Drugs often exert their effects by binding to targets within cells to alter subsequent actions of the target in an effort to treat disease. Below is the Therapeutic Target Dashboard summarizing evidence for treatments of HHV-8-negative/idiopathic multicentric Castleman disease (iMCD) that have been published in scientific literature. We were inspired by our colleagues at the Chordoma Foundation (https://www.chordomafoundation.org/targets/). While only two clinical trials have been performed on drugs specifically used to treat idiopathic multicentric Castleman disease (iMCD), the evidence compiled below suggests that additional targets including different proteins and signaling pathways can serve as therapeutic targets for treatment of iMCD. 

Treatment Target  Treatment Molecular Evidence (Rationale) Case Reports (Potential/Tested Therapies) Clinical Trials for iMCD
IL-6 Siltuximab yes yes yes, approved by FDA in 2014
  Tocilizumab yes yes yes, approved by Japanese regulatory agency in 2005
IL-1 Anakinra yes yes  
mTOR Sirolimus yes yes  
VEGF Sirolimus yes yes  
Proteasome Bortezomib yes yes  
Plasma cells Bortezomib yes yes  
NF-kB Bortezomib yes yes  
  Corticosteroids yes yes  
B-cells Rituximab yes yes  
T-cells Cyclosporin yes yes  
  Sirolimus yes yes
Calcineurin Cyclosporin yes yes  
NFAT  None yes    
Nonspecific cytotoxic immuno-depletion CHOP yes yes  
  CVP yes yes  
  Cyclophosphamide yes yes  
Non-specific immune activation Corticosteroids yes yes  
  IVIg yes yes  

HHV-8-negative/idiopathic Multicentric Castleman disease (iMCD): There are four main treatment categories (this is NOT a step-by-step listing of the order of therapies or a treatment algorithm; this is simply a listing of treatment options):

  1. Conventional anti-inflammatory and immunosuppressive therapies
  2. Blockade of IL-6 signaling with mAbs
  3. Cytotoxic elimination of inflammatory cells with chemotherapy (treatment of preference for HHV-8-associated MCD)
  4. Novel therapies targeting other cytokines and intracellular signaling pathways

1) Corticosteroids can improve symptoms during acute exacerbations of iMCD, but most patients relapse during steroid tapering. Immunosuppressive therapies, such as cyclosporine A and sirolimus, are being used more frequently as some physicians are treating MCD more like a systemic inflammatory disease.

2) Over the last decade, treatments directly targeting IL-6 have been employed. Tocilizumab, an anti-IL-6 receptor mAb that is approved to treat iMCD in Japan, has demonstrated effectiveness at inducing and maintaining remission. Siltuximab, an anti-IL-6 mAb that has been recently approved by the US Food & Drug Administration and European Medicines Agency, demonstrated durable tumor and symptomatic response at a significantly higher rate compared with placebo in the first randomized Phase II study in MCD (34% vs. 0%; p=0.0012). Both mAbs have shown clinical activity in iMCD and are potential candidates for frontline therapy. However, they require life-long administration and are not effective in all patients.

3) Rituximab, which eliminates B-lymphocytes, is effective in most cases of HHV-8-associated MCD and in some cases of iMCD, but typically does not provide long-term disease control for iMCD. Cytotoxic lymphoma-based chemotherapies (e.g. cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) induce responses in a large portion of the most severely ill MCD patients by eliminating a large portion of activated inflammatory cells, but relapses are common and side effects are significant.

4) Recently, therapeutic approaches targeting pathways upstream of IL-6 have been reported in iMCD and these deserve further exploration, particularly for anti-IL-6 refractory patients. Use of bortezomib, sirolimus, thalidomide, and anakinra (IL-1 receptor antagonist), have each been reported.

Unicentric Castleman disease (UCD): surgical excision is curative in almost all cases of UCD. If complete resection is not possible or curative, the above treatments for iMCD may also be used to treat UCD.

HHV-8-associated Multicentric Castleman disease (HHV-8-associated MCD): rituximab is highly effective in treating HHV-8-associated MCD. Occasionally, etoposide, liposomal doxorubicin, and/or antivirals are also used.

POEMS-associated Multicentric Castleman disease (POEMS-associated MCD): For patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Radiation to an isolated plasmacytoma is often curative (Dispenzieri, 2017). Corticosteroids are temporizing. Low dose conventional chemotherapy or high dose chemotherapy with autologous stem cell transplantation can be used if monoclonal plasma cells have spread throughout the body (Dispenzieri, 2015).

This therapeutic target database was last updated 6/2017. 

Please note that the Therapeutics Target Dashboard is for informational purposes only. The content is an aggregate of publicly available research studies and is not intended to be taken as medical advice. The Therapeutics Target Dashboard includes various targets of treatment options that have been used in idiopathic multicentric Castleman disease (iMCD) patients. Molecular evidence is generated by basic research studies to discover differences in genes, proteins and signaling pathways. The case reports included in the Dashboard were all published and included descriptions of the indicated therapeutic agent used in an iMCD patient and how the patient responded to the treatment. Clinical trials are conducted to test a therapeutic agent relevant to the target of interest in iMCD patients. Please consult your physician before pursuing any of these treatment options.