Current concepts in the diagnosis and management of cytokine release syndrome

Abstract

As immune-based therapies for cancer become potent, more effective, and more widely available, optimal management of their unique toxicities becomes increasingly important. Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon γ, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without corticosteroids, can reverse the syndrome. However, because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life-threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of CRS based on severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS.

Figures

Figure 1

IL-6 signaling and inhibition by tocilizumab. (A) Classic IL-6 signaling restricted to IL-6R–expressing cells shown in pink (macrophages, neutrophils, T cells, and hepatocytes), which predominates when IL-6 levels are low. IL-6 binds to cell-associated IL-6R, leading to homodimerization of gp130 and initiation of downstream pathways. (B) Both classic and trans-IL-6 signaling, which occurs when IL-6 levels are elevated, leading to IL-6 signaling on a broad array of cells, because gp130 is ubiquitously expressed. Tocilizumab binding to both cell-associated IL-6R and soluble IL-6R inhibits classic and trans-signaling. IL-6R–expressing cells are shown in pink, whereas non-IL-6R–expressing cells are shown in blue.

Figure 2

Treatment algorithm for management of CRS based on the revised CRS grading system. The algorithm uses the revised grading system for CRS to direct clinical management for patients with immunotherapy-associated CRS. We recommend vigilant supportive care including empiric treatment of concurrent bacterial infections and maintenance of adequate hydration and blood pressure for every grade. Immunosuppression should be used in all patients with grade 3 or 4 CRS and instituted earlier in patients with extensive comorbidities or older age. Grades 2-4 organ toxicities are dictated by CTCAE v4.0.

Figure 3

Cytokine changes associated with clinical findings in a hypothetical patient with grade 3 CRS. A dramatic rise in IL-6 and IFNγ levels is associated with the onset of fever at day 3 after CAR T-cell infusion. Despite vigilant supportive care, the patient becomes hypotensive, requiring the use of 1 vasopressor on day 5. After a brief period of cardiovascular stability, a second vasopressor is required to maintain adequate perfusion on day 6, at which time tocilizumab is administered. IL-6 levels continue to rise transiently after tocilizumab, because it continues to be produced and tocilizumab blocks IL-6R-mediated endocytosis. Vasopressor support is gradually weaned over the next 48 hours, although neurologic changes may persist or initially manifest after tocilizumab, but eventually resolve. Several other inflammatory cytokines, including TNFα, IL-2, GM-CSF, and others noted in the text are also likely to be elevated during the peak of the syndrome.