Updates in the pharmacologic management of various Castleman disease subtypes: A comprehensive review

Abstract

Objective

To review current pharmacologic strategies for Castleman disease (CD), integrating contemporary understanding of disease biology, diagnostic subclassification, and therapeutic approaches across unicentric Castleman disease (UCD); Human Herpesvirus-8 (HHV-8)–associated multicentric Castleman disease (MCD); polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma-cell disorder, skin changes (POEMS)–associated MCD; and idiopathic MCD (iMCD).

Data Sources

A comprehensive search of PubMed, Embase, and the Cochrane Library (2000–2025) was performed, supplemented by manual review of references and guidelines from the Castleman Disease Collaborative Network (CDCN), the National Comprehensive Cancer Network (NCCN), and the American Society of Clinical Oncology (ASCO). Included literature encompassed clinical trials, natural-history studies, and mechanistic work relevant to CD.

Data Summary

CD represents a biologically heterogeneous spectrum driven largely by dysregulated cytokine signaling, particularly interleukin-6 (IL-6). UCD is typically approached with surgical excision, whereas MCD requires subtype-specific systemic therapy. Rituximab remains the cornerstone of HHV-8–associated MCD. Management of POEMS-associated disease focuses on controlling the plasma-cell clone. In iMCD, IL-6–directed therapies (siltuximab or tocilizumab) represent first-line treatment, often supported by corticosteroids. Subtypes differ biologically: iMCD-idiopathic plasmacytic lymphadenopathy (iMCD-IPL) generally responds well to IL-6 blockade, whereas iMCD with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (iMCD-TAFRO) is aggressive and may require early escalation to cyclosporine, rituximab, or chemotherapy. Emerging data showing mTORC1 hyperactivation provide rationale for mTOR inhibition, while case-level responses to JAK-2 inhibitors warrant further study.

Conclusions

CD is clinically and biologically diverse. IL-6 blockade, B-cell-directed therapy, and plasma-cell-targeted strategies anchor current management, while mTOR and JAK-2 inhibitors merit investigation in the relapsed/refractory setting.