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Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are two of the most serious adverse events associated with bispecific antibody (BsAb) therapy:

• CRS is an exaggerated systemic inflammatory response triggered by the effects of T-cell engaging therapies like BsAbs, causing release of inflammatory cytokines. CRS symptoms range from mild flu-like symptoms to severe multi-organ failure[1].

• ICANS is neurologic toxicity caused by the inflammatory actions of cytokines released after BsAb therapy, disrupting the blood-brain barrier and causing accumulation of cytokines in the central nervous system. Symptoms include headache, confusion, hallucinations, tremors, ataxia, aphasia, seizures, and cerebral edema[1][2].

• ICANS typically develops within 2-3 days after onset of CRS, though it can occur concurrently or independently. CRS does not always precede ICANS[1][2][4].

• Rates of CRS and ICANS vary across BsAb trials, but are generally lower than with CAR-T cell therapies. In one study, the CRS rate was 17.5% (all grade 1-2) and ICANS rate was 8% (3% grade 3-4). Another reported 14.5% overall neurotoxicity, with 3% ICANS all grade 1-2[4].

• Prompt diagnosis and management is critical to prevent irreversible damage. Supportive care includes antipyretics, fluids, vasopressors, antibiotics, and respiratory support. Immunosuppression with steroids is the mainstay for moderate-severe CRS and ICANS. Tocilizumab, an IL-6 inhibitor, can be used for severe CRS but is less effective for established ICANS[2][4].

• Temporary or permanent BsAb discontinuation may be necessary for severe toxicity. Consultation with specialists is recommended for management[2].

In summary, CRS and ICANS are serious but manageable complications of BsAb therapy that require close monitoring and prompt treatment to optimize outcomes.

Citations: [1] https://www.va.gov/formularyadvisor/DOC_PDF/CRE_Bispecific_Antibody_CRS_and_ICANS_Neurotoxicity_Guidance_Feb2024.pdf [2] https://www.ncbi.nlm.nih.gov/books/NBK603709/ [3] https://www.nature.com/articles/s41408-024-00989-w [4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10378049/ [5] https://resources.advancedpractitioner.com/multiple-myeloma/focus-on-bsabs/management-of-adverse-effects-in-patients-with-multiple-myeloma-treated-with-bispecific-antibodies/