The first-ever iMCD treatment guidelines were published in the journal Blood in 2018. Please visit here for more information.
The below iMCD Treatment Target Dashboard summarizes evidence for treatments of HHV-8-negative/idiopathic multicentric Castleman disease (iMCD) that have been published in the scientific literature. For information on treatments for other sub-types of Castleman disease, click here. We were inspired by our colleagues at the Chordoma Foundation to create this dashboard.
Drugs often exert their effects by binding to targets within cells to alter subsequent actions of the target in an effort to treat disease. 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. If a target is not listed below, it has either not been reported in the medical literature for the treatment of iMCD or we have not yet come across the published paper describing its use. Please feel free to email info@castlemannetwork.org if you’re aware of a treatment target that should be listed below.
| 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 |
There are four main treatment categories (please visit here for specific recommendations):
- Blockade of IL-6 signaling with monoclonal antibodies
- Anti-inflammatory and immunosuppressive therapies
- Cytotoxic elimination of inflammatory cells with chemotherapy
- Novel therapies targeting other cytokines and intracellular signaling pathways
1) 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.
2) 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.
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.
For information regarding treatment for other sub-types of Castleman disease, please click here.
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.