What is the treatment approach for patients with severe Cytokine Release Syndrome (CRS) or sepsis, including the use of medications like tocilizumab (Interleukin-6 receptor antagonist) and hemoperfusion?

Management of Severe Cytokine Release Syndrome (CRS) and Sepsis

For severe Cytokine Release Syndrome (CRS) or sepsis, the recommended treatment approach includes tocilizumab as first-line therapy, followed by corticosteroids for refractory cases, with consideration of hemoperfusion techniques for cases unresponsive to standard therapies. 1

CRS Classification and Grading

• 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
• The American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system classifies CRS as:
  • Grade 1: Temperature ≥38°C without hypotension or hypoxia 2
  • Grade 2: Temperature ≥38°C with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min) 2
  • Grade 3: Temperature ≥38°C with hypotension requiring vasopressor and/or hypoxia requiring high-flow oxygen 2
  • Grade 4: Temperature ≥38°C with hypotension requiring multiple vasopressors and/or hypoxia requiring positive pressure ventilation 2

Initial Assessment and Monitoring

• Complete laboratory workup including:
  • CBC, CMP, magnesium, phosphorus, CRP, LDH, uric acid, fibrinogen, PT/PTT, and ferritin 1
  • Blood and urine cultures, chest radiograph if fever is present 1
  • Consider screening for CMV and EBV 1
• Cardiac monitoring with continuous telemetry and pulse oximetry for Grade 2+ CRS 1
• Consider echocardiogram to assess cardiac function in severe CRS 1
• Consider chest or abdominal CT imaging, brain MRI, and/or lumbar puncture 1

Treatment Algorithm by CRS Grade

Grade 1 CRS

• Supportive care with antipyretics, IV hydration, and symptomatic management 1
• Consider empiric broad-spectrum antibiotics if neutropenic 1
• Consider tocilizumab for prolonged CRS (>3 days) or in patients with significant comorbidities 2

Grade 2 CRS

• Tocilizumab 8 mg/kg IV (maximum 800 mg) 1
• Can repeat every 8 hours if no improvement; maximum 3 doses in 24 hours, 4 doses total 1
• Consider dexamethasone 10 mg IV every 12-24 hours for persistent refractory hypotension 1
• Cardiac monitoring and IV fluid boluses as needed 1

Grade 3 CRS

• Tocilizumab as per Grade 2 if maximum dose not reached within 24-hour period 1
• Add dexamethasone 10 mg IV every 6 hours 1
• Transfer patient to ICU 1
• Vasopressors as needed 1
• Supplemental oxygen as required 1

Grade 4 CRS

• Tocilizumab as per Grade 2 if maximum dose not reached within 24-hour period 1
• High-dose methylprednisolone: 500 mg IV every 12 hours for 3 days, followed by taper 1
• If not improving, consider methylprednisolone 1,000 mg IV twice daily 1
• Mechanical ventilation as needed 1

Management of Refractory CRS

• For cases refractory to tocilizumab and steroids, consider:
  • Anakinra (IL-1 receptor antagonist) 1, 3
  • Siltuximab (alternative IL-6 antagonist) 1, 4
  • Ruxolitinib 1
  • Cyclophosphamide 1
  • Intravenous immunoglobulin (IVIG) 1
  • Antithymocyte globulin 1
  • Extracorporeal cytokine adsorption with continuous renal replacement therapy (hemoperfusion) 1, 5

Hemoperfusion for Severe CRS/Sepsis

• CytoSorb hemadsorption has shown benefit in severe, refractory CRS cases 5
• Consider implementing hemoperfusion with CytoSorb in conjunction with sustained low-efficiency daily diafiltration for patients with:
  • Grade 4 CRS unresponsive to tocilizumab and high-dose corticosteroids 5
  • Severe hemodynamic instability requiring multiple vasopressors 5
  • Evidence of multi-organ dysfunction 5

Special Considerations

• 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 6, 7
• In pediatric patients <30 kg, tocilizumab is dosed at 12 mg/kg 1, 7
• 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, 4
• Consider antifungal prophylaxis in patients receiving steroids for CRS 1
• Earlier steroid use may reduce CAR T-cell treatment-related CRS and neurologic events for certain products 1

Important Pitfalls to Avoid

• Do not delay appropriate treatment due to concerns about CAR T-cell efficacy, as untreated severe CRS can be life-threatening 4
• Do not use GM-CSF in the setting of CAR T-cell therapy 1
• Be vigilant for concurrent immune effector cell-associated neurotoxicity syndrome (ICANS), which may require different management strategies 4
• Different subtypes of cytokine storm may respond differently to tocilizumab - in macrophage activation syndrome (MAS), tocilizumab may decrease mortality, while in standard CRS, careful monitoring is needed 8