SYLVANT is the only drug approved by the US Food and Drug Administration (FDA) that is indicated for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. A systematic literature review of HHV-8–negative MCD found that 90% to 100% of patients had elevated interleukin-6 (IL-6) levels.1,2
SYLVANT works by binding directly to IL-6 produced by the body to prevent it from interacting with both soluble and membrane-bound IL-6 receptors. Increased IL-6 signaling is one of the established drivers of idiopathic multicentric Castleman disease (iMCD).1-3
SYLVANT neutralizes circulating IL-6 and the resultant IL-6–driven cytokine storm in iMCD patients. This may lead to systemic inflammation, multicentric lymphadenopathy, cytopenia, and potentially fatal multiple organ dysfunction.3
Siltuximab (SYLVANT) is recommended by the National Comprehensive Cancer Network® (NCCN®) as a preferred treatment option for iMCD for plasmacytic/mixed histology. Siltuximab also continues to be the first-line therapy recommended by the Castleman Disease Collaborative Network (CDCN) guidelines with Category 1 evidence, regardless of histopathologic subtype.4,5
Please visit the following links to learn more: Download Treatment GuidelinesSYLVANT is an interleukin-6 (IL-6) antagonist indicated for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
Updates in Version 1.2020 of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas include new recommendations for the management of patients with iMCD.4
Abbreviations: C/A/P, chest-abdomen-pelvis; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; HHV-8, human herpesvirus-8; HIV, human immunodeficiency virus; IL-6, interleukin-6; iMCD, idiopathic multicentric Castleman disease; mAb, monoclonal antibody; MCD, multicentric Castleman disease; NCCN, National Comprehensive Cancer Network; PET, positron emission tomography.
Secondary analysis of siltuximab clinical trial data concluded that there was clinically relevant efficacy among patients with idiopathic multicentric Castleman disease (iMCD) with hyaline vascular histopathology. Real-world studies further demonstrated that patients with hyaline vascular histopathology responded to anti–IL-6 therapy. The US Food and Drug Administration (FDA) approved SYLVANT® (siltuximab) for use in all patients with HIV-negative and HHV-8–negative iMCD, regardless of histpathology.1,6
Castleman Disease Collaborative Network (CDCN), the same group that published the first consensus diagnostic criteria, has developed formal guidelines for the treatment of iMCD.5
In 2018, a working group of 42 international experts established the first evidence-based consensus treatment guidelines for iMCD, based on a review of 344 cases and expert opinion.5
Abbreviations: CD, Castleman disease; CDCN, Castleman Disease Collaborative Network; CR, complete response; HD, high-dose; IL-6, interleukin-6; iMCD, idiopathic multicentric Castleman disease; mAb, monoclonal antibody; NCCN, National Comprehensive Cancer Network; PR, partial response.
Category 1 | Based upon high-level evidence, there is uniform CDCN consensus that the intervention is appropriate |
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Category 2A | Based upon lower-level evidence, there is uniform CDCN consensus that the intervention is appropriate |
Category 2B | Based upon lower-level evidence, there is uniform CDCN consensus that the intervention is appropriate |
The treatment guidelines include recommendations for the use of products and treatment regimens that are not FDA approved. There are no head-to-head studies that have compared the treatment regimens described in the treatment guidelines. EUSA Pharma does not endorse the use of any product in an off-label manner.
Durable Tumor and Symptomatic Response (Independent Review)1
34% of patients receiving SYLVANT along with best supportive care (BSC) achieved the primary end point vs 0% of those on placebo and BSC
34% of patients receiving SYLVANT along with best supportive care (BSC) achieved the primary end point vs 0% of those on placebo and BSC.
Significant Improvement When at Least 2 Criteria Are Met9
NCCN recommends siltuximab (SYLVANT) as the preferred primary treatment for iMCD4
CDCN also recommends the frontline use of SYLVANT in treating iMCD5
Using Fisher’s exact test, patients who met at least 2 minor criteria were significantly more likely to respond to SYLVANT than those who did not (P=0.0003).
NCCN recommends siltuximab (SYLVANT) as the preferred primary treatment for iMCD4
CDCN also recommends the frontline use of SYLVANT in treating iMCD5
The phase 2 trial was a randomized, double-blind, placebo-controlled study conducted at 38 hospitals in 19 countries worldwide. The study included 79 patients with HIV-negative and HHV-8–negative MCD who underwent a 2:1 randomization to receive SYLVANT + BSC (n=53) or placebo + BSC (n=26). Efficacy was assessed until 48 weeks after the last patient began study treatment, which was approximately 3 years of follow-up. The primary end point measured percentage of patients achieving a durable tumor and symptomatic response. Key secondary end points included tumor response rate, median time to treatment failure, and number of patients who achieved ≥1.5 g/dL increase in hemoglobin.5
Most common adverse events occurring in >10% of patients in any group included1:
6% of patients had serious adverse events related to SYLVANT, including lower respiratory tract infections.8
This long-term safety study was a prespecified, open-label extension analysis of 60 patients who had previously completed either the phase 1 dose-finding study (NCT00412321) or the phase 2 placebo-controlled study (NCT01024036), with stable or improved disease. Except for 2 patients with unresectable unicentric disease included in the phase 1 trial, all patients had histologically confirmed, measurable, and symptomatic iMCD. All histological variants of iMCD were permitted. Only patients who had completed one of the preceding trials without progressive disease were permitted to enroll. The data cutoff for this trial was 6 years after the start of enrollment.10
SYLVANT [package insert]. Hertfordshire, UK: EUSA Pharma UK Ltd; 2019.
Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castlemans disease: a systematic literature review. Lancet Haematol. 2016;3(4):e163-e175.
Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018;132(22):2323-2330.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.1.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed February 10, 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 way.
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.
Fajgenbaum DC, Wu D, Goodman A, et al; Castleman Disease Collaborative Network Scientific Advisory Board diagnostic criteria international working group and treatment guidelines international working group. Insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease. Am J Hematol. Published online September 7, 2020. doi:10.1002/ajh.25992
NCCN Guidelines® & Clinical Resources: NCCN Categories of Evidence and Consensus. National Comprehensive Cancer Network® (NCCN®). https://www.nccn.org/professionals/physician_gls/categories_of_consensus.aspx. Accessed August 26, 2020.
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. Lancet Haematol. 2020;7(3):e209-e217.
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.
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.
Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT.
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.
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 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 or suggestive of GI perforation.
The most common adverse reactions (>10% compared to placebo) in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infections.
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).
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 additional important safety information.
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