What is the best approach for managing severe cytokine release syndrome (CRS) in a patient who has been given anakinra (Interleukin-1 receptor antagonist) and where the primary team is hesitant to administer high-dose steroids?

Management of Severe Cytokine Release Syndrome with Anakinra

For severe cytokine release syndrome (CRS) when high-dose steroids are not an option, anakinra is recommended as an effective alternative therapy.

Assessment and Grading

• CRS is classified according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system, with severity determined by fever, hypotension, and hypoxia 1
• Grade 3 CRS presents with temperature ≥38°C, hypotension requiring vasopressors, and/or hypoxia requiring high-flow oxygen 1
• Grade 4 CRS presents with temperature ≥38°C, hypotension requiring multiple vasopressors, and/or hypoxia requiring positive pressure ventilation 1

First-Line Treatment Options

• Tocilizumab is the first-line therapy for moderate to severe CRS at 8 mg/kg IV (maximum 800 mg), repeatable every 8 hours if no improvement 2, 1
• For Grade 3-4 CRS, tocilizumab should be administered with corticosteroids if possible 2
• If the primary team is hesitant to use high-dose steroids, consider:
  • Administering tocilizumab first, as this may provide sufficient response 2, 1
  • Using a lower dose of corticosteroids if any steroids are acceptable 2

Anakinra as Alternative Therapy

• Anakinra (IL-1 receptor antagonist) is recommended for CRS refractory to tocilizumab and/or when steroids cannot be used 2
• Dosing recommendations:
  • Start with 100 mg subcutaneous or IV 2-4 times daily 2
  • Higher doses (>200 mg/day IV) have been associated with faster CRS resolution and lower treatment-related mortality compared to lower doses 3
  • Doses up to 12 mg/kg/day IV have been safely administered 3

Monitoring and Supportive Care

• Transfer patient to ICU for close monitoring if presenting with Grade 3-4 CRS 2, 4
• Perform daily laboratory tests including CBC, comprehensive metabolic panel, CRP, ferritin, and fibrinogen 4
• Provide supplemental oxygen as needed to maintain oxygen saturation >92% 4
• Administer IV fluids for volume resuscitation if hypotensive, and consider vasopressors if hypotension persists 4
• Monitor for infections, as both tocilizumab and anakinra increase infection risk 4, 5

Additional Treatment Options

• If CRS remains refractory despite anakinra, consider other agents:
  • Siltuximab (alternative IL-6 antagonist) 2, 1
  • Ruxolitinib (JAK1/2 inhibitor) 2
  • Cyclophosphamide 2
  • Extracorporeal cytokine adsorption with continuous renal replacement therapy 2
  • Intravenous immunoglobulin (IVIG) 2
  • Antithymocyte globulin 2

Important Considerations

• Anakinra treatment has shown an overall response rate of 77% after CAR T-cell therapy, suggesting limited impact on CAR T-cell efficacy 3
• Anakinra has demonstrated rapid reductions in fever and inflammatory cytokines associated with CRS 6
• Antifungal prophylaxis should be strongly considered in patients receiving immunosuppressive therapy for CRS 2, 1
• Empiric broad-spectrum antibiotics should be administered if neutropenic 2
• While anakinra is generally well-tolerated, discontinuation due to side effects occurs in approximately 7% of patients 3

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
• Avoid using GM-CSF, as it is not recommended in the setting of CAR T-cell therapy 2
• Do not rely solely on fever for grading CRS in patients receiving antipyretics or anticytokine therapy; instead, use hypotension and/or hypoxia for grading 2, 1
• Be vigilant for concurrent immune effector cell-associated neurotoxicity syndrome (ICANS), which may require different management strategies 2