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Tocilizumab alternatives in the management of cytokine release syndrome secondary to chimeric antigen receptor T therapies

Chimeric antigen receptor T (CAR-T) therapies have resulted in durable remissions for patients with refractory hematologic malignancies; however, patients can experience many side effects following administration. Cytokine release syndrome (CRS) occurs as a result of rapid immune activation induced by CAR-Ts and is one of the most significant treatment-related toxicities associated with CAR-T cell therapy.1 Prior to administration of CAR-T cell therapy, manufacturers require institutions to have at least 2 doses of tocilizumab (Actemra®) on hand for each patient, for management of CRS. Tocilizumab is an interleukin-6 (IL-6) receptor antagonist, and upon administration, tocilizumab leads to a reduction in circulating cytokines.2 Recently, tocilizumab was approved for the treatment cytokine release secondary to COVID-19.2 Since this approval, tocilizumab has been on shortage due to the increased demand. Siltuximab (Sylvant®) and anakinra (Kineret®) have both been postulated for use in management of CRS.

Siltuximab (Sylvant®) works by binding with high affinity to IL-6 and prevents IL-6 from binding to its receptor, thus lowering IL-6 levels in the body.3 It is currently approved for use in adult patients with multicentric Castleman Disease (MCD) who are human immunodeficiency virus (HIV)-negative and human herpes virus type 8 (HHV-8)-negative.3 Off-label use of siltuximab has been postulated for use in cytokine release syndrome (CRS) as a second- or third-line agent in grade 4 refractory CRS following CAR-T cell therapy, after tocilizumab and corticosteroids.1 Siltuximab use has been reported in 2 pivotal trials, ZUMA-3 and ZUMA-4; however no data is available regarding its use. Currently, 2 case reports have documented its use in refractory CRS, the patients died shortly after, likely due to delayed administration and disease progression.4,5 Additionally, the CAR-T-cell-therapy-associated TOXicity (CARTOX) working group recommends use of either tocilizumab or siltuximab for persistent CRS, defined as lasting greater than 3 days.6

Anakinra (Kineret®) is an interleukin-1 (IL-1) receptor antagonist, which upon administration, leads to a reduction in circulating cytokines.7 It is currently approved for IL-1 deficiency, frequent gout flares, and rheumatoid arthritis.7 Similar to siltuximab, its off-label use for CRS has been postulated. In a study done by Strati and colleagues, 6 patients were treated with anakinra first-line for CRS and 4 had clinical benefit.8 Additionally, in another study, anakinra was administered to patients after grade ≥2 and no patients experienced grade escalation.9

While there is not robust literature validating the place in therapy of siltuximab or anakinra for CRS management, guidelines do list these agents as a potential last-line option in tocilizumab-refractory CRS.1 In the setting of tocilizumab shortage, siltuximab and anakinra remain promising options to alleviate CRS; however, it is still recommended to obtain tocilizumab prior to initiation of CAR-T-cell therapy and utilize the supply as first-line prior to initiation of these agents.

1. National Comprehensive Cancer Network. Management of Immunotherapy Related Toxicities. (Version 3.2021). https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed August 27th, 2021
2. Tocilizumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL Accessed August 27, 2021
3. Siltuximab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL Accessed August 27, 2021
4. Turtle CJ, Hay KA, Hanafi LA, et al. Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor-Modified T Cells After Failure of Ibrutinib. J Clin Oncol. 2017;35(26):3010-3020. doi:10.1200/JCO.2017.72.8519
5. Vithlani, S. Evidence for use of siltuximab or anakinra as second line therapies (after failure of tocilizumab) for Cytokine Release Syndrome (CRS) following use of Chimeric Antigen Receptor T-cell (CAR-T) therapy [Internet]. London Medicines Information Service. [updated Feb 2020; cited 2020 May 20]. Available from: https://www.sps.nhs.uk/articles/evidence-for-use-of-siltuximab-or-anakinra-as-second-line-therapies-after-failure-of-tocilizumab-for-cytokine-release-syndrome-following-use-of-chimeric-antigen-receptor-t-cell-car-t-therapy/
6. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62. doi:10.1038/nrclinonc.2017.148
7. Anikinra. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL Accessed August 27, 2021
8. Strati P, Ahmed S, Kebriaei P, et al. Clinical efficacy of anakinra to mitigate CAR T-cell therapy-associated toxicity in large B-cell lymphoma. Blood Adv. 2020;4(13):3123-3127. doi:10.1182/bloodadvances.2020002328
9. Caspian Oliai, Anna Crosetti, Sven De Vos, et al. IL-1 receptor antagonist for prevention of severe immune effector cell-associated neurotoxicity syndrome. Journal of Clinical Oncology 2021 39:15_suppl, 7566-7566