Molecular Evidence

  • Interleukin 6 or IL-6 is a proinflammatory mutlifunctional cytokine believed to be released in excess by malignant immune cells activated by unknown causes. 
  • Animal studies have shown that excess IL-6 causes characteristic histopathological and clinical changes in patients with iMCD and leads to multiple organ dysfunctions.
    • Human IL-6 recombinant mice + mice infected with IL-6 expressing recombinant retrovirus develop iMCD-like syndrome; can be improved with anti-IL-6 receptor mAb administration.
  • Induces plasmacytosis and hypergammaglobulinemia, VEGF secretion, thromocytosis, acute inflammatory protein production in liver, and activation of macrophages and T cells.
  • Hypercytokinaemia or a cytokine storm sparked by IL-6 is believed to result in enlarged lymph nodes characteristically seen in iMCD patients.
    • The "hypercytokine-secreting cells" responsible for iMCD hypercytokinaemia through IL-6 secretion have not been identified and may differ between patients and histological subtypes.  
  • May also be responsible for autoimmune phenomena in iMCD such as hemolytic anemia by inducing expansion of autoantibody-producing CD5-positive B lymphocytes.
Clinical Evidence

  • In a systemic literature review of case reports on iMCD covering 128 clinical patients, IL-6 levels were reported for 63 patients and elevated in 57 (90%). Subsets of symptomatic patients have normal or only slightly elevated IL-6 levels and do not respond to anti-IL-6 treatment.
    • This suggests that the disease may not be purely driven by IL-6 alone and likely involved other cytokines.
    • Anti-IL-6 agents may need lifelong administration because relapse has been reported on cessation.
  • Patients with IL-6 secreting hematologic and solid malignancies develop iMCD-like histopathoogy and symptomatology, which resolve with IL-6 blockade or tumor incision.
  • Administration of pharmalogical doses of recombinant IL-6 in humans can lead to an iMCD-like syndrome.
  • An increased frequency of 2 single nucleotide polymorphisms in the IL-6 receptor was seen among 58 iMCD patients compared with 50 controls in one recent study. Higher levels of soluble IL-6 receptor among individuals with these polymorphisms was also seen.
  • Serum IL-6 levels have been correlate with symptom severity in patients, and interruption of the IL-6 signalling cascade can ameliorate symptoms and lead to lymph node involution.

Approved Clinical Therapies

  1. Siltuximab: human-murine antibody that binds with high affinity to IL-6. It is the only approved treatment for multicentric Castleman’s disease in North America and Europe. 
    • Findings of a double-blind, placebo controlled phase 2 trial showed significantly higher durable tumor response (lymph node regression) and symptomatic response (2% complete and 32% partial response) compared with placebo (0%; p=0.0012). 
    • 66% of patients with iMCD did not respond in randomized clinical trial. 
    • Used in first-line treatment without in cytotoxic agent in 11 patients and with cytotoxic agent in 4. 
    • Anti-IL-6 therapy with siltuximab was most effective first-line treatment with ten (91%) of 11 patients achieving complete initial response and two of 11 patients failing first-line treatment by follow-up. 
  2. Tocilizumab: humanized IL-6 receptor antagonist that is capable of almost completely blocking transmembrane signaling of IL-6. Reduces inflammation related to IL-6 signaling cascade. Currently approved for treatment of multicentric Castleman disease in Japan and used off-label worldwide for treatment of iMCD. 
    • In open-label prospective study of 28 patients on tocilizumab, ten (43%) of 23 patients with enlarged lymph nodes at baseline saw a decrease in size below 10mm after 16 weeks.