Natural History Study of Idiopathic Multicentric Castleman Disease Identifies Effective Treatments for a Large Proportion of Patients but Treatment-Refractory Patients Remain
Authors: Pierson Sheila K , Ren Yue , Khor Johnson , Haljasmaa Eric , Ziglar Jasira , Floess Katherine , NaPier Erin , Akhter Faizaan , Liu Amy Y , Gibson Damilola , Kanhai Karan , Martin Rabecka , Chadburn Amy , Srkalovic Gordan , Lim Megan S. , Casper Corey , Uldrick Thomas S. , Jaffe Elaine S. , van Rhee Frits , Lee Hongzhe , Fajgenbaum David C 
Published: November 2019

Background
Human herpes-virus 8-negative/idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder involving multicentric lymphadenopathy with characteristic histopathology. Clinical presentation is heterogenous and includes cytokine-driven constitutional symptoms, cytopenias, systemic inflammation, and multi-organ dysfunction. International consensus treatment guidelines are based on a large cohort of case studies and a few clinical trials, but the available evidence is limited. Siltuximab, an anti-IL-6 therapy, is the only FDA-approved treatment for iMCD; 34% of patients achieved durable symptomatic and tumor response in the phase II trial. Tocilizumab, an anti-IL-6 receptor therapy, is frequently used off label and demonstrated promising results in an open-label study in Japan. The treatment guidelines recommend siltuximab ± corticosteroids (CS) as first-line therapy for all iMCD patients and tocilizumab as a substitute when siltuximab is not available. Rituximab, a CD20 antibody, is recommended as an alternate first-line therapy in patients who are non-severe and do not exhibit marked cytokine-driven symptoms. In all other patients, rituximab is recommended second-line; however, it has never been systematically evaluated in iMCD. Chemotherapies, immunosuppressants, and immunomodulators are recommended second- or third-line, but again, effectiveness is not well described. Better understanding of treatment effectiveness is urgently needed. Herein, we describe treatment and response in a real-world cohort of iMCD patients.
Methods
Data were collected and abstracted for 68 patients enrolled in an on-going IRB-approved natural history study of Castleman disease. Diagnosis is graded by an expert panel of clinicians and pathologists on an on-going basis; patients unlikely to have iMCD were excluded from analysis (N=12). Of the 56 patients included, 37 (66%) are expert panel-confirmed and 19 (34%) are awaiting confirmation. Durable response is defined as achieving ≥50% improvement in the proportion of abnormal iMCD minor clinical and laboratory diagnostic criteria sustained for ≥1 year. Small sample size prevented statistical comparisons.
Results
Median age at diagnosis is 33 years (range: 1-65 years). The cohort is 52.9% female, 63% white, and 4 (7%) patients died. Thirty-three unique drugs, including anti-IL-6 therapies, CS, chemotherapies, immunosuppressants, and others have been administered across the 56 patients. Rituximab is the most frequently used drug, administered to 39 (70%) patients. Siltuximab (29 patients, 52%) and tocilizumab (19 patients, 34%) are the next two most frequently used targeted therapies. There was a 52% response (15/29) to regimens inclusive of siltuximab, 50% response (9/18) to those inclusive of tocilizumab, and 25% response (9/26) to those inclusive of rituximab. Siltuximab±CS induced response in 15/24 (63%) patients, tocilizumab±CS in 4/7 (57%), and rituximab±CS in 2/13 (15%). Among the 37 expert-confirmed iMCD patients, we found a 58% response (11/19) to regimens inclusive of siltuximab, 47% (8/17) to those inclusive of tocilizumab, and 27% (7/26) to those inclusive of rituximab. Further, in these patients, siltuximab±CS induced response in 11/16 (69%), tocilizumab±CS in 3/6 (50%), and rituximab±CS in 1/6 (17%) patients. Of note, 3 of 4 deceased patients received both anti-IL-6 therapy and rituximab and all 4 received chemotherapies and immunosuppressants but did not respond to any drug.
Discussion
These data reveal that despite there being one FDA-approved treatment, iMCD is treated with a variety of agents. Among the full cohort, siltuximab±CS demonstrated a 63% durable response, which was higher than the response reported in the clinical trial (not statistically compared). This may reflect differences in response criteria and/or disease activity of patients in clinical trials versus real world settings. Siltuximab and tocilizumab have never been systematically compared; in this cohort they demonstrated similar response. Considering the morbidity and mortality of iMCD, these data suggest that current therapies demonstrate important activity. However, additional agents are needed for refractory patients, who have few options and are at risk of death due to disease progression. Further data are needed to compare groups and identify optimal treatment protocols.

Disclosures
Liu: BridgeBio Pharma: Employment, Equity Ownership. Gibson:EUSA Pharma: Employment. Kanhai:EUSA Pharma: Employment. Martin:EUSA Pharma: Employment. Srkalovic:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Foundation Medicine: Speakers Bureau; EUSA Pharma: Speakers Bureau. Uldrick:Patent: Patents & Royalties: co-inventor on US Patent 10,001,483 entitled ; Celgene: Other: research support from Celgene through a CRADA at the NCI; Roche: Other: commercial research support through a CTA with Fred Hutchinson Cancer Research Center; Merck: Other: drug for a clinical trial from Merck through a CRADA with the NCI. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; Karyopharm Therapeutics: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Castleman Disease Collaborative Network: Consultancy. Fajgenbaum:Janssen Pharmaceuticals: Research Funding.

OffLabel Disclosure:
Tocilizumab, a monoclonal antibody directed against IL-6-receptor, is approved for use in rheumatoid arthritis in the US. It is frequently used off-label in idiopathic multicentric Castleman disease (iMCD) and is recommended as a substitute first-line therapy in the International Consensus iMCD treatment guidelines. Rituximab, a monoclonal antibody directed against CD20, is used in rheumatoid arthritis and other autoimmune and cancerous disorders. It is frequently used off-label in iMCD and is recommended as an alternate first-line or a second-line therapy in the International Consensus iMCD treatment guidelines. Corticosteroids are used broadly in iMCD and are recommended as needed as useful adjunctive therapy in the International Consensus iMCD treatment guidelines.