Analysis of Inflammatory and Anemia-Related Biomarkers in a Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL6 Monoclonal Antibody) in Patients With Multicentric Castleman Disease.

Abstract

Siltuximab (IL6 antibody) is approved for the treatment of multicentric Castleman disease (MCD). Effects of IL6 inhibition on the inflammatory milieu accompanying MCD have not been characterized. Trends in inflammatory- and anemia-associated markers, measured over the course of a placebo-controlled study of siltuximab (11 mg/kg q3w) in patients with MCD (n = 79), were characterized. Baseline IL6 and C-reactive protein (CRP) levels were significantly correlated (r = 0.708; P < 0.0001). CRP levels decreased (median, 92%) by cycle 1 day 8 (C1D8), remaining suppressed during siltuximab treatment while remaining stable in the placebo group. There were no associations between baseline CRP or IL6 and MCD symptom burden, histologic subtype, ethnicity, maximum CRP decrease, and response parameters. A hemoglobin response (change ≥ 15 g/L at week 13) was observed with siltuximab (61%; P = 0.0002). Median hepcidin decrease from baseline at C1D8 with siltuximab was 47% versus median 11% increase with placebo. Maximum post-baseline changes in hepcidin levels among siltuximab recipients were correlated with maximum changes for hemoglobin (r = -0.395; P = 0.00607), total iron-binding capacity (TIBC; r = -0.354; P = 0.01694), and ferritin (r = 0.599; P = 0.0001). Greater median changes from baseline in ferritin, hemoglobin, and TIBC were observed in anemic siltuximab-treated patients. IL6 neutralization with siltuximab resulted in sustained CRP suppression and improvement of anemia, in part, by hepcidin pathway inhibition.