UNDERSTANDING iMCD

Diagnosing iMCD

Criteria from the Castleman Disease Collaborative Network (CDCN) help identify and diagnose iMCD1

Major criteria (both needed)

  1. Histopathologic lymph node features consistent with iMCD
  2. Enlarged lymph nodes (≥1 cm in short-axis diameter) in ≥2 lymph node stations (eg, neck and armpit)

Minor criteria (need ≥2 of 11 criteria with ≥ 1 laboratory criterion)

Laboratory

  1. Elevated CRP or ESR
  2. Anemia
  3. Thrombocytopenia/
    thrombocytosis
  4. Hypoalbuminemia
  5. Renal dysfunction or proteinuria
  6. Polyclonal hypergammaglobulinemia

Clinical

  1. Constitutional symptoms
  2. Enlarged spleen and/or liver
  3. Fluid accumulation
  4. Eruptive cherry hemangiomatosis or violaceous papules
  5. Lymphocytic interstitial pneumonitis

Exclusion Criteria

  1. Must rule out diseases that can mimic iMCD (malignant, infectious, and autoimmune disorders)
An image of an excisional and core biopsy

Image courtesy of Dr. Jadee Neff, Duke University Medical Center

CRP, C-reactive protein; ESR, Erythrocyte sedimentation rate.

Excisional biopsies are recommended by the CDCN as the most effective way to diagnose iMCD1,2

  • An excisional biopsy provides a more complete picture of the histopathological changes in an affected lymph node2
  • Fine needle or core biopsies are unlikely to capture affected tissue and may be inadequate for accurate diagnosis2
Icons of a man and a woman with thought bubbles over their heads

Clinical collaboration with pathology helps accelerate diagnosis and treatment plan1

  • Provide excisional biopsy—or full architecture—to facilitate definitive diagnosis
  • Share full patient picture (lab values, history)

World Health Organization (WHO) also recognizes the complexity of iMCD diagnosis3,4

Requirements for iMCD Diagnosis3

  1. Fulfillment of morphologic, clinical, and laboratory criteria
  2. Exclusion of other diseases, including HIV infection, Kaposi sarcoma herpesvirus (KSHV)/ HHV-8 infection, and other forms of Castleman disease

Histopathology3

  1. The histopathologic findings in iMCD are variable and non-specific, with morphologic findings showing overlap with other forms of Castleman diseasea

Essential diagnostic criteria3

  1. Enlarged lymph nodes in ≥2 sites
  2. Lymph node morphology showing Grade 2 or 3 regressed germinal centers or plasmacytosis
  3. Clinical, laboratory, and exclusion criteria fulfilled

World Health Organization (WHO) Classification of iMCD: Contributors to the 5th edition of the WHO Classification of Haematolymphoid Tumors, composed of expert members in hematopathology, hematology, oncology, genetics, epidemiology, radiation oncology, immunology, and molecular biology, convened in 2021 to provide guidelines for the diagnosis and treatment of hematolymphoid tumors, including iMCD.4

aOverlapping histopathological findings may include unicentric CD, MCD-POEMS (plasma cell neoplasm with associated paraneoplastic syndrome), and KSHV/HHV‑8‑associated MCD.3

HHV-8, human herpesvirus-8; HIV, human immunodeficiency virus; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes.

How SYLVANT Works

Discover the binding power of Sylvant.

References:
1. 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. 2. Montes-Moreno S, Climent F, Fraga M, et al. Expert consensus on the integrated diagnosis of idiopathic multicentric Castleman disease. Rev Esp Patol. 2023;56(3):158-167. 3. WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [internet; beta version ahead of print]. WHO classification of tumours series, 5th ed; vol. 11. Lyon (France): International Agency for Research on Cancer; 2022. Accessed July 22, 2024. https://tumourclassification.iarc.who.int/chapters/63. 4. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720-1748.

INDICATIONS AND USAGE

SYLVANT® (siltuximab) is an interleukin-6 (IL-6) antagonist 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.

IMPORTANT SAFETY INFORMATION

SYLVANT is contraindicated in patients experiencing a severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT. Hypersensitivity reactions, including anaphylactic reaction, hypersensitivity, and drug hypersensitivity have been reported in patients treated with siltuximab.

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.

Vaccinations: Do not administer live vaccines to patients or infants born to patients receiving SYLVANT because IL-6 inhibition may interfere with the normal immune response to new antigens.

Infusion Related Reactions and Hypersensitivity: SYLVANT may cause infusion-related reactions and anaphylaxis. 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: 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) during treatment with SYLVANT in the MCD clinical trial were rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia.

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases, Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch.

Drug Interactions with Cytochrome P450 (CYP450) Substrates: Inhibition of IL-6 signaling in patients treated with SYLVANT may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment with SYLVANT.

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).

Pregnancy and Lactation: SYLVANT may cause embryo-fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with SYLVANT and for 3 months after the last dose. Advise patients not to breastfeed during treatment with SYLVANT and for 3 months after the final dose.

Pediatric Use: The safety and efficacy of SYLVANT have not been established in pediatric patients.

Dosing and Administration: 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 Table 1 of the Prescribing Information are not met, consider delaying treatment with SYLVANT. Do not reduce dose.

SYLVANT® (siltuximab) for injection, for intravenous use, is available as 100 mg or 400 mg of lyophilized powder in a single-dose vial.

Please see the accompanying full Prescribing Information.

INDICATIONS AND USAGE

SYLVANT® (siltuximab) is an interleukin-6 (IL-6) antagonist 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.

IMPORTANT SAFETY INFORMATION

SYLVANT is contraindicated in patients experiencing a severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT. Hypersensitivity reactions, including anaphylactic reaction, hypersensitivity, and drug hypersensitivity have been reported in patients treated with siltuximab.