Results of peripheral blood immune analysis in patients receiving immune checkpoint inhibitor therapy and correlation with immune-related adverse events.

Abstract

e19568 Background: Immune-related adverse events (irAEs) result from T-lymphocyte activation induced by immune checkpoint inhibitor (ICI) therapy. Although T cells are central to irAE pathogenesis, a contributory role for B cells is suggested by the mechanistic overlap between irAEs and autoimmune diseases. Monoclonal gammopathy of undetermined significance (MGUS), has also been increasingly associated with autoimmune conditions. We investigated the occurrence of MGUS in cancer patients who developed irAEs following ICI therapy. Methods: We conducted a retrospective, single-center observational study of patients treated with ICIs who developed irAEs, evaluating for the presence of MGUS. Peripheral blood samples were analyzed by serum protein electrophoresis and immunofixation to detect monoclonal gammopathy. MGUS status was correlated with tumor type, ICI regimen, and the presence and severity of irAEs. Results: Twenty-four patients that developed toxicity following ICI were identified, including those treated with pembrolizumab (n = 8), nivolumab (n = 6), cemiplimab (n = 3), or combination ipilimumab/nivolumab (n = 7). Tumor types included cutaneous melanoma (n = 16), head and neck cancer (n = 2), cutaneous squamous cell carcinoma (n = 2), and one case each of spindle cell carcinoma, cutaneous T-cell lymphoma, Merkel cell carcinoma, and basal cell carcinoma. MGUS was detected in 12 patients (Group A) (50%): IgM (n = 7), IgG (n = 4), and IgA (n = 1), with kappa light-chain restriction in 9 and lambda in 3 patients. The remaining 12 patients (Group B) had no detectable MGUS. Median age was 78 and 76 between Groups A and B, respectively. Our results show a Male:Female ratio of 8:4 and 7:5 respectively between Groups A and B. Grade III-IV irAEs occurred in 11/12 patients with MGUS compared with 2/12 patients without MGUS. Severe cutaneous toxicity predominated among patients with MGUS, with grade III–IV skin rash observed in 6 of 7 patients with skin involvement. Additional irAEs included grade III diarrhea/gastritis (n = 1) and severe fatigue (n = 1). Among patients with IgM MGUS, two developed cryoglobulinemia and one developed antiphospholipid antibody syndrome with vasculitis, resulting in significant morbidity. In patients without MGUS, severe irAEs were limited to skin rash (n = 1) and colitis (n = 1). Conclusions: MGUS was frequently detected in cancer patients who developed severe irAEs following ICI therapy and was strongly associated with grade III–IV toxicity. IgM MGUS and kappa light-chain restriction were predominant and were associated with immune-complex–mediated complications. These findings suggest that clonal B-cell activity may contribute to irAE severity in a subset of patients. Larger studies are warranted to validate these observations, help elucidate this mechanism and help detect tissue biomarkers of B cell activity.