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 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|
|Nonspecific cytotoxic immuno-depletion||CHOP||yes||yes|
|Non-specific immune activation||Corticosteroids||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):
- Conventional anti-inflammatory and immunosuppressive therapies
- Blockade of IL-6 signaling with mAbs
- Cytotoxic elimination of inflammatory cells with chemotherapy (treatment of preference for HHV-8-associated MCD)
- 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 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, doxorubicin, and/or antivirals are also used.
This therapeutic target database was last updated 4/2017.