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Idiopathic Multicentric Castleman Disease: Identifying Prevalence and New Treatment Targets

November 24, 2021

November 2021 Bonus ASH Annual Meeting Preview Edition


Two recent studies published in Blood Advances explored idiopathic multicentric Castleman disease (iMCD). Researchers led by Sudipto Mukherjee, MD, MPH, of Cleveland Clinic, provided an updated understanding of the epidemiology of iMCD and identified an unmet need for interleukin-6 (IL-6) directed therapy for patients with iMCD in the U.S. Another study, led by Sheila K. Pierson, MS, of the University of Pennsylvania, examined the responses of patients with iMCD to anti-IL-6 therapy siltuximab and discovered a new therapeutic pathway for patients with iMCD who did not respond to siltuximab.

Prevalence of iMCD in the U.S.

To estimate the total number of iMCD cases in the U.S., Dr. Mukherjee and colleagues applied a claims-based algorithm to a base sample population of 30.7 million insured healthy individuals and patients with medical conditions. This algorithm included a Castleman disease–specific ICD-10 diagnosis code (D47.Z2) and relied on the presence of ≥2 codes corresponding to minor international evidence-based diagnostic criteria for iMCD. The investigators sourced deidentified longitudinal patient data from the IBM MarketScan Research Databases of inpatient and outpatient claims from January 2006 through March 2020.

Prior to this study, limited data was available on the epidemiology and treatment of iMCD – and Castleman disease more broadly – because of nonspecific diagnostic coding, according to Dr. Mukherjee.

In the U.S., the annual incidence and prevalence of iMCD was estimated at 3.4 cases per million (95% CI 1.4-9.2) and 6.9 cases per million (95% CI 3.7-13.3), respectively. According to the authors’ estimates, approximately 2,246 patients with iMCD (95% CI 1,223-4,348) were alive in the U.S. in 2017 and 3,172 in 2018 (95% CI 1,820-5,835).

Unmet Treatment Needs

Dr. Mukherjee and colleagues also performed a treatment pattern analysis and found that only 9.8% of patients with iMCD received an IL-6–targeted therapy, while 33.1% received no treatment, and 39% received corticosteroid monotherapy. “Given that siltuximab is the only FDA- and EMA-approved treatment for iMCD based on randomized controlled trial data and considering the morbidity and mortality associated with this condition, it is surprising that 90.2% of iMCD patients did not receive IL-6 targeted therapies,” Dr. Mukherjee wrote.

“Our findings highlight significant treatment gaps for iMCD patients, a large unmet treatment need for IL-6–directed therapies, and poor adherence to treatment guidelines,” he wrote.

Response to Siltuximab and New Treatment Pathways

Using a hierarchical clustering algorithm, Ms. Pierson and colleagues characterized the serum proteome of iMCD in the context of clinico-pathologically overlapping diseases Hodgkin lymphoma (HL), rheumatoid arthritis (RA), and human herpesvirus 8 (HHV8)-associated MCD. The researchers obtained samples from 73 patients with iMCD from a randomized phase II study of siltuximab and samples from 15 patients from real-world practice at six clinical sites.3 For comparison, they also obtained samples from 60 patients with HHV8-associated MCD (n=20), HL (n=20), and RA (n=20), as well as 42 healthy individuals. A validation cohort comprised 23 patients with iMCD who were enrolled in a phase I study of siltuximab.4

Among patients with iMCD whose disease did not respond to siltuximab, significant signaling of IL-6-JAK-STAT3 was observed in the enrichment analysis, despite the fact that IL-6 inhibition is ineffective in this subgroup. One-quarter of patients with iMCD in the study clustered with HL. In HL, increased IL-6 and IL-6 receptor expression are associated with worse survival outcomes, JAK-mediated signaling, sensitivity to the JAK1/2 inhibitor ruxolitinib, and increased pSTAT3 expression. Additionally, the researchers found that the peripheral blood mononuclear cells of patients in remission from iMCD demonstrated hypersensitivity to IL-6 simulation in vitro. “Together, these data suggest dysregulation of the IL-6-JAK-STAT3 signaling pathway may be important in iMCD,” Ms. Pierson wrote.

For patients with iMCD who do not respond to siltuximab, targeting the IL-6-JAK-STAT3 pathway with ruxolitinib, which has demonstrated activity in other hyperinflammatory, cytokine-driven diseases, may be useful, according to the investigators. Through their enrichment analysis, Ms. Pierson and colleagues identified additional pathways contributing to disease process in patients with iMCD that can be targeted with FDA-approved agents, including TNF alpha, interferon gamma, IL-2, and components of the allograft rejection signature. Considering their clinical activity in autoimmune diseases like RA and the proteomic overlap between some patients with iMCD and RA, “anti-TNF alpha drugs should be further investigated,” the authors wrote.

Study authors report no relevant conflicts of interest.


  1. Pierson SK, Shenoy S, Oromendia AB, et al. Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease. Blood Adv. 2021;5(17):3445-3456.
  2. Mukherjee S, Martin R, Sande B, et al. Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6 directed therapy [published online ahead of print, 2021 Sep 17]. Blood Adv. doi: 10.1182/bloodadvances.2021004441.
  3. van Rhee F, Wong RS, Munshi N, et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014;15(9):966-974.
  4. Kurzrock R, Voorhees PM, Casper C, et al. 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;19:3659-3670.


  January 2022


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