What are the most critical CRS types and their treatment?

Critical CRS Types and Their Management

Cytokine Release Syndrome (CRS) is primarily managed with tocilizumab (IL-6 antagonist) for lower-grade CRS and with corticosteroids for refractory, prolonged, or higher-grade CRS, with treatment escalation based on severity. 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." 1 The American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading system is recommended:

• Grade 1: Temperature ≥38°C without hypotension or hypoxia 1
• Grade 2: Temperature ≥38°C with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min) 1
• Grade 3: Temperature ≥38°C with hypotension requiring vasopressor (with/without vasopressin) and/or hypoxia requiring high-flow oxygen delivery 1
• Grade 4: Temperature ≥38°C with hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure ventilation 1

Management Algorithm by CRS Grade

Grade 1 CRS Management

• Supportive care with antipyretics, IV hydration, and symptom management 1
• For prolonged CRS (>3 days) or in patients with significant comorbidities: consider tocilizumab 8 mg/kg IV (not exceeding 800 mg) 1
• Product-specific considerations:
  • For axicabtagene ciloleucel/brexucabtagene autoleucel: consider tocilizumab if symptoms persist >24 hours 1
  • For lisocabtagene/idecabtagene: consider tocilizumab plus dexamethasone 10 mg for early-onset CRS (<72 hours) 1

Grade 2 CRS Management

• Tocilizumab 8 mg/kg IV (not exceeding 800 mg), repeatable after 8 hours if no improvement 1
• Maximum: 3 doses in 24 hours, 4 doses total 1
• Consider dexamethasone 10 mg IV every 12-24 hours for persistent hypotension after 1-2 doses of tocilizumab 1
• Cardiac monitoring until resolution to grade 1 or less 1
• For persistent hypotension after fluid boluses and tocilizumab: start vasopressors, transfer to ICU, obtain echocardiogram 1

Grade 3 CRS Management

• Continue tocilizumab as in Grade 2 1
• Dexamethasone 10 mg IV every 6 hours 1
• Transfer to ICU, obtain echocardiogram, implement hemodynamic monitoring 1
• Provide supplemental oxygen, IV fluids, and vasopressors as needed 1

Grade 4 CRS Management

• Continue tocilizumab as in Grade 2 1
• High-dose methylprednisolone: 500 mg IV every 12 hours for 3 days, followed by taper (250 mg IV q12h for 2 days, 125 mg IV q12h for 2 days, 60 mg IV q12h until improvement to Grade 1) 1
• If refractory, consider methylprednisolone 1,000 mg IV twice daily or alternative therapies 1
• Mechanical ventilation as needed 1

Alternative Therapies for Refractory CRS

For CRS refractory to tocilizumab and steroids, consider:

• Anakinra (IL-1 receptor antagonist) 1
• Siltuximab (alternative IL-6 antagonist) 1
• Ruxolitinib 1
• Cyclophosphamide 1
• Antithymocyte globulin 1
• Extracorporeal cytokine adsorption with continuous renal replacement therapy 1

Important Monitoring and Supportive Care

• Laboratory monitoring: CBC, CMP, magnesium, phosphorus, CRP, LDH, uric acid, fibrinogen, PT/PTT, ferritin 1
• Infection assessment: Blood and urine cultures, chest radiograph if fever present 1
• Cardiac monitoring: For Grade 2+ CRS, implement continuous cardiac telemetry and pulse oximetry 1
• Consider screening: CMV and EBV 1
• Imaging: Consider chest/abdominal CT, brain MRI, and/or lumbar puncture as indicated 1

Special Considerations

• Fever is not required to grade subsequent CRS severity in patients receiving antipyretics or anticytokine therapy; instead, grading is based on hypotension and/or hypoxia 1
• 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
• CRS may be associated with cardiac, hepatic, and/or renal dysfunction 1
• FDA approval of tocilizumab for CAR T-cell-induced CRS was based on a 69% response rate in patients with severe or life-threatening CRS 2

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS is the second major complication of CAR T-cell therapy, often occurring concurrently with or shortly after CRS 1. Symptoms include encephalopathy, aphasia, altered consciousness, cognitive impairment, motor weakness, seizures, and rarely cerebral edema 1. Management is primarily supportive with corticosteroids as the mainstay of treatment 1.