Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors: Systematic review of the literature

Immune checkpoint inhibitors (ICIs) are associated with a wide range of immune-related adverse events (irAEs). As oncological indications for ICIs widen, their rare side effects become increasingly visible in clinical practice and impact therapy decisions. Here, we 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 until 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 was 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 underreporting. 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 non-fatal in the majority of patients. Limited data support the use of IL-6 inhibitors in combination with ICIs to augment the antitumoral effect and reduce hyperinflammation.