Clinical UM Guideline

 

Subject: Siltuximab (Sylvant®)
Guideline #: CG-DRUG-79 Publish Date:    12/27/2017
Status: New Last Review Date:    11/02/2017

Description

This document addresses the indications for the use of siltuximab (Sylvant, Janssen Biotech, Inc, Horsham, PA). Siltuximab is a human-mouse chimeric monoclonal antibody that binds human interleukin-6 (IL-6), effectively hampering the uncontrolled proliferation of lymphatic cells.

Note: Please see the following related documents for additional information:

Clinical Indications

Medically Necessary:

Siltuximab is considered medically necessary as a treatment for individuals with multicentric Castleman’s disease (MCD) when all the following criteria are met:

  1. Human immunodeficiency virus (HIV)-negative; and
  2. Human herpes virus-8 (HHV-8)-negative; and
  3. No concurrent clinically significant infection (for example, Hepatitis B or C); and
  4. No concurrent lymphoma.

Not Medically Necessary:

Siltuximab is considered not medically necessary when the above criteria are not met and for all other indications.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J2860

Injection, siltuximab, 10 mg [Sylvant]

 

 

ICD-10 Diagnosis

 

D47.Z2

Castleman disease

Discussion/General Information

Castleman’s disease (CD), also known as angiofollicular lymph node hyperplasia, is a rare condition characterized by enlarged lymph nodes (lymphadenopathy). Involvement of a single node is classified as unicentric CD, a condition with a milder clinical course and substantially better survival outcome than multicentric Castleman’s disease (MCD). MCD, by contrast, is characterized by generalized lymphadenopathy and hepatomegaly, fevers, night sweats and, frequently immunosuppression and HHV-8 infection. Both unicentric CD and MCD are associated with multiple malignancies. Recent U.S. estimates from a review by Fajgenbaum and colleagues (2014) report approximately 1000-1300 Americans currently have this rare disease; most cases in the U.S. are attributable to HIV or HHV-8. Diagnosis is usually achieved by resection of an affected lymph node and histologic evaluation. Timeliness of diagnosis is hampered by the tendency of clinicians to rule-out other potential causes before exploring the possibility of MCD.

Although the etiology of MCD is not well understood, levels of IL-6 and other inflammatory cytokines are consistently elevated with this diagnosis. IL-6 is associated with a wide range of malignancies and autoimmune diseases and uncontrolled proliferation of this inflammatory marker plays a pivotal role in the cascade of symptoms that characterize MCD.

Siltuximab is a human-mouse chimeric monoclonal antibody that binds human interleukin-6 (IL-6). It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of MCD in HIV-negative and HHV-8-negative individuals; a subset of MCD which has most recently been identified as idiopathic MCD (iMCD). Prior to siltuximab, there was no FDA approved treatment for this disease. 

From 2010-2013, van Rhee and colleagues conducted a randomized, double-blind, placebo-controlled study of individuals with MCD (van Rhee, 2014). Out of 140 participants screened, a total of 79 with symptomatic MCD were enrolled and randomized 2:1, using block randomization, to receive siltuximab 11 mg/kg (n=53) or placebo (n=26), every 3 weeks. Participants were enrolled across 38 hospitals in 19 countries and were comparable demographically across both study arms. Criteria for inclusion included the following: at least 18 years of age, measurable and symptomatic MCD, adequate organ function, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or better, and stable or decreasing use of no more than 1 mg/kg/day of corticosteroids in at least the 4 weeks preceding enrollment. Exclusion criteria included the following: HIV seropositive, HHV-8 seropositive, skin lesions as the only measurable symptomatology of MCD, malignancies (except treated basal and squamous cell carcinoma of the skin, and carcinoma in situ of the cervix, if no evidence of disease in the 3 preceding years), comorbid diseases that could interfere with study participation (for example, Hepatitis B or C, concurrent or a history of lymphoma), and previous exposure to IL-6 or IL-6 receptor targeted therapies. Between 50-60% of both arms had received prior systemic treatment for MCD. All study participants’ treatment continued until treatment failure, and best supportive care was administered in both arms. Participants in the placebo arm were permitted to cross-over to the siltuximab arm in the event of treatment failure; 13 (50%) chose to do so. The primary endpoints of improvement in durable tumor response (complete response or partial response; via radiologic imaging) and symptomatic response (pre-determined MCD relevant criteria) were met in 34% of the siltuximab arm and 0% of the placebo arm (P=0.001; 95% confidence interval [CI], 11.1-54.8). Furthermore, a superior response was also observed in the secondary endpoints of tumor response rate and time to treatment failure. Concentrations of C-reactive protein were measured as a proxy for IL-6 concentration (siltuximab treatment affects direct measure of IL-6 concentration) and significant reductions from baseline were observed in the siltuximab arm. Placebo concentrations remained stable. The median time to measurable response was 33 days and median duration of masked treatment was 375 days in the treatment group and 152 days in the placebo arm. Serious adverse events occurred in 23% of the siltuximab arm, in comparison to 19% of the placebo group. Types of adverse reactions that occurred more frequently (> 10%) in the treatment group included upper respiratory infection, weight gain, localized edema, pruritus and rash. A total of 3 participants experienced serious adverse events that were reasonably related to siltuximab treatment; sepsis, lower respiratory infection and anaphylaxis. It is noteworthy that 2 participants (4%) died due to disease progression in the siltuximab arm and 4 (15%) died in the placebo arm (3 due to disease progression, 1 due to co-morbid serious illness); no treatment-related deaths were reported. Finally, no significant difference was seen in response rates or adverse and serious events in newly diagnosed MCD participants compared to those with refractory disease. Authors concluded that siltuximab is an active, effective and safe agent in both treatment naïve individuals with MCD and individuals who have failed other therapies. FDA approval was granted on the basis of this pivotal clinical trial.

A phase II, open-label, extension-study was conducted by van Rhee and colleagues (2016) in which 19 individuals with stable MCD, were followed for a median duration of 5.1 years and administered siltuximab intravenously, 11mg/kg every 3 weeks. The most frequent grade 3 or higher adverse events included hypertension, nausea, cellulitis and fatigue. Less frequent grade 3 or higher adverse events included leukopenia, lymphopenia and polycythemia. Hypertriglyceridemia and hypercholesterolemia were also reported in approximately 50% of study enrollees. During the course of follow-up (range; 3.4-7.2 years including the phase I study), no disease relapses occurred (evaluated by radiologic response); 8 of the 19 study participants were switched to an every 6-week dosing regimen.

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (CPG) for non-Hodgkin’s lymphoma (V3.2016) includes a 2A recommendation for the treatment of unicentric castleman’s disease (CD) with siltuximab as a second-line therapy for relapsed or refractory presentation. The guideline does not contain any explanation for the recommendation. To date, the treatment of unicentric CD with siltuximab has only been studied in phase I dose-finding clinical trials.

Siltuximab’s effectiveness lies in its ability to bind to IL-6, hindering the signaling cascade that produces the proliferation of lymphatic cells in MCD. Siltuximab is not intended to cure MCD but has demonstrated considerable benefit in management of the condition. Siltuximab was not studied in individuals with MCD who are HIV positive or HHV-8 positive because it has not been shown to be effective at binding to virally produced IL-6 in pre-clinical studies. Siltuximab suppresses the body’s immune response through inhibition of IL-6 and subsequently C-reactive protein; as a result, siltuximab is not recommended for use in individuals with severe, active infections (for example, Hepatitis B or C). Of the participants treated with siltuximab in clinical studies, 35% (127) were 65 years of age or older. No overall differences in safety profiles have been observed in the geriatric population (Product Information [PI] Label, 2017).

Warnings and Adverse Events
The FDA PI Label (2017) includes the following information and recommendations:

Adverse Events

Other Warnings and Precautions

Definitions

Castleman’s disease (CD): A rare, non-cancerous disorder that affects the lymph nodes and other immune-cell structures throughout the body; CD has two variants: unicentric CD and multicentric Castleman’s disease (MCD), and is also known as giant lymph node hyperplasia and angiofollicular lymph node hyperplasia.

Chimeric antibody: A recombinant or genetically engineered antibody which contains polypeptides from a different species (i.e., mouse) than the species it is intended to treat (i.e., human).

C-reactive protein: C-reactive protein (CRP) is a substance produced by the liver that increases in the presence of inflammation in the body; it is considered a non-specific "marker" for disease.

Interleukin-6 (IL-6): A cytokine that is primarily produced at sites of acute and chronic inflammation, where it is secreted into the serum and triggers an inflammatory response.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

References

Peer Reviewed Publications:

  1. Fajgenbaum D, van Rhee R, Nabel C. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood. 2014; 123(19):2924-2933.
  2. Kurzrock R, Voorhees PM, Casper C, et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res. 2013; 19(13):3659-3670.
  3. Liu Y, Stone K, van Rhee F. Siltuximab for multicentric Castleman disease. Expert Rev Hematol. 2014; 7(5): 545-557.
  4. van Rhee F, Casper C, Voorhees PM, et al. A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease. Oncotarget. 2015; 6(30):30408-30419.
  5. van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. J Clin Oncol. 2010; 28(23):3701-3708.
  6. 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.

Government Agency, Medical Society and Other Authoritative Publications:

  1. Janssen Research and Development, LLC. A Randomized, Double Blind, Placebo Controlled Study to Assess the Efficacy and Safety of CNTO 328 (Anti IL 6 Monoclonal Antibody) Plus Best Supportive Care Compared With Best Supportive Care in Subjects With Multicentric Castleman's Disease. NLM Identifier: NCT01024036. Last updated on October 5, 2016. Available at: http://clinicaltrials.gov/ct2/show/study/NCT01024036?term=siltuximab&rank=12. Accessed on September 16, 2017.
  2. National Cancer Institute (NCI). Siltuximab. Last updated on July 31, 2014. Available at: http://www.cancer.gov/cancertopics/druginfo/siltuximab. Accessed on September 16, 2017.
  3. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 16, 2017.
  4. NCCN Clinical Practice Guidelines in Oncology®. © 2017 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org/index.asp. Accessed on September 16, 2017.
    • Non-Hodgkin’s Lymphomas (V4.2017). Revised September 08, 2017.
  5. Siltuximab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised October 30, 2015. Accessed on September 16, 2017.
  6. Siltuximab (Sylvant). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated February 01, 2017. Available at: http://www.micromedexsolutions.com. Accessed on September 16, 2017.
  7. Sylvant® [Product Information], Horsham, PA; Updated April 04, 2017. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=451f535b-8b6b-4ecf-9f19-d921b72eea39. Accessed on September 16, 2017.
  8. U.S. Food and Drug Administration (FDA). Center for Drug Evaluation and Research (CDER). Siltuximab Summary Review. FDA. Rockville, MD. April 23, 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125496Orig1s000SumR.pdf. Accessed on September 16, 2017.
Websites for Additional Information
  1. American Cancer Society (ACS). Castleman Disease. Last updated May 23, 2016. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003093-pdf.pdf. Accessed on September 16, 2017. 
  2. National Cancer Institute (NCI). Available at: http://www.cancer.gov/. Accessed on September 16, 2017.
Index

Multicentric Castleman’s Disease
Monoclonal Antibody
Sylvant

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

New

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

New

11/01/2017

Hematology/Oncology Subcommittee review. Initial document development. Moved content of DRUG.00070 Siltuximab (Sylvant®) to new clinical utilization management guideline document with the same title.