Chimeric antigen receptor-modified T (CAR T) cells that target CD19 have produced durable remission for many patients with relapsed and refractory B cell malignancies. There are currently 2 approved agents on the market — tisagenlecleucel and axicabtagene ciloleucel — but CAR T therapy is being investigated for uses beyond targeting CD19 and in other types of malignancies. Although relatively few patients have received this therapy, its use is expected to expand, and as a result, understanding the unique acute toxicities associated with the use of CAR T cells is increasingly important. These toxicities can be fatal and require specialized monitoring and prompt treatment.
The most common adverse event observed after CAR T therapy is cytokine release syndrome (CRS), an escalated immune response that, on rare occasions, can evolve into fulminant hemophagocytic lymphohistiocytosis, also known as macrophage activation syndrome. CRS is caused by the rapid immune activation induced by CAR T cells and can be life threatening. A review article published in Biology of Blood and Marrow Transplantation discussed CRS and its management, risk factors, and possible methods of prevention.
CRS generally develops within 1 to 14 days after infusion, depending on the product and patient characteristics, and its duration can be quite variable. CRS initially presents with a low grade fever that can escalate to temperatures greater than 105°F, myalgias, and fatigue but can rapidly progress to life-threatening vasodilatory shock, capillary leak, hypoxia, and end organ dysfunction. Intervention is variable; some cases are self-limiting and require only supportive care with antipyretics and intravenous fluids, but others necessitate anticytokine-directed therapy such as corticosteroids or tocilizumab.
Although few CRS-related deaths have been reported, it remains a potentially life-threatening complication, and a major focus of clinical trials has been to identify potentially modifiable risk factors. Some risk factors and predictors for severe CRS include high disease burden in acute lymphoblastic leukemia (ALL), high infusion dose, fludarabine-containing lymphodepletion, concurrent infectious disease, and early cytokine elevations.
The evidence strongly suggests that the CAR T cell infusion dose affects both safety and efficacy, and higher doses have been linked to more severe cases of CRS. Various dosing strategies have been used in an attempt to limit toxicity; for example, some centers give a lower initial dose of cells to patients with ALL and higher disease burden in an “adaptive dosing” strategy.
Different anti-CD19 CAR T cells and manufacturing techniques may eventually improve both safety and efficacy, but, to date, comparative data are limited, and no randomized trials have directly compared the products. The authors noted that interpretation of toxicities across studies “needs to be done with caution” because of differences in the disease being treated, disease stage, trial design, study population, and CRS grading scale used. For example, dose intensity and selection of pre-CAR T cell lymphodepletion agents vary significantly across studies. Combining fludarabine and cyclophosphamide appears to correlate with higher in vivo expansion and a potentially better response, but this combination is also associated with higher incidence of severe CRS compared with cyclophosphamide alone. Some CRS prevention strategies under investigation include pretreatment cytoreduction, inverse dose adjustment by disease burden, fractionated dosing schemes, and prophylactic anticytokine therapy.
Management of CRS
Tocilizumab, a humanized monoclonal antibody with activity against interleukin (IL)-6 receptor used mainly for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis, has come to the forefront of CRS treatment and has received a U.S. Food and Drug Administration approval for this indication. It is effective for most patients, and those who do not initially respond will often improve after a second administration or the addition of corticosteroids. In addition to effectively managing CRS symptoms, tocilizumab’s ability to block the IL-6 receptor allows management of toxicity without negative influence on the antitumor effect of CAR T cells. In contrast, corticosteroids, which are sometimes needed to help control CRS can have a detrimental effect on CAR T cells if administered in high doses. Whether prophylactic or earlier intervention with tocilizumab would improve safety without affecting efficacy has not been determined.