Cytokine release syndrome (CRS)
CD19-directed CAR T cell products, including tisagenlecleucel, report similar treatment-related toxicities with the most common being CRS. CRS describes a constellation of inflammatory symptoms resulting from cytokine elevations associated with T cell expansion, proliferation, immune system activation, and tumor cell elimination and is not restricted to anti-CD19 therapies 23,24. CRS is initially characterized by fevers and myalgias and can progress to hypotension, hypoxia, and/or multiorgan toxicity25,26. The overall goal of management of CRS is to minimize symptoms and avoid life-threatening organ toxicity without compromising the CAR T cell function. For pediatric patients with mild to moderate CRS symptoms, management includes supportive care and close monitoring for hypotension, tachypnea, and hypoxia. Severe CRS (grade 3-4) is characterized by unstable hypotension or significant respiratory insufficiency. The management of severe CRS was revolutionized by the observation in our initial patients that interleukin 6 (IL-6) is a key driver of the CRS reaction 18,27. Severe CRS is treated with the IL-6 receptor inhibitor tocilizumab, which is currently the only FDA-approved therapy for CRS, as targeted anti-cytokine therapy23. Tocilizumab has allowed corticosteroids, which are lympholytic and at high and prolonged doses can jeopardize the function and persistence of CAR T cells, to be avoided as first-line management. Severe CRS from tisagenlecleucel is managed in a stepwise fashion, starting with tocilizumab in one or two doses, then adding corticosteroids, followed by another tocilizumab dose. After these interventions, most severe CRS is controlled, as indicated by resolution of fever and minimal to no need for pressor support. In cases where CRS continues, which are generally the most challenging to manage, other interventions such as high-dose steroids and siltuximab, a direct IL-6 antagonist 25, may be considered. Although siltuximab has been proposed as a first-line agent in one publication25, no clinical experience or published data exists to support its use as first-line management 28. The utility of siltuximab is an especially important question during the COVID-19 pandemic, where tocilizumab is being used off-label to treat COVID-19 CRS 29, and there may be concerns about drug supply. Having tocilizumab available in the pharmacy for patients undergoing cell therapy is required by the risk evaluation and mitigation strategy (REMS) of the product, and remains standard of care. For now, the place for siltuximab in the management of CRS remains an important area of active study 30,31. In addition, recent pre-clinical studies have also demonstrated potential activity of dasatinib, a multityrosine kinase inhibitor, for patients refractory to standard CRS treatment by potently and reversibly inhibiting CAR T cell function 32,33. Investigators from multiple centers recently convened to unify CRS grading across trials and commercial CAR T products, producing the ASTCT grading scale for CRS (Table 1)34.