Castleman's disease: from basic mechanisms to molecular therapeutics

Abstract

Castleman's disease is a rare lymphoproliferative disorder in which there has been recent progress in elucidating underlying mechanisms with potential therapeutic implications. Unicentric Castleman's disease is an indolent condition that is often treated with local approaches. In contrast, patients with multicentric Castleman's disease (MCD) have a less favorable prognosis and require systemic treatment. Cytotoxic chemotherapy, with its attendant risk for toxicity, has been widely used to treat MCD, with variable efficacy. The discovery of putative etiologic factors and targets in MCD, particularly human herpes virus 8, CD20, and interleukin (IL)-6, has been translated into the use of rituximab and anti-IL-6-based therapy, as well as antiviral agents. In this article, we review the current state of the art of our understanding of Castleman's disease and its treatment and we provide insight into future treatment strategies based on disease biology.

Figure 1.

Proposed unified model of the pathophysiology of CD representing the different known and suggested mechanisms involved in that disease. HHV-8–infected cells secrete vIL-6^a, which in turn enhances the production of VEGF by the nonlymphoid or plasma cell^b. VEGF induces vascular proliferation, a major component of MCD. The endothelium itself is a source of IL-6 production,^c thereby contributing to the systemic manifestations of MCD and further enhancing lymphocytic and vascular proliferation. In HHV-8⁻ CD patients, an undefined upstream stimulus might be responsible for IL-6 production.^d We believe that the IL-1^e production by many cells, such as macrophage or follicular dentritic cells,^f induces the generation of IL-6 through the NF-κB signaling pathway. Dysregulation at any level can lead to overproduction of IL-6, which has a pivotal impact on the disease. Several key molecular functions may provide potential therapeutic targets in the management of Castleman's disease (i.e., siltuximab targeting IL-6, tocilizumab targeting IL-6R, steroid and bortezomib targeting the NF-κB pathway, rituximab targeting CD20⁺ lymphocytes, ganciclovir targeting HHV-8, cetuximab targeting EGFR on follicular dentritic cells, bevacizumab targeting VEGF receptor, anakinra targeting the IL-1 receptor). Of note, the black arrows represent an activation function, whereas the purple arrows represent blocking function. Abbreviations: CD, Castleman's disease; EGFR, epidermal growth factor receptor; HHV-8, human herpes virus 8; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; IL-1R, IL-1 receptor; IL-6R, IL-6 receptor; MCD, multicentric Castleman's disease; NF-κB, nuclear factor κB; VEGF, vascular endothelial growth factor; vIL-6, viral IL-6.