache in the CAR-T Context

Clinical Significance and Timing

• Headaches occur commonly during CAR-T therapy, typically appearing within 2-7 days after infusion as part of CRS, or 4-10 days after infusion as part of ICANS 1
• Headache alone is not considered a useful diagnostic symptom for ICANS, as it is very common and frequently co-occurs with fever 1
• Headaches are not included in the ASTCT ICANS consensus grading scale, though they may warrant careful attention and directed therapy 1
• In patient-reported outcomes, headache was identified by 29% of CAR-T recipients as a treatment-related symptom 2

Distinguishing Headache Context

• When headache presents with fever alone (Grade 1 CRS), manage with supportive care including antipyretics and IV hydration 1, 3
• When headache occurs with altered mental status, encephalopathy, or other neurologic symptoms, evaluate for ICANS using the ICE score (or CAPD score in children <12 years) 1
• Headache accompanied by signs of elevated intracranial pressure (papilledema, cranial nerve VI palsy, Cushing's triad) requires immediate escalation to Grade 4 ICANS management 1

Supportive Management Algorithm

First-Line Symptomatic Treatment

• Administer antipyretics for headache associated with fever 1, 3
• Provide IV hydration to maintain adequate perfusion 1, 3
• Ensure aspiration precautions and elevate head of bed if any neurologic symptoms present 1
• Avoid medications that cause CNS depression 1

Monitoring Requirements

• Perform neurologic evaluation including ICE score assessment at least twice daily during the high-risk period (first 1-2 weeks post-infusion) 1
• Monitor vital signs every 4-8 hours, or more frequently if clinical status changes 1
• Check daily laboratory tests including CBC, CMP, CRP, and ferritin for CRS surveillance 1, 3

When Headache Signals More Serious Toxicity

Red Flags Requiring Neuroimaging

• Obtain brain MRI with and without contrast (or CT if MRI not feasible) for Grade ≥2 ICANS, which includes any altered level of consciousness, confusion, or ICE score 3-6 1
• Consider baseline brain imaging before CAR-T infusion in high-risk patients or those with pre-existing neurologic conditions 1
• Repeat neuroimaging every 2-3 days for persistent Grade ≥3 neurotoxicity 1

Escalation Criteria

• If headache occurs with ICE score 3-6, mild somnolence, or confusion (Grade 2 ICANS), initiate dexamethasone 10 mg IV and reassess, repeating every 6-12 hours if no improvement 1
• For headache with severe altered consciousness, seizures, or focal neurologic deficits (Grade 3-4 ICANS), administer methylprednisolone 1,000 mg IV 1-2 times daily for 3 days 1
• Initiate neurology consultation for any patient with signs of neurotoxicity beyond isolated headache 1

Seizure Prophylaxis Considerations

Prophylactic Approach

• Consider levetiracetam 500-750 mg orally every 12 hours for 30 days starting on day of infusion, especially for CAR-T products known to cause severe neurotoxicity (axicabtagene ciloleucel, brexucabtagene autoleucel) 1
• Seizure prophylaxis is particularly important for patients with seizure history, CNS disease, or neoplastic brain lesions 1
• Continue prophylactic levetiracetam if EEG shows no seizure activity; escalate treatment if non-convulsive status epilepticus detected 1

Critical Management Pitfalls to Avoid

Common Errors

• Do not routinely administer corticosteroids as pre-medication before CAR-T infusion, as this may mask early toxicity symptoms 1, 3
• Do not dismiss headache in the context of other neurologic symptoms—always perform formal ICE score assessment 1
• Avoid using tocilizumab for isolated ICANS symptoms, as it has not been shown to mitigate neurologic toxicity and may worsen ICANS 1
• Do not delay lumbar puncture if Grade ≥2 ICANS is present, as this helps exclude infectious or other etiologies 1

Special Considerations for Concurrent CRS and ICANS

• When Grade 2 ICANS occurs with Grade 1 CRS (fever alone), prioritize steroids over tocilizumab, as management of ICANS takes precedence 1
• If both CRS and ICANS are present at Grade ≥2, administer tocilizumab for CRS while simultaneously initiating corticosteroids for ICANS 1