Castleman disease

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9 regimens on this page 9 variants on this page

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.

HIV-associated multicentric Castleman's disease

Rituximab monotherapy

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Regimen

Study	Evidence
Gérard et al. 2007 (ANRS 117 CastlemaB)	Phase II
Bower et al. 2007	Phase II

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once per week

4-week course

References

1. 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 verified protocol 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 verified protocol PubMed
3. Bower M. How I treat HIV-associated multicentric Castleman disease. Blood. 2010 Nov 25;116(22):4415-21. Epub 2010 Aug 5. link to original article PubMed

HHV-8-negative/"Idiopathic" Multicentric Castleman’s disease

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

Anakinra monotherapy

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Regimen

Study	Evidence
Galeotti et al. 2008	Case report

Therapy

• Anakinra (Kineret) 1 mg/kg SC once per day

References

1. 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

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Regimen

Study	Evidence
Galeotti et al. 2008	Case report

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11

21-day cycle for six cycles

References

1. 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

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Regimen

Study	Evidence
Inoue et al. 2013	Case report

To be completed

Immunosuppressive therapy

• Cyclosporin A

References

1. 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

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Regimen

Study	Evidence	Comparator	Efficacy
van Rhee et al. 2014	Phase III	Siltuximab	Inferior durable tumor and symptomatic response for at least 18 weeks

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

References

1. 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

Rituximab monotherapy

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Regimen

Study	Evidence
Ide et al. 2006	Pilot

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once per week

4 to 8 doses

After the rituximab administration, oral predonisolone (15 mg/d, tapered to 5 mg/d) and/or alkylating agent (cyclophosphamide 100 mg/d 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

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Regimen

Study	Evidence	Comparator	Efficacy
van Rhee et al. 2014	Phase III	Placebo	Superior durable tumor and symptomatic response for at least 18 weeks

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

Chemotherapy

• Siltuximab (Sylvant) 11 mg/kg IV over 1 hour once on day 1

Supportive medications

• All patients received "best supportive care"

21-day cycles, given until treatment failure

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

References

1. Phase I: 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. link to original article contains verified protocol PubMed content property of HemOnc.org
   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. 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

Sirolimus monotherapy

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Regimen

Study	Evidence
Iwaki et al. 2016	Case report

To be completed

Immunosuppressive therapy

• Sirolimus (Rapamycin)

References

1. 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

Tocilizumab monotherapy

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Regimen

Study	Evidence
Nishimoto et al. 2005	Phase II

Chemotherapy

• Tocilizumab (Actemra) 8 mg/kg IV once every 2 weeks

16-week course; 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 verified protocol PubMed

Chemotherapy

Regimen

• R-CHOP or CHOP or [R]-CHOEP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin (also called Doxorubicin or Adriamycin), Oncovin (or Vincristine), Etoposide, Prednisone or Prednisolone)
• 'CVP or COP or R-CVP' (Rituximab, Cyclophosphamide, Vincristine (Oncovin), and Prednisone)
• CAV, 'CVAD or hyper-CVAD' (Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone)
• ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine)
• Vincristine plus prednisone
• Etoposide plus corticosteroids

References

1. For a list of chemotherapy regimens used plus their references, please visit http://www.cdcn.org/about-castleman-disease/treatments/nonspecific-cytotoxic-immuno-depletion