Stage 4 Cytokine Release Syndrome Caused by the First Dose of Nivolumab and Ipilimumab Combination Therapy in a Patient with Metastatic Melanoma Successfully Treated with Methylprednisolone, Tocilizumab, and Etanercept

Abstract

The authors report the first case of stage 4 cytokine release syndrome (CRS) (graded by the National Cancer Institute Common Terminology Criteria for Adverse Effects scale) involving a patient with advanced metastatic melanoma who was treated with the combination of two monoclonal antibodies, nivolumab (anti-programmed cell death receptor 1 inhibitor [PD-1]) and ipilimumab (a cytotoxic T lymphocyte-associated antigen 4 inhibitor [CTLA-4]) after her first dose of both. The patient was treated initially with methylprednisolone and tocilizumab but was refractory to treatment. A trial of etanercept was initiated due to her elevated levels of TNF-α which elicited a satisfactory response. Monoclonal antibody therapy is a new tool for the treatment of many cancers, and therefore there may be a subsequent rise in the cases of CRS and this case exemplifies a treatment algorithm. Utilizing levels of cytokines assists in tailoring treatment such as in this case where etanercept, a TNF-α inhibitor, was utilized due to the patient’s elevated levels of TNF-α.

Severe cytokine release syndrome induced by immune checkpoint inhibitors in cancer patients – A case report and review of the literature

“…Massive T cell stimulation has also been proposed as a cytokine storm in the context of severe viral infections such as influenza [ 39 , 40 ]. Lately, with the successful use of new T-cell immunotherapy drugs in solid tumors, leukemias, and lymphomas has led to an increase in the incidence of CRS [ 30 ]. As an irAE, CRS can be a severe and life-threatening complication.…”

“…In our case series, 15 patients received tocilizumab, with only one patient experiencing life-threatening toxicity eventually. Other cytokine-targeted therapies such as etanercept (TNF-α inhibitor), dalclizumab (IL-2R antagonist) and anakinra (IL-1R antagonist), as well as IVIg and PE, may have a potential role in managing the syndrome [ 30 , 60 , 61 ]. However, their efficacy, indications and limitations have yet to be evaluated.…”

“…Subsequently, an additional seven papers were excluded upon closer inspection, as they pertained to hemophagocytic lymphohistiocytosis, capillary-leak syndrome, or anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In total, we accurately summarized 22 papers [ [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] ]. A total of 49 patients were enrolled.…”

Cytokine release syndrome and cancer immunotherapies – historical challenges and promising futures

“…A case of fulminant CRS complicated by dermatomyositis was reported during the treatment of a renal cell carcinoma patient with Nivolumab and Ipilimumab (152). Another instance of Stage 4 CRS with Nivolumab and Ipilimumab combination therapy was observed in a patient with metastatic melanoma (153). Factors associated with high-grade CRS related to the use of immune checkpoint inhibitors are not well characterized.…”

Cytokine release syndrome as a consequence of check point inhibitors nivolimumab and iplimumab

“…1 They mediate T-cell induced tumor cell destruction by blocking malignant cells' ability to negatively regulate T cell activity, leading to activation of immune and non-immune cells and ultimately a massive release of cytokines. 2,3 In addition to its antitumor effect, checkpoint inhibition can lead to loss of maintenance of self-tolerance, leading to immune-mediated adverse events (irAEs). 4 We report a 46-year-old woman diagnosed with grade IV left renal cell carcinoma with liver and skeletal metastasis, who was started on nivolimumab and iplimumab as third line chemotherapy.…”