Managing CRS and ICANS in Real-World Practice: What to Know About CAR T and Bispecific Toxicities

Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) remain the most clinically significant toxicities associated with T-cell–engaging therapies, including chimeric antigen receptor (CAR) T-cell therapies and CD20 × CD3 bispecific antibodies. Current real-world data suggest that while these toxicities are common, standardized step-up dosing, early intervention protocols, and multidisciplinary management have significantly reduced severe outcomes. With the expansion of these therapies into earlier lines of hematologic malignancy treatment, there is a growing need for toxicity prevention, recognition, and management.^1,2

CRS and ICANS in T-Cell–Engaging Therapies

CRS and ICANS are immune-mediated toxicities driven by rapid T-cell activation and cytokine release following engagement with malignant B cells. CRS is commonly presented through adverse effects such as fever, hypotension, hypoxia, and elevated inflammatory markers, while ICANS is displayed through confusion, aphasia, seizures, or decreased level of consciousness.³

These toxicities are most frequently associated with CAR T-cell therapies such as tisagenlecleucel (Kymriah; Novartis Pharmaceuticals Corporation), axicabtagene ciloleucel (Yescarta; Kite Pharma Inc), and lisocabtagene maraleucel (Breyanzi; Juno Therapeutics, Inc), as well as bispecific antibodies including epcoritamab (Epkinly; Genmab/AbbVie) and glofitamab (Columvi; Genentech, Inc).¹

It is crucial to understand the pharmacology of these agents, as their mechanism—redirecting cytotoxic T cells toward CD19- or CD20-expressing malignant cells—directly underpins the inflammatory cascade responsible for these toxicities.

Clinical Trial Foundations and Toxicity Patterns

Data from trials across CAR T-cell therapies and bispecific antibodies have consistently demonstrated that CRS occurs in most patients, although most cases are grade 1 to 2 and manageable with supportive care or targeted interventions. In the ZUMA-1 trial (NCT02348216) evaluating axicabtagene ciloleucel, CRS was found in over 90% of patients, with severe cases significantly reduced after protocol refinements and earlier use of tocilizumab (Actemra; Genentech, Inc).⁴

Similarly, in the EPCORE NHL-1 study (NCT03625037) of epcoritamab, CRS was observed frequently, but was predominantly low grade due to step-up dosing. Although CRS rates were generally lower in bispecific antibody trials than those reported with CAR T-cell therapies, CRS remains a critical safety concern, particularly in heavily pretreated patients.⁵

Across data, standardized toxicity grading systems, such as the American Society for Transplantation and Cellular Therapy consensus criteria, have improved comparability and guided intervention timing, underscoring the necessity of early recognition and protocol-driven management.³

Practical CRS and ICANS Management Strategies

In the context of clinical practice, CRS management is primarily driven by early recognition and rapid intervention. In mild cases, first-line treatment includes antipyretics, intravenous fluids, and oxygen support, while in moderate to severe circumstances, CRS typically requires IL-6 inhibition with tocilizumab and corticosteroids.³

Managing ICANS is more complex due to its neurologic presentation and lack of a direct cytokine-targeted therapy. High-dose corticosteroids continue as the cornerstone of treatment, with supportive measures such as seizure prophylaxis and frequent neurologic assessments.³

Step-up dosing strategies using agents such as glofitamab and epcoritamab progressively reduced severe CRS incidence in real-world settings by gradually increasing T-cell engagement intensity, enabling immune adaptation.⁵

Crucially, outpatient administration of certain bispecific antibodies has shifted the weight of toxicity monitoring toward structured ambulatory protocols, requiring clear escalation pathways and patient education.

CRS and ICANS are predictable, although potentially severe, toxicities that are associated with CAR T-cell therapies and bispecific antibodies. However, real-world implementation of step-up dosing, standardized grading systems, and rapid intervention protocols has significantly improved safety outcomes.

REFERENCES

1. Neelapu, SS, Locke, FL, Bartlett, NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/nejmoa1707447

2. Thieblemont C, Karimi YH, Ghesquieres H, et al. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia. 2024;38(12):2653-2662. doi:10.1038/s41375-024-02410-8

3. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758

4. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7

5. Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase I trial. J Clin Oncol. 2021;39(18):1959-1970. doi:10.1200/JCO.20.03175