BURLINGTON, Mass., Feb. 10, 2020/PRNewswire
EUSA Pharma today announced that the National Comprehensive Cancer Network (NCCN) has updated their Clinical Practice Guidelines in Oncology for B-Cell Lymphomas to include SYLVANT® (siltuximab) 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 SYLVANT® 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 SYLVANT® is currently the only FDA-approved therapy indicated for iMCD. The NCCN guidelines also state to continue treatment with SYLVANT® until disease progression occurs, as noted in the prescribing information.1,2
The NCCN recommendations also include the consensus diagnostic criteria for iMCD created by the Castleman Disease Collaborative Network (CDCN). The CDCN convened an international working group comprising 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 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 SYLVANT® being chosen as the preferred first-line treatment option for patients with iMCD with a plasmacytic or mixed phenotype, and EUSA Pharma is committed to supporting patients with iMCD through their treatment journey," said Jeff Hackman, President of EUSA Pharma, North America.
The NCCN based their recommendation on data from the phase 2 randomized clinical study evaluating the safety and efficacy of SYLVANT® and a retrospective analysis performed by the CDCN on the same data, as the diagnostic criteria did not exist at the time SYLVANT® was approved. In the phase 2 study, more than one-third of patients in the SYLVANT® 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 SYLVANT® study, SYLVANT®-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,” said 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. “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 1 and phase 2 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 SYLVANT® was well tolerated in the vast majority of patients. Two patients (3%) had progressive disease during the study. There were no unexpected toxicities.5
Adverse events grade 3 or higher and serious adverse events were similar between SYLVANT® 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.
Castleman disease (CD) is 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 Multicentric CD 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 hence, 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 Every year, 544 to 957 patients in the United States are diagnosed with iMCD.6,7 Treating 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 HV 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
SYLVANT® is a monoclonal antibody that blocks the action of interleukin 6 (IL-6), a multifunctional cytokine detected at elevated levels in iMCD patients. SYLVANT® is approved in a number of jurisdictions and indicated for the treatment of patients with MCD who are HIV–negative and HHV-8–negative. iMCD is a rare, life-threatening and debilitating lymphoproliferative disorder, which causes abnormal overgrowth of immune cells and shares many symptomatic and histological features with lymphoma.
EUSA Pharma has exclusive rights to SYLVANT® in the United States. EUSA Pharma has granted BeiGene, Ltd., exclusive rights to SYLVANT® in Greater China.
Indications and Usage
SYLVANT® (siltuximab) is indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
Limitations of Use: SYLVANT® was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT® did not bind to virally produced IL-6 in a nonclinical study.
Contraindications: Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT®.
SYLVANT® Important Safety Information
Concurrent Active Severe Infections
Do not administer SYLVANT® to patients with severe infections until the infection resolves. SYLVANT® may mask signs and symptoms of acute inflammation including suppression of fever and of acute Phase reactants such as C-reactive protein (CRP). Monitor patients receiving SYLVANT® closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT® until the infection resolves.
Do not administer live vaccines to patients receiving SYLVANT® because IL-6 inhibition may interfere with the normal immune response to new antigens.
Infusion Related Reaction and Hypersensitivity
If treatment criteria outlined in Table 1 of the Dosage & Administration section of the Prescribing Information are not met, consider delaying treatment with SYLVANT®. Do not reduce dose.
Stop the infusion of SYLVANT® if the patient develops signs of anaphylaxis. Discontinue further therapy with SYLVANT®.
Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the SYLVANT® infusion may be restarted at a lower infusion rate. Consider medicating with antihistamines, acetaminophen, and corticosteroids.
Discontinue SYLVANT® if the patient does not tolerate the infusion following these interventions.
Administer SYLVANT® in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.
Gastrointestinal (GI) Perforation
Gastrointestinal (GI) perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated with or suggestive of GI perforation.
Most common adverse reactions (>10% of patients) included rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia.
Cytochrome P450 Substrates
Upon initiation or discontinuation of SYLVANT®, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of SYLVANT® on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when SYLVANT® is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).
Dosage and Administration
Administer SYLVANT® 11 mg/kg over 1 hour as an intravenous infusion every 3 weeks until failure.
Perform hematology laboratory tests prior to each dose of SYLVANT® therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in the Prescribing Information are not met, consider delaying treatment with SYLVANT®. Do not reduce dose.
Do not administer SYLVANT® to patients with severe infections until the infection resolves.
Discontinue SYLVANT® in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.
Please see full Prescribing Information for SYLVANT® for additional information. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
About EUSA Pharma
Founded in March 2015, EUSA Pharma is a world-class biopharmaceutical company focused on oncology and rare disease. The company has extensive commercial operations in the United States and Europe, alongside a direct presence in select other markets across the globe. EUSA Pharma is led by an experienced management team with a strong record of building successful pharmaceutical companies and is supported by significant funding raised from leading life science investor EW Healthcare Partners. For more information, please visit www.eusapharma.com.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 1.2020. Published January 22, 2020.
SYLVANT® [package insert]. Hertfordshire, UK: EUSA Pharma UK Ltd; 2019.
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.
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.
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
Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 2016;3(4):e163-e175.
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.
National Comprehensive Cancer Network®, Inc. 2020. To view the most recent and complete version of the guideline, go online to NCCN.org.
NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any wa
SYLVANT® is a registered trademark of EUSA Pharma in the United States. All trademarks are properties of their respective owners.
EUSA Pharma (US) LLC
SOURCE: EUSA Pharma
©EUSA Pharma. All Rights Reserved. US-SIL-2000015