COMPLICATIONS OF CAR-T CELL THERAPY IN HEMATOLOGIC MALIGNANCIES — A CURRENT CLINICAL REVIEW OF TOXICITIES AND MANAGEMENT STRATEGIES
DOI:
https://doi.org/10.31435/ijitss.2(50).2026.5565Keywords:
Chimeric Antigen Receptor T-cell Therapy (CAR-T); Cytokine Release Syndrome (CRS); Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS); Hematologic Toxicity; Immunotherapy; Biomarkers; B-cell Aplasia; Infectious ComplicationsAbstract
Chimeric antigen receptor T-cell (CAR-T) therapy represents an innovative treatment for relapsed or refractory hematologic malignancies, such as acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Despite its significant clinical efficacy, CAR-T therapy is associated with a spectrum of toxicities resulting from the activation of the immune system.
This review summarizes current understanding of the mechanism, clinical presentation, and management of CAR-T–related complications. Particular attention is given to cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic toxicities, and infectious complications, as well as long-term effects such as B-cell aplasia and hypogammaglobulinemia.
Additionally, predictive biomarkers, such as inflammatory markers, cytokine profiles, and CAR-T expansion kinetics, are examined in relation to risk stratification and early treatment strategies. Understanding these mechanisms is necessary to improve patient safety and optimize clinical outcomes.
In conclusion, although CAR-T therapy is a significant progress in hemato-oncology, additional research is required to improve toxicity prediction models and develop safer, next-generation cellular therapies.
References
Abramson, J. S., Palomba, M. L., Gordon, L. I., et al. (2020). Lisocabtagene maraleucel in relapsed or refractory large B-cell lymphoma. The Lancet, 396(10254), 839–852. https://doi.org/10.1016/S0140-6736(20)31366-0
European Medicines Agency. (2014). Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells.
Fried, S., Avigdor, A., Bielorai, B., et al. (2019). Early and late hematologic toxicity following CD19 CAR T cells. Biology of Blood and Marrow Transplantation, 25(3), 231–238. https://doi.org/10.1016/j.bbmt.2018.09.031
Giavridis, T., van der Stegen, S. J. C., Eyquem, J., et al. (2018). CAR T-cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nature Medicine, 24(6), 731–738. https://doi.org/10.1038/s41591-018-0041-7
Gorovits, B., & Koren, E. (2019). Immunogenicity of chimeric antigen receptor T-cell therapeutics. BioDrugs, 33(3), 275–284.
Gust, J., et al. (2017). Endothelial activation and blood–brain barrier disruption in neurotoxicity after CAR T-cell therapy. Blood, 130(18), 218–230.
Hay, K. A., Hanafi, L. A., Li, D., et al. (2017). Kinetics and biomarkers of severe cytokine release syndrome after CD19 CAR T-cell therapy. Blood, 130(21), 2295–2306.
Hill, J. A., Li, D., Hay, K. A., et al. (2018). Infectious complications of CD19-targeted CAR T-cell therapy. Blood, 131(1), 121–130.
Hill, J. A., & Seo, S. K. (2020). How I prevent infections in patients receiving CAR T-cell therapy. Blood, 136(8), 925–935.
Jain, T., Knezevic, A., Pennisi, M., et al. (2020). Hematologic toxicity and outcomes after CAR T-cell therapy. Blood Advances, 4(16), 3770–3780.
June, C. H., et al. (2018). CAR T cell immunotherapy for human cancer. Science, 359(6382), 1361–1365.
Lee, D. W., et al. (2014). Current concepts in the diagnosis and management of cytokine release syndrome. Blood, 124(2), 188–195.
Lee, D. W., et al. (2019). ASTCT consensus grading for cytokine release syndrome and neurologic toxicity. Biology of Blood and Marrow Transplantation, 25(4), 625–638.
Locke, F. L., Ghobadi, A., Jacobson, C. A., et al. (2019). Long-term safety and activity of axicabtagene ciloleucel. The Lancet Oncology, 20(1), 31–42.
Mackensen, A., Müller, F., Mougiakakos, D., et al. (2022). Anti-CD19 CAR T-cell therapy for lupus. Nature Medicine, 28, 2124–2132.
Maude, S. L., Laetsch, T. W., Buechner, J., et al. (2018). Tisagenlecleucel in acute lymphoblastic leukemia. The New England Journal of Medicine, 378(5), 439–448.
Muhammad, N., Mao, Q., & Xia, H. (2017). CAR T-cells for cancer therapy. Biotechnology & Genetic Engineering Reviews, 33(1), 190–226.
Munshi, N. C., et al. (2021). Idecabtagene vicleucel in multiple myeloma. The New England Journal of Medicine, 384(8), 705–716.
Nastoupil, L. J., Jain, M. D., Spiegel, J. Y., et al. (2020). Real-world CAR T-cell outcomes. Journal of Clinical Oncology, 38(27), 3119–3128.
Neelapu, S. S., Locke, F. L., Bartlett, N. L., et al. (2017). Axicabtagene ciloleucel in lymphoma. The New England Journal of Medicine, 377(26), 2531–2544.
Neelapu, S. S., Tummala, S., Kebriaei, P., et al. (2018). CAR T-cell toxicities. The New England Journal of Medicine, 378(2), 147–159.
Neelapu, S. S., et al. (2023). Five-year follow-up of ZUMA-1. Blood, 141(19), 2307–2315.
Norelli, M., Camisa, B., Barbiera, G., et al. (2018). IL-1 and IL-6 in cytokine release syndrome. Nature Medicine, 24(6), 739–748.
Park, J. H., Rivière, I., Gonen, M., et al. (2018). Long-term follow-up of CAR T-cell therapy in acute lymphoblastic leukemia. The New England Journal of Medicine, 378(5), 449–459.
Pennisi, M., Jain, T., Santomasso, B. D., et al. (2020). CAR T-cell toxicity grading systems. Blood Advances, 4(15), 3883–3892.
Rubin, D. B., et al. (2019). Neurologic toxicity after CAR T-cell therapy. Blood, 134(23), 1935–1945.
Sadelain, M., Brentjens, R., & Rivière, I. (2013). CAR design principles. Cancer Discovery, 3(4), 388–398.
Sadelain, M., Rivière, I., & Riddell, S. (2017). Therapeutic T-cell engineering. Cancer Discovery, 7(10), 1132–1144.
Santomasso, B. D., et al. (2018). Neurotoxicity correlates. Cancer Discovery, 8(8), 958–971.
Schuster, S. J., et al. (2019). Tisagenlecleucel in diffuse large B-cell lymphoma. The New England Journal of Medicine, 380(1), 45–56.
Sermer, D., & Brentjens, R. (2019). CAR T-cell therapy. Hematology/Oncology, 37(S1), 95–100.
Siegler, E. L., & Kenderian, S. S. (2020). Neurotoxicity and cytokine release syndrome. Frontiers in Immunology, 11, 1973.
Turtle, C. J., Hanafi, L. A., Berger, C., et al. (2016). CAR T-cell persistence and toxicity. Journal of Clinical Investigation, 126(6), 2123–2138.
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Copyright (c) 2026 Weronika Wagner, Patryk Twardy , Jakub Białożyt, Anna Dędniak, Maciej Gutarowicz, Patryk Modelewski, Kaja Nieradka, Krystyna Klahs, Michał Armatys, Maciej Muraszko-Kuźma
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