Abstract
Castleman’s disease is a rare lymphoproliferative disorder in which overproduction of interleukin (IL)-6 causes a polyclonal B cell proliferation resulting in lymph node enlargement and debilitating symptoms, including autoimmune phenomena, systemic inflammatory manifestations (e.g., fever, fatigue, and weight loss) and markedly abnormal laboratory findings (e.g., anemia, hyper-γ-globulinemia, hypoalbuminemia, thrombocytosis and increases in acute-phase proteins like CRP, ESR and fibrinogen). There is no satisfactory systemic treatment for Castleman’s disease. CNTO 328 is a chimeric monoclonal antibody that binds with both high specificity and high affinity while neutralizing the biological activity of human IL-6. In an ongoing phase 1 study of CNTO 328, 22 patients with Castleman’s disease (9 newly diagnosed) were treated according to the following schedule: 3 mg/kg q 2 weeks (n= 1), 6 mg/kg q 2 weeks (n=2), 12 mg/kg q 2 weeks (n=3), 9 mg/kg q 3 weeks (n=5), 12 mg/kg q 3 weeks (n=8), or 6 mg/kg weekly (n=3). Disease types included hyaline vascular (9), plasmacytic (11), mixed (1) and undetermined (1). No patients are known to be either HIV+ or HHV−8+. The average number of infusions received was 23 with median drug exposure of 295 days (up to 1015 days). CNTO 328 was well tolerated with 10 patients (45%) having no drug-related toxicity greater than grade 1 and three patients (14%) with drug-related toxicity of grade 3 or higher (anemia, vomiting, herpes zoster). The most common drug related side effects, seen in more than 10% of patients were elevated ALT, hypertriglyceridemia, hypercholesterolemia and upper respiratory tract infection. There were no deaths attributed to CNTO 328. Most patients (18/22 or 82%) experienced clinical benefit response, defined as improvement in at least one of the 6 measures (hemoglobin, fatigue, anorexia, fever/night sweats, weight, or size of largest lymph node) with all other measures stable or better on at least one assessment. Additional evidence of clinical benefit included increased hemoglobin [median maximum increase of 2.15 g/dL (range: 0.3–7.2 g/dL)]. A high frequency of tumor response (both complete response [CR] and partial response [PR]) as per modified International Working Group criteria was confirmed by independent radiological review. Seven of 11 evaluable patients [64%, 95% CI (31%, 89%)] treated with 12mg/kg on either the q 2 week or q 3 week schedule responded (1 CR, 5 PR, 1 unconfirmed PR), with time to initial response ranging from 9 to 36 weeks. No radiologic response was seen at doses lower than 12mg/kg. All 6 patients who required steroids at study entry were able to discontinue steroid use. Complete suppression of CRP (a surrogate for IL-6 activity) on at least one follow up assessment was observed in 83% of patients with post-baseline CRP values (median baseline level of 13.6 mg/L (range 1-260 mg/L). These interim results appear to demonstrate substantial benefit of CNTO 328 in Castleman’s disease, which merits further investigation.
Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease
