Siltuximab (Sylvant). Castleman's disease: good symptomatic efficacy in some patients

Multicentric Castleman's disease is a rare lymphoproliferative disorder characterised by disseminated lymphadenopathy. Symptoms and outcomes differ widely from one patient to another. The median survival time is about 2.5 years. There is no consensus on treatment. Siltuximab, a monoclonal antibody that antagonises interleukin-6, has been authorised in the European Union for patients with multicentric Castleman's disease who are not infected with HIV or HHV-8. In a randomised, double-blind trial in 79 patients, most of whom had mild or moderate symptoms, the estimated one-year survival rate was 100% in the siltuximab group versus 92% in the placebo group after a median follow-up of 60 weeks. However, half of the patients in the placebo group received siltuximab after disease progression. Symptoms disappeared for at least 18 weeks in one-quarter of patients in the siltuximab group versus none of those in the placebo group; the median symptom-free period in the siltuximab group was about 16 months. The known adverse effects of siltuximab are related to its immunosuppressive effect. They include frequent infections, neutropenia and thrombocytopenia. Reactions can occur during the infusion, and mouth sores have been reported. Other adverse events that appear to be more frequent with siltuximab include cutaneous disorders, oedema, renal and cardiac disorders, and peripheral neuropathy. Cases of gastrointestinal perforation have been reported in trials in other clinical settings. Siltuximab can mask the signs and symptoms of acute inflammation, in particular by suppressing fever and acute-phase markers such as C-reactive protein. Interleukin-6 is a cytochrome P450 inhibitor. Siltuximab activates its isoenzymes and can thus reduce the effectiveness of the numerous drugs that are substrates of this enzyme system. This risk of interactions is likely to persist up to several weeks after siltuximab withdrawal, because of its long plasma elimination half-life (about 16 days). In practice, the only available trial suggests that siltuximab has a marked impact on the symptoms of mild or moderate multicentric Castleman's disease in patients who are not infected with HIV or HHV-8. Siltuximab seems to be a reasonable option in this setting, despite its numerous adverse effects, provided patients are fully informed of the many unknowns and are closely monitored.