Necrotizing and non-Necrotizing Granulomatous Reactions in Cancer Patients Treated with Immune Checkpoint Inhibitors: a Systematic Literature Review.

Abstract

OBJECTIVE Immune checkpoint inhibitors (ICI) have improved cancer outcomes but often cause immune-related adverse events (irAE), including granulomatous reactions (GR). We analyzed GR in patients receiving anti-CTLA4, anti-PD1/PDL1 and combination anti-CTLA4/PD1 therapies. METHODS We performed a literature review of GR in patients receiving ICI. Data were extracted from 166 articles, including demographics, GR organ distribution and pathological findings. RESULTS In 261 patients, the mean age of GR onset was 59.3 ± 13.0 years. The most common cancer types were melanoma (57%) and lung cancer (21%). Lymph nodes (35%) and skin (24%) were the predominantly affected organs, however GR also involved the liver, kidney, and bone. Granulomas were non-necrotizing in 64% of cases and necrotizing in 15% of cases. Forty-five percent of patients were treated with systemic steroids, and eleven percent required a steroid-sparing agent. Median follow-up time was 10.1 [4, 22] months. Most GR (64%) had resolved by last follow-up. Compared to those treated with combination ICI, patients treated with anti-PD1/PDL-1 monotherapy were older and had a longer time to onset of the GR. They were less likely to be treated with steroids for GR. In melanoma patients, necrotizing GR were more common in combination ICI. GR in the lungs and nodes were more likely to be non-necrotizing, and GR in the liver were more commonly necrotizing. CONCLUSION GR in cancer patients treated with ICI can occur in many organ systems and were most commonly non-necrotizing. Patients treated with combination ICI had more severe reactions. Most granulomatous reactions resolved with steroid treatment or ICI discontinuation.