What are the treatments for Cytokine Release Syndrome (CRS) and neurotoxicity?

From the Guidelines

Treatment for cytokine release syndrome (CRS) and neurotoxicity primarily involves tocilizumab and corticosteroids, with the goal of reducing morbidity, mortality, and improving quality of life. For CRS, tocilizumab (8 mg/kg IV, maximum 800 mg) should be administered promptly when moderate to severe symptoms develop, with additional doses given every 8 hours if needed (maximum 3 doses in 24 hours) 1. Corticosteroids like dexamethasone (10 mg IV every 6 hours) are added for refractory cases or severe CRS. For neurotoxicity, dexamethasone is the first-line treatment (10 mg IV every 6 hours), with higher doses of methylprednisolone (1000 mg/day) for severe cases 1.

Key Considerations

• Supportive care is essential for both conditions, including vasopressors for hypotension, oxygen for hypoxemia, and seizure prophylaxis with levetiracetam (500-750 mg twice daily) for neurotoxicity.
• These complications typically occur after CAR T-cell therapy or certain immunotherapies, with CRS manifesting as fever, hypotension, and organ dysfunction, while neurotoxicity presents as confusion, aphasia, or seizures.
• Early recognition and intervention are crucial, as prompt treatment significantly improves outcomes and reduces mortality.
• Treatment should be tapered gradually once symptoms resolve to avoid recurrence.

Management by Grade

• For Grade 1 CRS, supportive care and tocilizumab (8 mg/kg IV, maximum 800 mg) may be considered if symptoms persist for more than 24 hours 1.
• For Grade 2-4 CRS, tocilizumab and corticosteroids are recommended, with the addition of ICU care for Grade 3-4 CRS 1.
• For neurotoxicity, dexamethasone is the first-line treatment, with higher doses of methylprednisolone for severe cases, and ICU care is recommended for Grade 3-4 neurotoxicity 1.

Special Considerations

• Antifungal prophylaxis should be strongly considered in patients receiving steroids for the treatment of CRS or neurotoxicity 1.
• Patients with grade 3 neurotoxicity or higher should receive ICU care and undergo assessment for papilledema or other signs of elevated intracranial pressure 1.

From the FDA Drug Label

In a retrospective analysis of pooled outcome data from multiple clinical trials 45 patients were treated with tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T-cell-induced CRS A median of 1 dose of tocilizumab (range, 1-4 doses) was administered.

The treatment for Cytokine Release Syndrome (CRS) and neurotoxicity using tocilizumab (IV) is administered at a dose of 8 mg/kg (12 mg/kg for patients less than 30 kg), with or without additional high-dose corticosteroids, with a median of 1 dose (range, 1-4 doses) administered 2.

• Key points:
  • Tocilizumab is used to treat severe or life-threatening CAR T-cell-induced CRS.
  • The dose of tocilizumab is 8 mg/kg (12 mg/kg for patients less than 30 kg).
  • Additional high-dose corticosteroids may be used in conjunction with tocilizumab.
  • A median of 1 dose of tocilizumab is administered, with a range of 1-4 doses.

From the Research

Treatment for CRS and Neurotoxicity

• The current treatment guidelines for Cytokine Release Syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) include the use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids 3, 4.
• Anakinra, an IL-1 receptor antagonist, has emerged as a promising agent for the treatment of refractory CRS and ICANS, with studies showing its safety and efficacy in CAR-T therapy recipients 3, 5.
• The optimal management of severe and/or refractory CRS/ICANS remains ill-defined, and prospective comparative studies are needed to confirm the findings of anakinra treatment 5.
• Other treatment options, such as siltuximab, ruxolitinib, dasatinib, and cyclophosphamide, have been reported on an anecdotal basis for refractory CRS 3.
• Tocilizumab treatment has also been used to treat CRS in hospitalized patients with coronavirus disease 2019 (COVID-19), with observed improvements in survival and clinical outcomes 6.

Anakinra Treatment

• Anakinra treatment was feasible and safe, with discontinuation of therapy due to anakinra-related side effects reported in only 3 patients (7%) 5.
• The overall response rate (ORR) to CAR-T therapy was 77%, and the cumulative incidence of treatment-related mortality (TRM) was 7% at 28 days and 23% at 60 days after CAR-T infusion 5.
• Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM 5.

Emerging Pharmacotherapies

• Emerging pharmacotherapies for CRS, neurotoxicity, and hemophagocytic lymphohistiocytosis-like syndrome due to CAR T cell therapy include IL-1 receptor antagonism, IFNγ and IL-6 neutralizing antibodies, and janus kinase inhibitors 7.
• Novel pharmacologic targets and safety features engineered into CAR T cells themselves may also reduce toxicities 7.