Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors: case report and systematic review of the literature

Abstract

Immune checkpoint inhibitors (ICIs) are associated with a wide range of immune-related adverse events. As oncological indications for ICIs widen, their rare side effects become increasingly visible in clinical practice and impact therapy decisions.Here, we report a rare case of early-onset, mild cytokine release syndrome (CRS) in a patient who received ICIs for a metastasized renal cell carcinoma, which led to treatment discontinuation.We further provide a systematic review of the literature of CRS and related life-threatening side effects of ICI treatment, such as hemophagocytic lymphohistiocytosis (HLH). We searched Medline, Embase and the Web of Science Core Collection from inception to October 2021 for reports on CRS, cytokine storm, macrophage activation syndrome, HLH, and related hyperinflammatory disorders in patients with solid cancers receiving ICIs. We found n=1866 articles, which were assessed for eligibility independently by two examiners. Of those, n=49 articles reporting on n=189 individuals were eligible for review. We found that the median time from last infusion to the occurrence of CRS/HLH was approximately nine days, while the onset of symptoms varied from immediately after infusion to one month after treatment. Most patients were treated with either corticosteroids or the anti-interleukin 6 (IL-6) antibody tocilizumab, and although the majority of patients recovered, a few cases were fatal. Concomitant IL-6 and ICI treatment were reported as beneficial for both the antitumoral effect and for limiting side effects. Data from international pharmacovigilance databases underscored that ICI-related CRS and HLH are rare events, but we identified significant differences in reported frequencies, which might suggest substantial under-reporting.The results from this first systematic review of CRS/HLH due to ICI therapy highlight that life-threatening systemic inflammatory complications of ICIs are rare and might be associated with fatal outcome in approximately 10% of patients. Limited data support the use of IL-6 inhibitors in combination with ICIs to augment the antitumoral effect and reduce hyperinflammation.

Keywords: Immunotherapy; Inflammation Mediators; Lung Neoplasms; Melanoma.

Figure 1

Laboratory tests after immune checkpoint inhibitor (ICI) treatment in a patient with metastatic renal cell carcinoma. (A) Routine blood tests for the indicated markers at the first admission after treatment with ipilimumab and nivolumab; legend as indicated in (C). Left y-axis in lower panel for leukocytes, right y-axis for thrombocytes and hemoglobin. (B) The same blood tests as in (A) at the occasion of the second admission after treatment with nivolumab. Day ‘1’ is the day of treatment, which was also the day of admission in both cases. (C and D) Graphic illustration of the timing of treatment on first (C) and second (D) admission. ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; CRP, C reactive protein; GGT, gamma-glutamyltransferase, Hb, hemoglobin; Ipi, ipilimumab, Nivo, nivolumabb; PCT, procalcitonin.