The National Comprehensive Cancer Network® (NCCN®) has updated their Clinical Practice Guidelines in Oncology for B-Cell Lymphomas to include siltuximab (Sylvant®; EUSA Pharma) as a preferred primary treatment for patients with human immunodeficiency virus-negative [HIV(-)] and human herpesvirus 8–negative [HHV-8(-)] multicentric Castleman disease (MCD), also known as idiopathic multicentric Castleman disease (iMCD), with plasmacytic or mixed pathology. [1]

Siltuximab is a monoclonal antibody that blocks the action of interleukin 6 (IL-6), a multifunctional cytokine detected at elevated levels in iMCD patients. a rare, life-threatening and debilitating lymphoproliferative disorder, which causes an abnormal overgrowth of immune cells and shares many symptomatic and histological features with lymphoma.

Siltuximab is currently approved in more than 40 countries worldwide for the treatment of all histopathologic subtypes of iMCD, a rare, life-threatening and debilitating orphan condition of the lymph nodes and related tissues. [2][3]

The drug is the only FDA-approved therapy indicated for iMCD. The updated guidelines state to continue treatment with siltuximab until disease progression occurs, as noted in the prescribing information. [1][2]

The updated recommendations include the consensus diagnostic criteria for iMCD created by the Castleman Disease Collaborative Network (CDCN). The CDCN convened an international working group that included 34 pediatric and adult hematopathology, hematology/oncology, rheumatology, immunology, and infectious disease experts in iMCD and related disorders to establish the first-ever evidence-based, patient-guided, expert consensus diagnostic criteria for the treatment of iMCD. [3]

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The criteria define diagnosis by the presence of multicentric lymphadenopathy with defined plasmacytic, mixed, or hyaline histopathologic subtypes, at least two clinical/laboratory abnormalities, and exclusion of diseases mimicking iMCD. [3]

“I’m pleased that the body of evidence presented to the NCCN has resulted in siltuximab being chosen as the preferred first-line treatment option for patients with iMCD with a plasmacytic or mixed phenotype,” said Jeff Hackman, President of EUSA Pharma, North America.

“We’re is committed to supporting patients with iMCD through their treatment journey,”  Hackman added.

Retrospective analysis
The NCCN based their recommendation on data from the phase II randomized clinical study evaluating the safety and efficacy of siltuximab and a retrospective analysis performed by the CDCN on the same data, as the diagnostic criteria did not exist at the time siltuximab was approved.

In the phase II study, more than one-third of patients in the siltuximab arm had a durable tumor and symptomatic response to treatment plus best supportive care (BSC), compared with none of the patients who received placebo plus BSC (34% versus 0%; 95% CI, 11.1-54.8; P=0.0012). [4]

A durable response was defined as tumor and symptomatic response (reduction in tumor size and disease symptoms) that persisted for a minimum of 18 weeks without treatment failure. [4] Applying the diagnostic criteria to the siltuximab study, siltuximab-treated patients meeting the minimum criteria for a diagnosis of iMCD had a durable tumor and response rate of 43%, and patients meeting at least four minor criteria had a durable tumor and response rate of 55%. [3]

“I am very excited that the NCCN now endorses siltuximab for the treatment of iMCD and recognizes the importance of the diagnostic guidelines established by the CDCN,” noted Frits van Rhee, M.D., Ph.D., professor of medicine and clinical director of the University of Arkansas for Medical Sciences Myeloma Center, who was the lead investigator on the siltuximab studies.

Benjamin Castleman was an American physician and pathologist best known for describing angiofollicular lymphoid hyperplasia, a disease which is named after him. This photo was taken by the International Academy of Pathology in 1961, in recognition of his contributions to pathology.

Castleman disease
Castleman disease, first described by Benjamin L. Castleman, MD, in the 1950s, also known as giant lymph node hyperplasia and angiofollicular lymph node hyperplasia (AFH) is a lymphoproliferative disorder, not cancer.

As a proliferative disorder of the lymph nodes and related tissues, it can be easily confused with other autoimmune, cancerous, or infectious disorders and is often misdiagnosed. [3][4]

Furthermore, while Castleman disease is not officially cancer, one form of this disease, known as multicentric Castleman disease, acts very much like lymphoma and many patients with this disease eventually develop lymphomas. Multicentric Castleman disease, which is often treated with chemotherapy or radiation therapy, affects multiple groups of lymph nodes throughout the body and can present as idiopathic, or iMCD, causing histopathological changes, without HIV or HHV-8 infection.

iMCD shares characteristics across different malignancies, autoimmune conditions, and infectious disorders. [3] The symptoms vary from patient to patient, and as a result, it becomes very challenging to diagnose.

The symptoms can be as mild as fever or as severe as a life-threatening cytokine storm spreading throughout the body, leading to organ failure and death. [3]

According to the American Cancer Society, the number of people diagnosed with Castleman disease each year is not clear. Although the National Cancer Institute (NCI) keeps track of the number of people diagnosed with different forms of cancer, Castleman disease is not cancer it is not included. However, recent studies looking at medical records of patients with Castleman disease suggest there may be about 4,300 to 5,100 new cases of the disease per year in the US. Furthermore, this data suggests that 544 to 957 patients in the United States are diagnosed with iMCD. [5][6]

Treating this disease effectively will improve overall survival, as there is a threefold increased prevalence of malignancy if not treated. [3]

The hyaline vascular (HV) histopathologic subtype of Castleman disease is considered to only occur in unicentric CD (UCD) based on the classic descriptions by Benjamin Castleman, and a few HV-UCD features, such as follicular dendritic cell (FDC) dysplasia and sclerotic vessels, are not often observed in MCD. [3][5]

Hyaline vascular features have been described in iMCD patients with TAFRO syndrome, characterized by a constellation of symptoms: thrombocytopenia, anasarca, reticulin fibrosis of the bone marrow, renal dysfunction and organomegaly. [3]

Randomized study
“Siltuximab is supported by the only randomized study in Castleman disease, as well as a long-term safety study. The final results of the long-term safety study have just been published in The Lancet Haematology, and siltuximab provided safe and durable disease control. I hope that the use of siltuximab will continue to improve the outcome of patients with iMCD.”

Sixty patients enrolled in the long-term safety extension studies from the phase I and phase II clinical trials, with hyaline vascular, plasmacytic, or mixed histology. [5] Durable disease control was recorded in 70% of patients for up to 6 years, and siltuximab was well tolerated in the vast majority of patients. Two patients (3%) had progressive disease during the study. There were no unexpected toxicities. [8]

Adverse events grade 3 or higher and serious adverse events were similar between siltuximab and placebo arms. The most common adverse events occurring in >10% of patients in any group included rash, pruritus, upper respiratory tract infections, edema, hyperuricemia, and weight gain.

In January EUSA Pharma and BeiGene announced that they have entered into an exclusive development and commercialization agreement for the orphan biologic products, including siltuximab) and in Greater China.

[1] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 1.2020. Published on January 22, 2020.
[2] SYLVANT [package insert]. Hertfordshire, UK: EUSA Pharma UK Ltd; 2019.
[3] Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-1657.
[4] 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.
[5] Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 2016;3(4):e163-e175.
[6] Van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018;132(20):2115-2124.
[7] Castleman B, Towne VW. Case records of the Massachusetts General Hospital; weekly clinicopathological exercises; founded by Richard C. Cabot. N Engl J Med. 1954;251:396–400.
[8] van Rhee F, Casper C, Voorhees PM, et al. Long-term safety of siltuximab in patients with idiopathic multicentric Castleman disease: a prespecified, open-label, extension analysis of two trials [published online February 3, 2020]. Lancet Oncol. doi:10.1016/S2352-3026(19)30257-1

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