Siltuximab Efficacy in Multicentric Castleman’s Disease Is Independent of Baseline Symptom Burden
Multicentric Castleman’s Disease (MCD) is a rare, highly symptomatic, systemic lymphoproliferative disorder driven by dysregulated interleukin (IL)-6 signaling. Siltuximab, a chimeric monoclonal antibody against human IL-6, was recently approved for the treatment of HIV-negative and human herpesvirus (HHV)-8–negative patients with MCD based on a randomized, double-blind, multicenter study where siltuximab provided durable tumor and symptomatic responses compared with placebo (Wong RS, et al. Blood. 2013;122. Abstract 505). At ASH 2014, Wong and colleagues presented ad hoc subgroup analyses based on baseline MCD-related signs and symptoms burden (Wong RS, et al. ASH 2014. Abstract 4454).
A total of 79 patients with symptomatic, measurable, HIV-negative and HHV-8–negative MCD were randomly assigned 2:1 to receive siltuximab (N = 53) or placebo (N = 26) every 3 weeks with best supportive care to manage the symptoms of MCD. At baseline and every 3 weeks, the investigators assessed 34 possible MCD-related signs and symptoms (general MCD-related, autoimmune phenomena, fluid retention, neuropathy, skin disorders), and a total score of all symptoms (MCD-related overall symptom score) was calculated as the sum of the severity grades. The effects of baseline symptom burden on the primary end point of durable tumor and symptomatic response (defined as partial or complete response and improvement or stabilization in MCD-related symptoms for ?18 weeks) and the secondary end point of durable symptomatic response were evaluated in the subgroup with ?4 MCD-related signs and symptoms at baseline and patients with MCD-related overall baseline symptom scores of <10 or ?10.
The most frequently reported MCD symptoms at baseline (all patients) were fatigue (86%), malaise (61%), night sweats (52%), peripheral sensory neuropathy (38%), anorexia (37%), pruritus (37%), and dyspnea (35%). The median treatment durations were 375 days versus 152 days for siltuximab and placebo, respectively.
For patients with baseline MCD-related overall symptom scores of <10, the durable tumor and symptomatic response rate was 29% with siltuximab and 0% with placebo (P = .0439). For patients with baseline MCD-related overall symptom scores of ?10, the durable tumor and symptomatic response rate was 42% with siltuximab and 0% with placebo (P = .0104). After adjusting for the MCD-related overall symptom score at baseline, a significant difference favoring siltuximab was still observed (P = .0003). The durable symptom response rates for placebo versus siltuximab were 17% and 50%, respectively (P = .0858) and 21% versus 68%, respectively (P = .0134) in the <10 and ?10 overall symptom score groups.
Siltuximab was generally well-tolerated, with no increased incidence of grade ?3 adverse events (AEs) or serious AEs compared with placebo (grade ?3 AEs, 47% vs 54%, respectively; serious AEs, 23% vs 19%, respectively), despite a longer treatment duration with siltuximab. These results were consistent with the primary and the secondary end points in the overall study population, indicating that siltuximab improves outcome regardless of the baseline symptom burden.