Abstract
To evaluate the safety and pharmacokinetics of siltuximab, an anti-interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease. In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease. Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose-toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR. No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma.
Highlights
Interleukin (IL)-6 is involved in the pathogenesis ofB-cell lymphoid malignancies and plays an important role in multiple myeloma, inducing proliferation and preventing programmed cell death in neoplastic plasma cells [1,2,3,4]
A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained C-reactive protein (CRP) suppression
Randomized studies are ongoing in Castleman disease and multiple myeloma
Summary
Interleukin (IL)-6 is involved in the pathogenesis of. B-cell lymphoid malignancies and plays an important role in multiple myeloma, inducing proliferation and preventing programmed cell death in neoplastic plasma cells [1,2,3,4]. High serum IL-6 levels correlate with worse prognosis and survival in patients with lymphoma and multiple myeloma [5,6,7,8,9,10,11]. Castleman disease is an atypical lymphoproliferative disorder. Overproduction of IL-6 from affected lymph nodes is responsible for systemic manifestations. Lee Moffitt Cancer & Research Institute, Tampa, Florida; 11Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and 12Janssen
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