What is the treatment for Cytokine Release Syndrome (CRS)?

Treatment of Cytokine Release Syndrome (CRS)

The treatment of Cytokine Release Syndrome requires a graded approach with anti-IL-6 therapy (tocilizumab) as first-line treatment for moderate to severe cases, followed by corticosteroids for refractory cases. 1

CRS Grading and Classification

• CRS is defined as a "supraphysiologic response following immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells" 2
• Grading system according to ASTCT consensus criteria:
  • Grade 1: Fever ≥38°C without hypotension or hypoxia 1, 2
  • Grade 2: Fever with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min) 1, 2
  • Grade 3: Fever with hypotension requiring vasopressor (with/without vasopressin) and/or hypoxia requiring high-flow oxygen 1
  • Grade 4: Fever with hypotension requiring multiple vasopressors and/or hypoxia requiring positive pressure ventilation 1

Initial Evaluation and Monitoring

• Complete laboratory workup including:
  • CBC, comprehensive metabolic panel, magnesium, phosphorus, CRP, LDH, uric acid, fibrinogen, PT/PTT, and ferritin 1
  • Blood and urine cultures, chest radiograph if fever is present 1
• Continuous cardiac telemetry and pulse oximetry for Grade 2 or higher CRS 1
• Consider echocardiogram to assess cardiac function in severe CRS 1

Treatment Algorithm by CRS Grade

Grade 1 CRS:

• Supportive care with antipyretics and IV hydration 1, 2
• For prolonged CRS (>3 days) or in patients with comorbidities/elderly: Consider tocilizumab 8 mg/kg IV (not exceeding 800 mg) 1, 2
• Empiric broad-spectrum antibiotics if neutropenic 1
• Consider G-CSF if neutropenic 1

Grade 2 CRS:

• Tocilizumab 8 mg/kg IV (not exceeding 800 mg) 1
• May repeat tocilizumab in 8 hours if no improvement; maximum 3 doses in 24 hours, not exceeding 4 doses total 1
• For persistent refractory hypotension after 1-2 doses of tocilizumab: Add dexamethasone 10 mg IV every 12-24 hours 1
• If no improvement within 24 hours after starting anti-IL-6 therapy, manage as Grade 3 1

Grade 3 CRS:

• Tocilizumab as per Grade 2 1
• Dexamethasone 10 mg IV every 6 hours 1
• Transfer to ICU for hemodynamic monitoring 1
• Supplemental oxygen as needed 1
• If refractory, manage as Grade 4 1

Grade 4 CRS:

• Tocilizumab as per Grade 2 1
• Dexamethasone 10 mg IV every 6 hours 1
• If refractory, consider methylprednisolone 1000 mg/day IV for 3 days 1
• If still refractory, consider dosing every 12 hours 1
• ICU care with mechanical ventilation as needed 1

Refractory CRS Management

• For CRS refractory to tocilizumab and steroids, consider:
  • Anakinra (IL-1 receptor antagonist) 1, 2
  • Siltuximab (alternative IL-6 antagonist) 1, 2
  • Clazakizumab (alternative IL-6 antagonist) 1

Special Considerations

• Tocilizumab is FDA-approved for the treatment of CAR T cell-induced severe or life-threatening CRS in adults and pediatric patients 2 years and older 3
• In pediatric patients <30 kg, tocilizumab is dosed at 12 mg/kg 1
• Fever is not required to grade subsequent CRS severity in patients receiving antipyretics; grading is based on hypotension and/or hypoxia 1, 2
• Consider antifungal prophylaxis in patients receiving steroids for CRS 2
• Early intervention with tocilizumab has been shown to prevent progression to severe CRS without compromising CAR T-cell efficacy 4, 5

Important Pitfalls and Caveats

• Delay CAR T-cell infusion in patients with active infection until it is successfully treated or controlled 1
• CRS can be confused with infection; always perform appropriate infectious workup 1
• Corticosteroids may potentially reduce CAR T-cell efficacy, though evidence suggests that short courses do not significantly impact outcomes 1
• CRS may be associated with concurrent immune effector cell-associated neurotoxicity syndrome (ICANS), which requires separate management 1
• Tocilizumab may not be effective for ICANS and may potentially contribute to it 1