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.