The complexities of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain pivotal challenges in the administration of chimeric antigen receptor (CAR) T-cell therapy for hematologic malignancies. Despite significant strides in understanding these conditions, ongoing research continues to refine diagnostic criteria and management strategies. C. Brooke Adams, PharmD, BCOP, a clinical pharmacy specialist at Orlando Health, delved into these evolving standards during her presentation at the 2025 American Society for Transplantation and Cellular Therapy (ASTCT) and Center for International Blood and Marrow Transplant Research (CIBMTR) Tandem Meeting. This article explores the pathophysiology, clinical presentation, diagnostic criteria, and management strategies for CRS and ICANS, highlighting the importance of selecting appropriate CAR T-cell products based on patient risk factors.

CRS and ICANS are critical adverse effects associated with CAR T-cell therapy. These syndromes arise from an overwhelming inflammatory response that disrupts homeostatic mechanisms, leading to systemic inflammation affecting multiple organ systems. CRS is characterized by symptoms such as fever, hypotension, hypoxia, tachycardia, gastrointestinal disturbances, neurological issues, and elevated liver function tests. ICANS, often overlapping with CRS, presents with confusion, dysphagia, ataxia, seizures, motor dysfunction, and cerebral edema in severe cases. The pathophysiology of CRS is better understood compared to ICANS, primarily driven by cytokines like interleukin-6 (IL-6), IL-10, and interferon γ (IFN-γ).

Over the years, diagnostic criteria for CRS have evolved significantly. Early inconsistencies in grading methodologies posed challenges in interpreting clinical trial data. The ASTCT consensus criteria, established in 2019, standardized CRS assessment by incorporating fever, hypotension, and hypoxia as primary parameters. For ICANS, the ASTCT consensus criteria replaced previous grading systems with the Immune Effector Cell-Associated Encephalopathy (ICE) score, evaluating orientation, command-following ability, language function, handwriting, and motor weakness. This harmonized system allows for cross-comparisons between different clinical trials, enhancing our understanding of these toxicities.

The management of CRS revolves around targeting cytokine pathways, particularly IL-6. Tocilizumab, an IL-6 receptor antagonist, and corticosteroids are the mainstay treatments, with early intervention now favored to prevent severe complications. In contrast, ICANS does not respond to tocilizumab, necessitating corticosteroids as the primary therapy. High-dose methylprednisolone is often required for severe cases, with additional therapies under investigation including JAK-STAT pathway inhibitors and IL-1 blockers. Selecting the appropriate CAR T-cell product is crucial, as CD28-based therapies exhibit higher toxicity rates compared to 4-1BB-based therapies, which offer improved persistence and lower neurotoxicity risk.

Several factors influence CRS and ICANS risk, including disease type, tumor burden, CAR T-cell construct, and cell dose. High-risk conditions such as B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) exhibit higher toxicity rates, particularly in patients with aggressive disease and significant tumor burden. Choosing 4-1BB CAR T products for older or comorbid patients can mitigate severe CRS and ICANS risk. Retrospective analyses demonstrate no significant difference in survival outcomes between patients with and without CRS and/or ICANS, underscoring the importance of proactive toxicity management without compromising therapeutic effectiveness.

Selecting appropriate CAR T-cell products based on patient risk factors and implementing timely management strategies ensures optimal outcomes while minimizing treatment-associated toxicities. Continued research and real-world data collection will further refine these approaches, improving the safety and efficacy of CAR T-cell therapy for hematologic malignancies. The future of toxicity management lies in balancing efficacy with patient safety, ensuring that advancements in CAR T-cell therapy continue to benefit those in need.