Immune Effector Cell–Associated Neurotoxicity Syndrome

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), formerly known as CRES, is a clinical and neuropsychiatric syndrome that can occur following immunotherapy.

Key Characteristics

  • Associated Therapies: It is most frequently triggered by CAR T-cell therapies (like tisagenlecleucel) and the bispecific antibody blinatumomab.
  • Clinical Presentation: The symptoms are “pleomorphic” and overlapping, commonly including lethargy, confusion, slurred speech (aphasia), tremors, and in severe cases, seizures or altered consciousness.
  • Assessment: Clinicians use the ICE (Immune Effector Cell Encephalopathy) score to evaluate mental status and assign a grade from 1 to 4 based on the ASTCT Consensus Grading.
  • Management: Dexamethasone is the treatment of choice for ICANS. Unlike Cytokine Release Syndrome (CRS), tocilizumab is generally avoided for isolated neurotoxicity unless concurrent CRS is present.
  • Frequently occurs alongside Cytokine Release Syndrome (CRS), but may appear independently.

Onset & Risk Factors

  • Onset: Typically 4–10 days post–CAR T infusion (after CRS begins).
  • Risk factors:
    • Severe CRS
    • High tumor burden
    • CD28-based CAR constructs (earlier generation)
    • High-dose CAR T expansion

Grading (ASTCT Consensus Criteria)

Grade Findings
1 Mild confusion, word-finding difficulty, impaired handwriting; ICE score 7–9
2 Moderate impairment, ICE score 3–6
3 Severe impairment, ICE score 0–2; seizures responsive to meds
4 Life-threatening: obtundation, coma, unarousable, ↑ICP, cerebral edema

Monitoring

  • Baseline neuro exam + ICE score daily during hospitalization after CAR T.
  • If ICANS suspected → neuro checks q4h, EEG, MRI, lumbar puncture (to exclude infection or leukemic meningitis).

Management

  1. Supportive care
    • Seizure prophylaxis: Levetiracetam is often given prophylactically.
    • Avoid CNS depressants unless needed.
  2. Steroids (mainstay for ICANS)
    • Grade ≥2: Dexamethasone 10 mg IV q6h or methylprednisolone 1–2 mg/kg/day.
    • Taper when symptoms improve.
  3. Tocilizumab (IL-6R blocker)
    • Very effective for CRS, but not effective for isolated ICANS (doesn’t cross the BBB).
    • If CRS + ICANS → tocilizumab for CRS + steroids for neurotoxicity.
  4. Severe cases
    • ICU transfer, ICP management (mannitol, hyperventilation, neurology consult).

Oncology Pharmacy Pearls

  • Differentiate CRS vs ICANS: both can coexist, but ICANS needs steroids (tocilizumab won’t help).
  • Always start seizure prophylaxis in CAR T patients (levetiracetam).
  • Steroids do not reduce CAR T efficacy significantly if used appropriately for toxicity.
  • Document ICE score daily for early recognition.
  • High vigilance in first 2 weeks post-infusion (highest risk window).

Takeaway:

ICANS = neurotoxicity from CAR T/bispecific therapy → graded by ICE score → managed primarily with steroids (not tocilizumab unless CRS present too) + seizure prophylaxis/supportive care.

Links