Vol 52, No 1 (2021)
Review article
Published online: 2021-02-26

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Idiopathic multicentric Castleman disease: pathogenesis, clinical presentation and recommendations for treatment based on the Castleman Disease Collaborative Network (CDCN)

Beata Ostrowska1, Joanna Romejko-Jarosińska1, Katarzyna Domańska-Czyż1, Jan Walewski1
Acta Haematol Pol 2021;52(1):29-37.


Castleman disease is a very rare, lymphoproliferative disease, driven by dysregulation of the cytokine interleukin 6 (IL-6) and other proinflammatory cytokines with the development of symptoms of systemic inflammation, reactive proliferation of lymphocytes, and damage to numerous organs. HHV-8 infection plays a major role in the pathogenesis of human immunodeficiency virus (HIV+) multicentric Castleman disease (MCD). The aetiology of the idiopathic form of MCD (HIV/HHV-8 negative) is unknown. In 2017, a panel of Castleman Disease Collaborative Network (CDCN) experts developed unified diagnostic criteria necessary for the diagnosis of idiopathic MCD. The disease has a diverse course, with a broad spectrum from mild to severe. The drug of choice according to the CDCN recommendation of 2018 for patients requiring treatment is anti-IL-6 monoclonal antibody, siltuximab. Immunomodulatory and immunosuppressive drugs are an alternative first-line treatment when anti-IL-6/IL-6R drugs are unavailable, and in subsequent lines of treatment after the failure of anti-IL-6 antibodies. Chemotherapy is reserved for the treatment of severe forms of the disease. The prognosis in most patients is moderately good. Unfortunately, the availability of the new therapies remains limited.

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  1. Castleman B, Towne VW. Case records of the Massachusetts General Hospital; weekly clinicopathological exercises founded by Richard C. Cabot. N Engl J Med. 1954; 251: 396–400.
  2. Gaba AR, Stein RS, Sweet DL, et al. Multicentric giant lymph node hyperplasia. Am J Clin Pathol. 1978; 69(1): 86–90.
  3. Lachant NA, Sun NC, Leong LA, et al. Multicentric angiofollicular lymph node hyperplasia (Castleman's disease) followed by Kaposi's sarcoma in two homosexual males with the acquired immunodeficiency syndrome (AIDS). Am J Clin Pathol. 1985; 83(1): 27–33.
  4. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood. 1995; 86(4): 1276–1280.
  5. Fajgenbaum DC, Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018; 132(22): 2323–2330.
  6. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017; 129(12): 1646–1657.
  7. Takai K, Nikkuni K, Shibuya H, et al. [Thrombocytopenia with mild bone marrow fibrosis accompanied by fever, pleural effusion, ascites and hepatosplenomegaly] [Article in Japanese] . Rinsho Ketsueki. 2010; 51(5): 320–325.
  8. Simpson D. Epidemiology of Castleman disease. Hematol Oncol Clin North Am. 2018; 32(1): 1–10.
  9. Boutboul D, Fadlallah J, Chawki S, et al. Treatment and outcome of unicentric Castleman disease: a retrospective analysis of 71 cases. Br J Haematol. 2019; 186(2): 269–273.
  10. Dispenzieri A, Armitage JO, Loe MJ, et al. The clinical spectrum of Castleman's disease. Am J Hematol. 2012; 87(11): 997–1002.
  11. Oksenhendler E, Boutboul D, Fajgenbaum D, et al. The full spectrum of Castleman disease: 273 patients studied over 20 years. Br J Haematol. 2018; 180(2): 206–216.
  12. Iwaki N, Fajgenbaum DC, Nabel CS, et al. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol. 2016; 91(2): 220–226.
  13. Bower M, Newsom-Davis T, Naresh K, et al. Clinical features and outcome in HIV-associated multicentric Castleman's disease. J Clin Oncol. 2011; 29(18): 2481–2486.
  14. Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020; 135(16): 1353–1364.
  15. Nabel CS, Sameroff S, Shilling D, et al. Virome capture sequencing does not identify active viral infection in unicentric and idiopathic multicentric Castleman disease. PLoS One. 2019; 14(6): e0218660.
  16. Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castleman's disease: a systematic literature review. Lancet Haematol. 2016; 3(4): e163–e175.
  17. Li Z, Lan X, Li C, et al. Recurrent PDGFRB mutations in unicentric Castleman disease. Leukemia. 2019; 33(4): 1035–1038.
  18. You L, Lin Q, Zhao J, et al. Whole-exome sequencing identifies novel somatic alterations associated with outcomes in idiopathic multicentric Castleman disease. Br J Haematol. 2020; 188(5): e64–e67.
  19. Fajgenbaum DC, Langan RA, Japp AS, et al. Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease. J Clin Invest. 2019; 129(10): 4451–4463.
  20. El-Osta HE, Kurzrock R. Castleman's disease: from basic mechanisms to molecular therapeutics. Oncologist. 2011; 16(4): 497–511.
  21. Talat N, Belgaumkar AP, Schulte KM. Surgery in Castleman's disease: a systematic review of 404 published cases. Ann Surg. 2012; 255(4): 677–684.
  22. Yu Li, Tu M, Cortes J, et al. Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease. Blood. 2017; 129(12): 1658–1668.
  23. Rhee Fv, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018; 132(20): 2115–2124.
  24. van Rhee F, Casper C, Voorhees PM, et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res. 2013; 19(13): 3659–3670.
  25. van Rhee F, Casper C, Voorhees PM, et al. A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease. Oncotarget. 2015; 6(30): 30408–30419.
  26. van Rhee F, Wong RS, Munshi N, et al. Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014; 15(9): 966–974.
  27. Morra DE, Pierson S, Shilling D, et al. Predictors of response to anti‐IL6 monoclonal antibody therapy (siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phaseIIclinical trial data. Br J Haematol. 2018; 184(2): 232–241.
  28. Nishimoto N, Honda O, Sumikawa H, et al. A long-term (5-Year) sustained efficacy of tocilizumab for multicentric Castleman’s disease and the effect on pulmonary complications. Blood. 2007; 110(11): 646–646.
  29. Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008; 112(10): 3959–3964.
  30. Ramasamy K, Gandhi S, Tenant-Flowers M, et al. Rituximab and thalidomide combination therapy for Castleman disease. Br J Haematol. 2012; 158(3): 421–423.
  31. Zhang Lu, Zhao AL, Duan MH, et al. Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease. Blood. 2019; 133(16): 1720–1728.
  32. El-Osta H, Janku F, Kurzrock R. Successful treatment of Castleman's disease with interleukin-1 receptor antagonist (Anakinra). Mol Cancer Ther. 2010; 9(6): 1485–1488.
  33. Zhou X, Wei J, Lou Y, et al. Salvage therapy with lenalidomide containing regimen for relapsed/refractory Castleman disease: a report of three cases. Front Med. 2017; 11(2): 287–292.
  34. Khan AA, Siraj F, Bhargava M, et al. Successful treatment of multicentric Castleman's disease accompanying myeloma with bortezomib. BMJ Case Rep. 2012; 2012.
  35. Zhu SH, Yu YH, Zhang Y, et al. Clinical features and outcome of patients with HIV-negative multicentric Castleman's disease treated with combination chemotherapy: a report on 10 patients. Med Oncol. 2013; 30(1): 492.
  36. Masaki Y, Kawabata H, Takai K, et al. Proposed diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, 2015 version. Int J Hematol. 2016; 103(6): 686–692.
  37. Shirai T, Onishi A, Waki D, et al. Successful treatment with tacrolimus in TAFRO syndrome: two case reports and literature review. Medicine (Baltimore). 2018; 97(23): e11045.
  38. Fajgenbaum D, Shilling D, Partridge HL, et al. Prolonged remission achieved in a relapsing idiopathic multicentric castleman disease patient with a novel, targeted treatment approach [abstract]. Blood. 2017; 130(Suppl 1): 3593.
  39. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999; 17(4): 1244.