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.

An On-Treatment Decreased Trend of Serum IL-6 and IL-8 as Predictive Markers Quickly Reflects Short-Term Efficacy of PD-1 Blockade Immunochemotherapy in Patients with Advanced Gastric Cancer

“…The ability of IL-6 or IL-8 to discriminate between effective and ineffective treatment may be attributed to the nonspecific nature of PD-1 blockade. After receiving PD-1 antibody treatment, most tumor-related immune cells are activated, leading to an increase in various cytokines [ 26 ], as reflected in our results.…”

PD-1 Blockade-Induced Hemophagocytic Lymphohistiocytosis, a Dilemma Therapeutic Outcome in 2 Patients with CAEBV: A Case Series

“…High-dose glucocorticoids, etoposide, and cyclosporine are the core therapeutic drugs of the treatment regimen based on HLH-94 and 2004. 19 However, the HLH-94 and the HLH-2004 are mainly based on pediatric genetic forms of HLH, and the efficacy and outcomes of these regimens in some anti-PD1-induced HLH cases are still questionable. 20 There have also been some reports of patients with ICIs-induced HLH who died despite receiving high-dose steroid therapy.…”

Gastric cancer with brain metastasis: from molecular characteristics and treatment

“…In the study, the incidence of irAEs at grade 3 or higher was 6% in both the combination therapy and pembrolizumab groups, with 24% of patients in the former group and 21% in the latter experiencing irAEs ( 83 ). To mitigate toxicity from irAEs, cytokines such as IL-6 and GM-CSF have been proposed as potential targets for decoupling the immune response ( 137 , 138 ). It is worth noting that some studies suggest an uncertain correlation between irAEs and the clinical effectiveness of immunotherapy, which requires further investigation ( 139 ).…”