Castleman disease

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 Tarsheen Sethi, MD, MSCI
Yale University
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There are (at least) three distinct entities under this topic: unicentric Castleman's disease (UCD); HHV-8-positive multicentric Castleman's disease (MCD), which is usually (but not always) associated with HIV, and HHV-8-negative a.k.a. idiopathic MCD. UCD is usually treated with surgery or embolization. There are very few prospective trials for these diseases. The first-ever diagnostic criteria for HHV-8-negative "idiopathic" Multicentric Castleman disease can ensure diagnosis is correct and subsequent treatment is appropriate for the diagnosed subtype. You can read the full Diagnostic Criteria article here.

  • We have moved How I Treat articles to a dedicated page.
9 regimens on this page
9 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

CDCN

International Consensus guidelines

NCCN

HIV-associated multicentric Castleman disease, all lines of therapy

Rituximab monotherapy

Regimen

Study Dates of enrollment Evidence
Gérard et al. 2007 (ANRS 117 CastlemaB) 2003-03 to 2004-12 Phase 2
Bower et al. 2007 2003-2006 Phase 2

Targeted therapy

7-day cycle for 4 cycles (4-week course)

References

  1. ANRS 117 CastlemaB: Gérard L, Bérezné A, Galicier L, Meignin V, Obadia M, De Castro N, Jacomet C, Verdon R, Madelaine-Chambrin I, Boulanger E, Chevret S, Agbalika F, Oksenhendler E. Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's disease: ANRS 117 CastlemaB Trial. J Clin Oncol. 2007 Aug 1;25(22):3350-6. link to original article contains dosing details in manuscript PubMed
  2. Bower M, Powles T, Williams S, Davis TN, Atkins M, Montoto S, Orkin C, Webb A, Fisher M, Nelson M, Gazzard B, Stebbing J, Kelleher P. Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med. 2007 Dec 18;147(12):836-9. link to original article contains dosing details in manuscript PubMed

HHV-8-negative/"Idiopathic" multicentric Castleman disease, all lines of therapy

The first-ever diagnostic criteria for HHV-8-negative "idiopathic" multicentric Castleman disease was published in Blood in 2017. You can read the full PMC article here.

Anakinra monotherapy

Regimen

Study Evidence
Galeotti et al. 2008 Case report

Immunosuppressive therapy

Continued indefinitely

References

  1. Case report: Galeotti C, Tran TA, Franchi-Abella S, Fabre M, Pariente D, Koné-Paut I. IL-1RA agonist (anakinra) in the treatment of multifocal castleman disease: case report. J Pediatr Hematol Oncol. 2008 Dec;30(12):920-4. link to original article PubMed

Bortezomib monotherapy

Regimen

Study Evidence
Hess et al. 2006 Case report

Targeted therapy

21-day cycle for 6 cycles

References

  1. Case report: Hess G, Wagner V, Kreft A, Heussel CP, Huber C. Effects of bortezomib on pro-inflammatory cytokine levels and transfusion dependency in a patient with multicentric Castleman disease. Br J Haematol. 2006 Sep;134(5):544-5. link to original article PubMed
  2. Review: Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood. 2014 May 8;123(19):2924-33. Epub 2014 Mar 12. link to original article PubMed

Cyclosporine monotherapy

Regimen

Study Evidence
Inoue et al. 2013 Case report

Immunosuppressive therapy

References

  1. Case report: Inoue M, Ankou M, Hua J, Iwaki Y, Hagihara M, Ota Y. Complete resolution of TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) after immunosuppressive therapies using corticosteroids and cyclosporin A : a case report. J Clin Exp Hematop. 2013;53(1):95-9. link to original article PubMed

Placebo

Regimen

Study Evidence Comparator Comparative Efficacy
van Rhee et al. 2014 (CR016705) Randomized Phase 2 (C) Siltuximab Inferior durable tumor and symptomatic response for at least 18 weeks

No active treatment; all patients did receive "best supportive care."

References

  1. CR016705: van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fosså A, Simpson D, Capra M, Liu T, Hsieh RK, Goh YT, Zhu J, Cho SG, Ren H, Cavet J, Bandekar R, Rothman M, Puchalski TA, Reddy M, van de Velde H, Vermeulen J, Casper C. Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014 Aug;15(9):966-74. Epub 2014 Jul 17. Erratum in: Lancet Oncol. 2014 Sep;15(10):417. link to original article PubMed NCT01024036

Rituximab monotherapy

Regimen

Study Evidence
Ide et al. 2006 Pilot

Targeted therapy

7-day cycle for 4 to 8 cycles

Subsequent treatment

  • After the rituximab administration, oral prednisolone (15 mg/d, tapered to 5 mg/d) and/or alkylating agent (cyclophosphamide 100 mg/day or melphalan 2 mg/d) were started for maintenance therapy

References

  1. Ide M, Kawachi Y, Izumi Y, Kasagi K, Ogino T. Long-term remission in HIV-negative patients with multicentric Castleman's disease using rituximab. Eur J Haematol. 2006 Feb;76(2):119-23. link to original article PubMed
  2. Review: Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood. 2014 May 8;123(19):2924-33. Epub 2014 Mar 12. link to original article PubMed

Siltuximab monotherapy

Regimen

Study Evidence Comparator Comparative Efficacy
Kurzrock et al. 2013 (CR008566) Phase 1, >20 pts
van Rhee et al. 2014 (CR016705) Randomized Phase 2 (E-RT-esc) Placebo Superior durable tumor and symptomatic response for at least 18 weeks (primary endpoint)

Note: Patients had symptomatic, measurable, HIV-negative, and HHV-8-negative multicentric Castleman disease (MCD). Note that in the phase 1 study by Kurzrock et al. the MTD was 12 mg/kg, but the update reports using the 11 mg/kg dosing.

Immunosuppressive therapy

Supportive therapy

  • All patients received "best supportive care"

21-day cycles Patients in the extension of the phase 1 study could have their treatment interval lengthened to every 6 weeks if they had a documented PR/CR at 6 months.

References

  1. CR008566: Kurzrock R, Voorhees PM, Casper C, Furman RR, Fayad L, Lonial S, Borghaei H, Jagannath S, Sokol L, Usmani SZ, van de Velde H, Qin X, Puchalski TA, Hall B, Reddy M, Qi M, van Rhee F. 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 Jul 1;19(13):3659-70. Epub 2013 May 9. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org NCT00412321
    1. Update: van Rhee F, Casper C, Voorhees PM, Fayad LE, van de Velde H, Vermeulen J, Qin X, Qi M, Tromp B, Kurzrock R. 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 Oct 6;6(30):30408-19. link to original article link to PMC article PubMed
  2. CR016705: van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fosså A, Simpson D, Capra M, Liu T, Hsieh RK, Goh YT, Zhu J, Cho SG, Ren H, Cavet J, Bandekar R, Rothman M, Puchalski TA, Reddy M, van de Velde H, Vermeulen J, Casper C. Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014 Aug;15(9):966-74. Epub 2014 Jul 17. Erratum in: Lancet Oncol. 2014 Sep;15(10):417. link to original article PubMed NCT01024036

Sirolimus monotherapy

Regimen

Study Evidence
Iwaki et al. 2016 Case report

Immunosuppressive therapy

References

  1. Case report: Iwaki N, Fajgenbaum DC, Nabel CS, Gion Y, Kondo E, Kawano M, Masunari T, Yoshida I, Moro H, Nikkuni K, Takai K, Matsue K, Kurosawa M, Hagihara M, Saito A, Okamoto M, Yokota K, Hiraiwa S, Nakamura N, Nakao S, Yoshino T, Sato Y. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol. 2016 Feb;91(2):220-6. link to original article PubMed

TCP

TCP: Thalidomide, Cyclophosphamide, Prednisone

Regimen

Study Dates of enrollment Evidence
Zhang et al. 2019 (ZS-1159) 2015-06 to 2018-06 Phase 2

Targeted therapy

Chemotherapy

Glucocorticoid therapy

7-day cycle for 104 cycles (2 years)

References

  1. ZS-1159: Zhang L, Zhao AL, Duan MH, Li ZY, Cao XX, Feng J, Zhou DB, Zhong DR, Fajgenbaum DC, Li J. Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease. Blood. 2019 Apr 18;133(16):1720-1728. Epub 2019 Feb 13. link to original article contains dosing details in abstract PubMed NCT03043105

Tocilizumab monotherapy

Regimen

Study Evidence
Nishimoto et al. 2005 Phase 2

Immunosuppressive therapy

14-day cycle for 8 cycles; could be extended at physician discretion

References

  1. Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, Nakano N, Ikeda Y, Sasaki T, Nishioka K, Hara M, Taguchi H, Kimura Y, Kato Y, Asaoku H, Kumagai S, Kodama F, Nakahara H, Hagihara K, Yoshizaki K, Kishimoto T. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005 Oct 15;106(8):2627-32. Epub 2005 Jul 5. link to original article contains dosing details in manuscript PubMed
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