Abstract
Chimeric antigen receptor (CAR) T-cell therapy has ushered in a transformative era in the management of relapsed/refractory hematologic malignancies. The extensive phase II trials targeting relapsed/refractory non-Hodgkin lymphoma, including diverse subtypes such as diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, along with multiple myeloma and B-cell acute lymphoblastic leukemia, have culminated in the endorsement of various CAR T-cell products for these specific indications by the US Food and Drug Administration. Although CAR T-cell therapy has achieved remarkable success, it is important to recognize that this innovative approach often gives rise to notable toxicities and is frequently associated with a distinctive pattern of adverse effects. Advanced practice providers, including advanced practice nurses and physician associates, involved in the care of these patients should be able to recognize these toxicities and be versed in treatment strategies to mitigate their impact.
References
Abramson, J. S., Palomba, M. L., Gordon, L. I., Lunning, M. A., Wang, M., Arnason, J.,…Siddiqi, T. (2020). Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet, 396(10254), 839–852. https://doi.org/10.1016/s0140-6736(20)31366-0
Baird, J. H., Epstein, D. J., Tamaresis, J. S., Ehlinger, Z., Spiegel, J. Y., Craig, J.,...Sidana, S. (2021). Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma. Blood Advances, 5(1), 143–155. https://doi.org/10.1182/bloodadvances.2020002732
Berdeja, J. G., Madduri, D., Usmani, S. Z., Jakubowiak, A., Agha, M., Cohen, A. D.,...Jagannath, S. (2021). Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet, 398(10297), 314–324. https://doi.org/10.1016/s0140-6736(21)00933-8
Beyar-Katz, O., Perry, C., On, Y. B., Amit, O., Gutwein, O., Wolach, O.,...Ram, R. (2022). Thrombopoietin receptor agonist for treating bone marrow aplasia following anti-CD19 CAR-T cells-single-center experience. Annals of Hematology, 101(8), 1769–1776. https://doi.org/10.1007/s00277-022-04889-6
Bupha-Intr, O., Haeusler, G., Chee, L., Thursky, K., Slavin, M., & Teh, B. (2021). CAR-T cell therapy and infection: A review. Expert Review of Anti-Infective Therapy, 19(6), 749–758. https://doi.org/10.1080/14787210.2021.1855143
Celgene Corporation. (2021). Abecma (idecabtagene vicleucel) package insert. https://www.fda.gov/media/147055/download?attachment
Chakraborty, R., Hill, B. T., Majeed, A., & Majhail, N. S. (2021). Late effects after chimeric antigen receptor T cell therapy for lymphoid malignancies. Transplantation and Cellular Therapy, 27(3), 222–229. https://doi.org/10.1016/j.jtct.2020.10.002
Chekol Abebe, E., Yibeltal Shiferaw, M., Tadele Admasu, F., & Asmamaw Dejenie, T. (2022). Ciltacabtagene autoleucel: The second anti-BCMA CAR T-cell therapeutic armamentarium of relapsed or refractory multiple myeloma. Frontiers in Immunology, 13, 991092. https://doi.org/10.3389/fimmu.2022.991092
Chen, X., Li, P., Tian, B., & Kang, X. (2022). Serious adverse events and coping strategies of CAR-T cells in the treatment of malignant tumors. Frontiers in Immunology, 13, 1079181. https://doi.org/10.3389/fimmu.2022.1079181
Cohen, A. D., Parekh, S., Santomasso, B. D., Gállego Pérez-Larraya, J., van de Donk, N., Arnulf, B.,...Jagannath, S. (2022). Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies. Blood Cancer Journal, 12(2), 32. https://doi.org/10.1038/s41408-022-00629-1
El Chaer, F., Auletta, J. J., & Chemaly, R. F. (2022). How I treat and prevent COVID-19 in patients with hematologic malignancies and recipients of cellular therapies. Blood, 140(7), 673–684. https://doi.org/10.1182/blood.2022016089
Frey, N., & Porter, D. (2019). Cytokine release syndrome with chimeric antigen receptor T cell therapy. Biology of Blood and Marrow Transplantation, 25(4), e123–e127. https://doi.org/10.1016/j.bbmt.2018.12.756
Gea-Banacloche, J. C. (2023). Infectious complications of chimeric antigen receptor (CAR) T-cell therapies. Seminars in Hematology, 60(1), 52–58. https://doi.org/10.1053/j.seminhematol.2023.02.003
Gudiol, C., Lewis, R. E., Strati, P., & Kontoyiannis, D. P. (2021). Chimeric antigen receptor T-cell therapy for the treatment of lymphoid malignancies: Is there an excess risk for infection? The Lancet Haematology, 8(3), e216–e228. https://doi.org/10.1016/s2352-3026(20)30376-8
Haidar, G., Dorritie, K., Farah, R., Bogdanovich, T., Nguyen, M. H., & Samanta, P. (2020). Invasive mold infections after chimeric antigen receptor-modified T-cell therapy: A case series, review of the literature, and implications for prophylaxis. Clinical Infectious Diseases, 71(3), 672–676. https://doi.org/10.1093/cid/ciz1127
Hansen, D. K., Sidana, S., Peres, L. C., Colin Leitzinger, C., Shune, L., Shrewsbury, A.,...Patel, K. K. (2023). Idecabtagene vicleucel for relapsed/refractory multiple myeloma: Real-world experience rrom the myeloma CAR T consortium. Journal of Clinical Oncology, 41(11), 2087–2097. https://doi.org/10.1200/jco.22.01365
Hayden, P. J., Roddie, C., Bader, P., Basak, G. W., Bonig, H., Bonini, C.,...Yakoub-Agha, I. (2022). Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Annals of Oncology, 33(3), 259–275. https://doi.org/10.1016/j.annonc.2021.12.003
Hernani, R., Benzaquén, A., & Solano, C. (2022). Toxicities following CAR-T therapy for hematological malignancies. Cancer Treatment Reviews, 111, 102479. https://doi.org/10.1016/j.ctrv.2022.102479
Hill, J. A., Giralt, S., Torgerson, T. R., & Lazarus, H. M. (2019). CAR-T - and a side order of IgG, to go? - Immunoglobulin replacement in patients receiving CAR-T cell therapy. Blood Reviews, 38, 100596. https://doi.org/10.1016/j.blre.2019.100596
Hill, J. A., Li, D., Hay, K. A., Green, M. L., Cherian, S., Chen, X.,...Turtle, C. J. (2018). Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood, 131(1), 121–130. https://doi.org/10.1182/blood-2017-07-793760
Hill, J. A., & Seo, S. K. (2020). How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies. Blood, 136(8), 925–935. https://doi.org/10.1182/blood.2019004000
Ibrahim, Y.-A., Christian, C., Peter, B., Grzegorz, W. B., Halvard, B., Fabio, C.,...Nicolaus, K. (2020). Management of adults and children undergoing chimeric antigen receptor T-cell therapy: Best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica, 105(2), 297–316. https://doi.org/10.3324/haematol.2019.229781
Jain, T., Bar, M., Kansagra, A. J., Chong, E. A., Hashmi, S. K., Neelapu, S. S.,...Lin, Y. (2019). Use of chimeric antigen receptor T cell therapy in clinical practice for relapsed/refractory aggressive B cell non-Hodgkin lymphoma: An expert panel opinion from the American Society for Transplantation and Cellular Therapy. Biology of Blood and Marrow Transplantation, 25(12), 2305–2321. https://doi.org/10.1016/j.bbmt.2019.08.015
Jain, T., Knezevic, A., Pennisi, M., Chen, Y., Ruiz, J. D., Purdon, T. J.,...Mailankody, S. (2020). Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies. Blood Advances, 4(15), 3776–3787. https://doi.org/10.1182/bloodadvances.2020002509
Janssen Biotech, Inc. (2022). Carvykti (ciltacabtagene autoleucel) package insert. https://www.fda.gov/media/156560/download?attachment
Kambhampati, S., Sheng, Y., Huang, C. Y., Bylsma, S., Lo, M., Kennedy, V.,...Wong, S. W. (2022). Infectious complications in patients with relapsed refractory multiple myeloma after BCMA CAR T-cell therapy. Blood Advances, 6(7), 2045–2054. https://doi.org/10.1182/bloodadvances.2020004079
Kampouri, E., Walti, C. S., Gauthier, J., & Hill, J. A. (2022). Managing hypogammaglobulinemia in patients treated with CAR-T-cell therapy: Key points for clinicians. Expert Review of Hematology, 15(4), 305–320. https://doi.org/10.1080/17474086.2022.2063833
Lee, D. W., Santomasso, B. D., Locke, F. L., Ghobadi, A., Turtle, C. J., Brudno, J. N.,…Neelapu, S. S. (2019). ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biology of Blood and Marrow Transplantation, 25(4), 625–638. https://doi.org/10.1016/j.bbmt.2018.12.758
Logue, J. M., Peres, L. C., Hashmi, H., Colin-Leitzinger, C. M., Shrewsbury, A. M., Hosoya, H.,...Hansen, D. K. (2022). Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma. Blood Advances, 6(24), 6109–6119. https://doi.org/10.1182/bloodadvances.2022008320
Logue, J. M., Zucchetti, E., Bachmeier, C. A., Krivenko, G. S., Larson, V., Ninh, D.,...Locke, F. L. (2021). Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma. Haematologica, 106(4), 978–986. https://doi.org/10.3324/haematol.2019.238634
Martin, T., Usmani, S. Z., Berdeja, J. G., Agha, M., Cohen, A. D., Hari, P.,...Jagannath, S. (2023). Ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. Journal of Clinical Oncology, 41(6), 1265–1274. https://doi.org/10.1200/jco.22.00842
Munshi, N. C., Anderson, L. D., Jr., Shah, N., Madduri, D., Berdeja, J., Lonial, S.,...San-Miguel, J. (2021). Idecabtagene vicleucel in relapsed and refractory multiple myeloma. New England Journal of Medicine, 384(8), 705–716. https://doi.org/10.1056/NEJMoa2024850
National Comprehensive Cancer Network. (2023). NCCN Clinical Practice Guidelines in Oncology: Hematopoitic growth factors. https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf
Neelapu, S. S., Locke, F. L., Bartlett, N. L., Lekakis, L. J., Miklos, D. B., Jacobson, C. A.,…Go, W. Y. (2017). Axicabtagene ciloleucel CAR T-cell therapy in refractory large b-cell lymphoma. The New England Journal of Medicine, 377(26), 2531–2544. https://doi.org/10.1056/NEJMoa1707447
Patrick, N., Bahlis, N., & Peters, S. (2023). Chimeric antigen receptor-T cell mediated bilateral facial nerve palsy: A case report. Neurohospitalist, 13(3), 308–311. https://doi.org/10.1177/19418744231167290
Raje, N., Berdeja, J., Lin, Y., Siegel, D., Jagannath, S., Madduri, D.,...Kochenderfer, J. N. (2019). Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. New England Journal of Medicine, 380(18), 1726–1737. https://doi.org/10.1056/NEJMoa1817226
Sanoyan, D. A., Seipel, K., Bacher, U., Kronig, M. N., Porret, N., Wiedemann, G.,...Pabst, T. (2023). Real-life experiences with CAR T-cell therapy with idecabtagene vicleucel (ide-cel) for triple-class exposed relapsed/refractory multiple myeloma patients. BMC Cancer, 23(1), 345. https://doi.org/10.1186/s12885-023-10824-3
Schuster, S. J., Bishop, M. R., Tam, C. S., Waller, E. K., Borchmann, P., McGuirk, J. P.,…JULIET Investigators. (2019). Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. The New England Journal of Medicine, 380(1), 45–56. https://doi.org/10.1056/NEJMoa1804980
Shaikh, S., & Shaikh, H. (2023). CART Cell Therapy Toxicity. In StatPearls. StatPearls Publishing, StatPearls Publishing LLC.
Shouse, G., Danilov, A. V., & Artz, A. (2022). CAR T-cell therapy in the older person: Indications and risks. Current Oncology Reports, 24(9), 1189–1199. https://doi.org/10.1007/s11912-022-01272-6
Strati, P., Varma, A., Adkins, S., Nastoupil, L. J., Westin, J., Hagemeister, F. B.,...Neelapu, S. S. (2021). Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma. Haematologica, 106(10), 2667–2672. https://doi.org/10.3324/haematol.2020.254045
van de Donk, N., Usmani, S. Z., & Yong, K. (2021). CAR T-cell therapy for multiple myeloma: state of the art and prospects. The Lancet Haematology, 8(6), e446–e461. https://doi.org/10.1016/s2352-3026(21)00057-0
Van Oekelen, O., Aleman, A., Upadhyaya, B., Schnakenberg, S., Madduri, D., Gavane, S.,...Parekh, S. (2021). Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy. Nature Medicine, 27(12), 2099–2103. https://doi.org/10.1038/s41591-021-01564-7
Wang, M., Munoz, J., Goy, A., Locke, F. L., Jacobson, C. A., Hill, B. T.,…Reagan, P. M. (2020). KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. The New England Journal of Medicine, 382(14), 1331–1342. https://doi.org/10.1056/NEJMoa1914347
Wat, J., & Barmettler, S. (2022). Hypogammaglobulinemia after chimeric antigen receptor (CAR) T-cell therapy: Characteristics, management, and future directions. Journal of Allergy and Clinical Immunology: In Practice, 10(2), 460–466. https://doi.org/10.1016/j.jaip.2021.10.037
Wilson Dib, R., Ariza-Heredia, E., Spallone, A., & Chemaly, R. F. (2023). Respiratory viral infections in recipients of cellular therapies: A review of incidence, outcomes, treatment, and prevention. Open Forum Infectious Diseases, 10(4), ofad166. https://doi.org/10.1093/ofid/ofad166
Wudhikarn, K., Palomba, M. L., Pennisi, M., Garcia-Recio, M., Flynn, J. R., Devlin, S. M.,...Perales, M. A. (2020). Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma. Blood Cancer Journal, 10(8), 79. https://doi.org/10.1038/s41408-020-00346-7
Zhou, X., Rasche, L., Kortüm, K. M., Danhof, S., Hudecek, M., & Einsele, H. (2020). Toxicities of chimeric antigen receptor T cell Therapy in multiple myeloma: An overview of experience from clinical trials, pathophysiology, and management strategies. Frontiers in Immunology, 11, 620312. https://doi.org/10.3389/fimmu.2020.620312
