What is the treatment approach for Castleman's disease?

Treatment Approach for Castleman's Disease

Initial Classification and Diagnostic Workup

Castleman's disease must be classified as unicentric (UCD) or multicentric (MCD) at diagnosis, as this fundamentally determines treatment strategy. 1

• Unicentric disease involves a single lymph node region and is treated with local therapy 1, 2
• Multicentric disease involves multiple lymph node regions and requires systemic therapy, with further subdivision into HHV-8-associated MCD and idiopathic MCD (iMCD) 1, 3

Essential baseline evaluation includes:

• Complete blood count with differential and inflammatory markers 1
• HHV-8 testing to distinguish HHV-8-associated from idiopathic MCD 1
• HIV testing, as HHV-8-associated MCD occurs predominantly in HIV-positive patients 1
• Assessment for POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), which can coexist with Castleman's disease 1, 4

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Treatment of Unicentric Castleman's Disease

Surgical resection is the definitive treatment for UCD and is curative in the vast majority of cases. 2, 5

• Complete excision of the affected lymph node mass achieves excellent long-term outcomes 5
• For POEMS syndrome with solitary or limited sclerotic bone lesions associated with Castleman's disease, radiation therapy is first-line treatment, achieving 97% 4-year overall survival 4
• Post-surgical follow-up every 3-6 months is recommended to monitor for rare recurrence or malignant transformation 1

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Treatment of HHV-8-Associated Multicentric Castleman's Disease

Rituximab monotherapy is the first-line treatment for HHV-8-associated MCD. 1

Treatment algorithm by disease severity:

Mild to moderate disease:

• Rituximab monotherapy (375 mg/m² weekly × 4-8 doses) 1
• Antiretroviral therapy must be administered concurrently in all HIV-positive patients 1

Severe disease or inadequate response:

• Add etoposide to rituximab 1
• For patients with concomitant Kaposi sarcoma, use cytotoxic chemotherapy in combination with rituximab 1

Critical monitoring considerations:

• Follow-up every 3-6 months with surveillance for disease relapse 1
• Monitor for development of non-Hodgkin lymphoma, which remains elevated despite rituximab treatment reducing this risk 1
• Watch for reactivation or progression of Kaposi sarcoma 1

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Treatment of Idiopathic Multicentric Castleman's Disease (iMCD)

Siltuximab (anti-IL-6 monoclonal antibody) with or without corticosteroids is the preferred first-line therapy for iMCD. 3

Severity-based treatment algorithm:

First-line therapy:

• Siltuximab is the preferred anti-IL-6 agent 3
• If siltuximab is unavailable, tocilizumab is an acceptable alternative 3
• Corticosteroids can be added for additional symptom control 3

Severe disease or life-threatening presentations:

• Initiate siltuximab/tocilizumab plus corticosteroids 3
• Add combination chemotherapy (rituximab plus cyclophosphamide) as adjuvant therapy 1, 6, 3
• Triple therapy with corticosteroids, rituximab, and cyclophosphamide is recommended for severe inflammation or inadequate response to IL-6 blockade alone 1, 6

Second-line therapy (after first-line failure):

• Switch between anti-IL-6 agents (siltuximab ↔ tocilizumab) 3
• Add rituximab if not previously used 3
• Consider cytotoxic chemotherapy regimens 3

Third-line therapy:

• High-dose chemotherapy with autologous stem cell transplantation for refractory disease 7
• This approach can achieve durable long-term remissions in otherwise treatment-refractory cases 7

Special considerations for refractory cytopenias:

• Splenectomy may be considered for severe refractory anemia and thrombocytopenia 1

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Treatment of POEMS Syndrome with Castleman's Disease

For disseminated POEMS syndrome with Castleman's disease, systemic chemotherapy followed by autologous stem cell transplantation is the recommended approach. 4

Treatment selection by disease extent:

Localized disease (solitary/limited sclerotic lesions):

• Radiation therapy achieves 97% 4-year overall survival and 52% failure-free survival 4
• Improvement occurs in 50-70% of patients 4

Disseminated disease:

• Melphalan-dexamethasone is first-line systemic therapy, achieving 81% hematologic response and 100% improvement in neuropathy 4
• Lenalidomide-dexamethasone is preferred when neuropathy is present due to lower neurotoxicity risk 4
• Autologous stem cell transplantation should be offered after induction chemotherapy to eligible patients, achieving 100% clinical improvement 4

Critical pitfalls to avoid:

• Do not use radiation alone for disseminated disease—systemic therapy is mandatory 4
• Do not use bortezomib-based regimens as first-line despite high response rates, due to induced neuropathy risk 4
• Thalidomide should be used cautiously given neurotoxicity concerns 4
• Do not expect immediate neurologic improvement—neurologic response significantly lags behind hematologic response, with maximum improvement expected after 2-3 years of successful therapy 4

Monitoring:

• Serum VEGF levels should be monitored as a marker of disease activity and treatment response 4

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Special Populations and Complications

Renal failure with IgG4 disease overlap:

• For severe renal impairment with monoclonal immunoglobulin deposition disease (MIDD), bortezomib-based regimens may lead to deep and rapid responses 6
• Defer kidney transplantation until complete disease remission is achieved 6

Pediatric Castleman's disease:

• Evidence is limited to case reports 8
• Success has been reported with interferon-based therapies and anakinra 8
• Corticosteroid monotherapy has been successful in isolated cases 8
• Direct implementation of Langerhans cell histiocytosis protocols has been unsuccessful 8

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Duration of Therapy and Long-Term Management

Treatment should be continued indefinitely if tolerated, though attempting cessation may be reasonable for patients with minimal or stable disease burden for prolonged periods on a case-by-case basis. 8

• Clinical follow-up every 3-6 months is mandatory for all patients 1
• Monitor for disease relapse, development of non-Hodgkin lymphoma, and progression of associated conditions 1
• Long-term survival with modern therapies, particularly interferon-based treatment, shows 68% 5-year survival, with informal expert experience suggesting even better outcomes 8