Siltuximab Offers 'Durable' Tumor and Symptom Responses in Multicentric Castleman's Disease

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NEW ORLEANS—Siltuximab improves symptoms and clinical outcomes for patients with multicentric Castleman's disease (MCD), despite a high rate of drug discontinuation due to toxicities, according to results of a multicenter, randomized double-blind, placebo-controlled safety and efficacy trial described at the 55th American Society of Hematology Annual Meeting and Exposition.

MCD is a rare lymphoproliferative disorder driven by dysregulated interleukin (IL)-6 production. Siltuximab is a chimeric monoclonal antibody that targets IL-6 production.

“The efficacy of siltuximab in [patients with] MCD was demonstrated by durable tumor and symptom response, and clinical benefit was confirmed by marked improvement of time to treatment failure, MCD-related symptoms, Hb levels, and sustained reduction in inflammatory markers,” said Raymond S. Wong, MBChB, MD, of the Prince of Wales Hospital, Chinese University of Hong Kong, in Hong Kong, China, and colleagues.

The trial was the first randomized study of MCD, Wong noted.

“In conjunction with the tolerable safety profile in this population, this study provides compelling evidence that siltuximab should be considered a new treatment of choice for patients [with MCD],” the investigators reported.

Between 2010 and 2013, a total of 79 patients with symptomatic, measurable, HIV-negative and HHV-8-negative MCD were randomly assigned 2:1 to receive best supportive care (BSC) plus siltuximab (11 mg/kg; n = 53) or placebo (n = 26), delivered via 1 hour intravenous infusions every 3 weeks. Participants received infusions until treatment failure, after which half (13 patients) of those in the placebo-arm crossed over to siltuximab treatment.

“Median treatment duration was 375 versus 152 days with siltuximab versus placebo, with 64% vs. 27% completing 48 weeks of treatment,” the coauthors reported.

Siltuximab was associated with superior durable tumor and symptomatic response rates compared to placebo (34%, one complete response, 17 partial responses vs. 0%; P = 0.0012); median duration of tumor and symptom response with siltuximab was 340 days, indicating “prolonged disease control,” the authors noted. “Tumor response rate by central radiology review was 38% vs. 4% (P = 0.0022). Median time to treatment failure was not reached for siltuximab versus 134 days for placebo (P = 0.0084).”

“Sustained decreases in CRP ([C-reactive protein] a marker of IL-6 bioactivity), ESR [erythrocyte sedimentation rate], and fibrinogen, and increase in albumin were seen with siltuximab,” they added.

Safety profiles for siltuximab and placebo were “similar,” even with the duration of treatment being twice as long for those in the siltuximab arm. Grade 3 or higher adverse event (AE) rates of 47% versus 54% and serious AEs of 23% versus 19% were observed for the siltuximab and placebo arms, respectively. However, 23% of siltuximab-arm study participants discontinued therapy, and two of those patients died as a result of progressive disease.

The most frequent grade 3 or higher AEs among patients receiving siltuximab included fatigue (9%), night sweats (8%), hyperkalemia (4%), hyperuricemia (4%), localized edema (4%), hyperhidrosis (4%), neutropenia (4%), thrombocytopenia (4%), hypertension (4%), and weight increase (4%).

HB improvement by  15 g/L or more at week 13 was documented in 61% of anemic patients receiving siltuximab and 0% of anemic patients receiving placebo (P = 0.0002), the authors reported.

The coauthors reported research funding from Roche, Johnson & Johnson, Bayer, Pfizer, Amgen, and other funding and financial interests with pharmaceutical companies.

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