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 tocilizumab as first-line therapy for moderate to severe cases, followed by corticosteroids for refractory cases, with management tailored to the severity grade according to ASTCT consensus criteria. 1, 2

Grading of CRS

CRS severity is classified according to the American Society for Transplantation and Cellular Therapy (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
• Grade 3: Fever with hypotension requiring vasopressor (with/without vasopressin) and/or hypoxia requiring high-flow oxygen 1, 2
• Grade 4: Fever with hypotension requiring multiple vasopressors and/or hypoxia requiring positive pressure ventilation 1

Treatment Algorithm by CRS Grade

Grade 1 CRS

• Provide supportive care with antipyretics, IV hydration, and symptomatic management of constitutional symptoms 1
• Consider empiric broad-spectrum antibiotics if neutropenic 1
• For prolonged CRS (>3 days) or in patients with significant comorbidities, consider tocilizumab 8 mg/kg IV (not exceeding 800 mg) 1, 2
• For patients treated with axicabtagene ciloleucel or brexucabtagene autoleucel, consider tocilizumab if symptoms persist >24 hours 1

Grade 2 CRS

• Continue supportive care as per Grade 1 1
• Administer tocilizumab 8 mg/kg IV (not exceeding 800 mg) 1, 3
• Repeat tocilizumab every 8 hours if no improvement, maximum 3 doses in 24 hours or 4 doses total 1
• For persistent hypotension after fluid boluses and tocilizumab, consider dexamethasone 10 mg IV every 12-24 hours 1
• Cardiac monitoring is recommended 1, 2

Grade 3 CRS

• Continue supportive care and admit to ICU 1
• Administer tocilizumab as per Grade 2 1
• Add dexamethasone 10 mg IV every 6 hours 1, 2
• Obtain echocardiogram to assess cardiac function 1, 2
• Provide vasopressors as needed 1

Grade 4 CRS

• Continue supportive care as per Grade 3 plus mechanical ventilation as needed 1
• Administer tocilizumab as per Grade 2 1
• Initiate high-dose methylprednisolone 500 mg IV every 12 hours for 3 days 1
• Follow with tapered steroid regimen: 250 mg IV every 12 hours for 2 days, then 125 mg IV every 12 hours for 2 days, then 60 mg IV every 12 hours until CRS improves to Grade 1 1
• If not improving, consider methylprednisolone 1,000 mg IV twice daily or alternate therapy 1, 2

Management of Refractory CRS

For CRS refractory to tocilizumab and steroids, consider:

• Anakinra (IL-1 receptor antagonist) 1, 2
• Siltuximab (alternative IL-6 antagonist) 1
• Ruxolitinib, cyclophosphamide, or antithymocyte globulin in severe cases 1

Important Considerations and Monitoring

• Tocilizumab is FDA-approved for 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 2
• Fever is not required to grade subsequent CRS severity in patients receiving antipyretics or anticytokine therapy; grading is based on hypotension and/or hypoxia 1, 2
• Monitor complete blood count, comprehensive metabolic panel, C-reactive protein, ferritin, and fibrinogen daily 2, 4
• Perform cardiac monitoring with telemetry and pulse oximetry for Grade 2 or higher CRS 1, 2
• Consider antifungal prophylaxis in patients receiving steroids for CRS treatment 1, 4

Pitfalls and Caveats

• Delay CAR T-cell infusion in patients with active infection until successfully treated 1
• CRS can be confused with infection; always perform appropriate infectious workup 1, 2
• Short courses of tocilizumab and steroids do not significantly impact CAR T-cell efficacy in life-threatening situations 2, 4
• Tocilizumab may not be effective for immune effector cell-associated neurotoxicity syndrome (ICANS), which requires separate management 1, 2
• Patients should remain within 2 hours of the treating center for 4-8 weeks post-therapy 1
• Consider transfer to a specialty center with experience in CAR T toxicity management for moderate to severe CRS 1, 2