Siltuximab for multicentric Castleman disease

Abstract

Dysregulated secretion of IL-6 plays a pivotal role in the pathogenesis of Castleman disease (CD), a rare lymphoproliferative disorder. In contrast to unicentric CD for which surgery is considered the treatment of choice, there is no standard therapeutic approach for multicentric CD (MCD). Siltuximab (trade name: Sylvant, formerly known as CNTO 328) is a chimeric monoclonal antibody with high binding affinity for human IL-6. In a recent randomized placebo-controlled Phase II trial, subjects with HIV-negative, HHV8-negative MCD who received siltuximab demonstrated a significantly higher rate of durable tumor and symptomatic response with a tolerable safety profile, leading to its approval for the treatment of HIV-negative HHV8-negative MCD by the US FDA and the European Commission in April and May 2014, respectively. This article will cover the current treatment options of MCD, the drug profile of siltuximab and future directions in the management of MCD.

Keywords::

• Castleman disease
• IL-6
• monoclonal antibody
• siltuximab
• targeted therapy

Financial & competing interests disclosure

F van Rhee has received research funding from Johnson and Johnson and served on advisory boards. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Categorization of multicentric CD (MCD) by human herpesvirus-8 status rather than traditional HIV status is more appropriate based on the pathogenesis and clinical features.

• IL-6 plays a central role in the pathogenesis of MCD. The clinical manifestations of MCD are mainly driven by activation of IL-6 signaling pathway.

• In contrast to unicentric CD for which surgery is the treatment of choice with a good prognosis, MCD is more aggressive with more serious clinical symptomatology, which at times can be life-threatening.

• Application of rituximab in patients with HIV-positive MCD has improved outcome in HIV-positive MCD and reduced the risk of progression to lymphoma.

• Studies with siltuximab and tocilizumab in patients with idiopathic MCD show remarkable activity validating the IL-6 signaling cascade as important therapeutic target.

• Siltuximab has demonstrated a durable tumor and symptomatic response and a tolerable safety profile in patients with idiopathic MCD in a multi-institutional, international, randomized, placebo-controlled clinical trial, leading to its approval by the FDA and the European Commission in April and May 2014, respectively.

Notes