Mechanism of Action

SYLVANT® (siltuximab) Works by Neutralizing IL‑6 in Patients With iMCD

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

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Guidelines

Preferred by the NCCN and the CDCN for the Treatment of iMCD

Regardless of disease severity or histopathology, siltuximab is recommended by the National Comprehensive Cancer Network® (NCCN®) and the Castleman Disease Collaborative Network (CDCN) as the preferred first-line treatment option in patients with iMCD.4,5

Please visit the following links to learn more: Download Treatment Guidelines

Did you know?

SYLVANT is the only FDA-approved treatment for iMCD.1

SYLVANT 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.

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  • NCCN Logo - Siltuximab (SYLVANT) is recommended by the NCCN as the preferred treatment for idiopathic multicentric Castleman disease. SYLVANT is the first-line therapy recommended by CDCN.
  • CDCN Logo - Siltuximab (SYLVANT) is recommended by the NCCN as the preferred treatment for idiopathic multicentric Castleman disease. SYLVANT is the first-line therapy recommended by CDCN.
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NCCN Guidelines®

Updates in Version 2.2021 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

NCCN Guidelines on the treatment of idiopathic multicentric Castleman disease.

Abbreviations: C/A/P CT, chest-abdomen-pelvis computed tomography; DLBCL, diffuse large B-cell lymphoma; FDA, US Food and Drug Administration; HHV-8(–), human herpesvirus-8 negative; HIV-1(–), human immunodeficiency virus type 1 negative; iMCD, idiopathic multicentric Castleman disease; MCD, multicentric Castleman disease; PET-CT, positron emission tomography–computed tomography.

  1. See Criteria for Active Disease (CD-A) in the NCCN Guidelines for more information.
  2. See Diagnostic Criteria for Idiopathic MCD (CD-B) in the NCCN Guidelines for more information.
  3. Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion. This substitution cannot be made for rituximab used in combination with ibritumomab tiuxetan.
  4. An FDA-approved biosimilar is an appropriate substitute for rituximab.
  5. Response assessment using the imaging modalities performed during workup (C/A/P CT with contrast or PET-CT).
  6. Encourage biopsy to rule out transformation to DLBCL or concomitant development of other malignancies or opportunistic infections.
  7. Rituximab ± prednisone may repeat without limit if progression ≥6 months after completion of rituximab.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation   in clinical trials is especially encouraged.

Secondary analysis of siltuximab clinical trial data concluded that there was clinically relevant efficacy among patients with iMCD with hyaline vascular histopathology. Real-world studies further demonstrated that patients with hyaline vascular histopathology responded to anti–IL-6 therapy. The FDA approved SYLVANT for use in all patients with iMCD, regardless of histopathology.1,6

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CDCN Treatment Guidelines

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

METHODOLOGY

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

CDCN guidelines on the treatment of idiopathic multicentric Castleman disease.

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.

  1. Patients with iMCD should be stratified for disease severity per the Evidence Categories Defined figure above. Siltuximab is recommended as frontline therapy for patients with nonsevere iMCD. Tocilizumab can be used if siltuximab is not available or approved. Steroids are useful adjunctive therapy, and the dose can be tailored according to the severity of the disease. For patients responding to anti–IL-6 mAb therapy, treatment should be continued indefinitely.5
  2. According to NCCN Guidelines and CDCN Treatment Guidelines, rituximab is not the preferred drug for the treatment of patients with iMCD.4,5
  3. For patients with mild symptomatology, a limited course of rituximab is an alternative option. Patients not responding to anti–IL-6 mAb therapy should be considered for rituximab-based therapy + steroids ± immunomodulatory/immunosuppressive agents.5
  4. Immunomodulatory/immunosuppressive agents for second- or third-line therapy include thalidomide, cyclosporine A, sirolimus, anakinra, or bortezomib, but consulting with an expert is recommended at this stage. Severe iMCD must be closely monitored, as life-threatening events may occur in this population. Severely ill patients should be treated with siltuximab and high-dose steroids, but if no clear response occurs within 1 week (or if status worsens at any time), then combination chemotherapy should be considered. When possible, expert advice should be sought to identify the most appropriate therapy for a given patient. Further therapy is best individualized.5
  5. Examples of chemotherapy include R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-VDT-PACE (rituximab, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide), or etoposide/cyclophosphamide/rituximab. Siltuximab is the preferred anti–IL-6 therapy. However, in countries where siltuximab is not available or approved, tocilizumab can be used instead.5
Evidence Categories Defined5,7
Category 1 Based upon high-level evidence, there is uniform CDCN consensus that the intervention is appropriate
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.

Efficacy

Clinical Efficacy for SYLVANT Has Been Proven in the Only Randomized Clinical Trial in Patients With iMCD

Durable Tumor and Symptomatic Response (Independent Review)1

34% (P=0.0012)
Graph showing the efficacy of SYLVANT (siltuximab) compared with placebo in people with idiopathic multicentric Castleman disease.

34% of patients receiving SYLVANT along with best supportive care (BSC) achieved the primary end point vs 0% of those on placebo and BSC

  1. All patients received best supportive care (BSC), which included management of effusions, use of antipyretic, antipruritic, antihistamine, and pain drugs, management of infections and transfusions, and standard management of infusion-related reactions, as specified in institutional guidelines.8

34% of patients receiving SYLVANT along with best supportive care (BSC) achieved the primary end point vs 0% of those on placebo and BSC.

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SYLVANT Produces Better Outcomes When More of the CDCN Diagnostic Criteria Are Met

Significant Improvement When at Least 2 Criteria Are Met9

At least 4 (n=22) At least 3 (n=28) At least 2 (n=35) 60% 50% 40% 30% 20% 10% 0% None (n=16) 55% 46% 43% 0% Patients 34% previously achieving the primary end point Number of Minor Criteria Met 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).
Graph showing the efficacy of SYLVANT (siltuximab) in people with idiopathic multicentric Castleman disease.

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

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STUDY DESIGN

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

Safety

Serious Adverse Events Were Similar Between SYLVANT and Placebo

Per-Patient Incidence of Common Adverse Reactions in the Pivotal Trial During Initial 8 Infusions of SYLVANT1,5,a
Data showing adverse events of SYLVANT (siltuximab) and placebo on patients with idiopathic multicentric Castleman disease.
OF PATIENTS >10%

Most common adverse events occurring in >10% of patients in any group included1:

  • Rash
  • Pruritus
  • Upper respiratory tract infections
  • Edema
  • Hyperuricemia
  • Weight gain
6% OF PATIENTS

6% of patients had serious adverse events related to SYLVANT, including lower respiratory tract infections.8

  1. To control for disparate exposure between arms, this table reports the per-patient incidence of adverse reactions that occurred during the first 8 infusions.1
  2. All patients received best supportive care (BSC), which included management of effusions, use of antipyretic, antipruritic, antihistamine, and pain drugs, management of infections and transfusions, and standard management of infusion-related reactions, as specified in institutional guidelines.8
  3. Anaphylactic reaction.1
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Image of a doctor ordering SYLVANT (siltuximab) on an iPAD.

Long-term Safety

Clinical Safety and Efficacy Have Been Studied in Patients for Over 10 Years1,a

97% of patients maintained or achieved disease control at their last on-study assessment10,b

Image of a doctor ordering SYLVANT (siltuximab) on an iPAD.
  • Median treatment duration of 5.5 years (range, 0.8 to 10.8 years)1,10
  • This study is a prespecified, open-label extension analysis of the phase 1 and phase 2 SYLVANT trials, enrolling 60 patients with histologically confirmed iMCD who completed the previous trials without disease progression on SYLVANT10
  • SYLVANT was well tolerated, with no evidence of cumulative toxicity within 6 years10
  • Durable disease control recorded in 70% of patients treated with SYLVANT for up to 6 years10
  • The most common adverse events (≥ grade 3) were as follows10:
    • Hypertension (13%)
    • Fatigue (8%)
    • Nausea (7%)
    • Neutropenia (7%)
    • Vomiting (5%)
  • Only 2 of 60 patients (3%) discontinued due to either adverse events or disease progression
  • No deaths were reported during the 6-year period10
STUDY DESIGN

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

  1. Median follow-up time.
  2. Some of these patients discontinued before the 6-year data cutoff point.
References:
  1. SYLVANT [package insert]. Hertfordshire, UK: EUSA Pharma UK Ltd; 2019.

  2. Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castlemans disease: a systematic literature review. Lancet Haematol. 2016;3(4):e163-e175.

  3. Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018;132(22):2323-2330.

  4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.2.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed February 25, 2021. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

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