OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 09 April 2016

• Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 517-53.

  (Expert review of hepatotoxicity published in 1999 before the availability of siltuximab and other monoclonal antibodies and anticytokines).
• Krensky AM, Bennett WM, Vincenti F. Immunosuppressants, tolerogens, and immunostimulants. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1005-29.

  (Textbook of pharmacology and therapeutics).
• Fizazi K, De Bono JS, Flechon A, Heidenreich A, Voog E, Davis NB, Qi M, et al. Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer 2012; 48: 85-93. [PubMed: 22129890]

  (Among 97 patients with advanced prostate cancer treated with siltuximab or placebo with mitoxantrone and prednisone, survival rates were similar, but adverse events were greater in the siltuximab group; no mention of ALT elevations or hepatotoxicity).
• Dorff TB, Goldman B, Pinski JK, Mack PC, Lara PN Jr, Van Veldhuizen PJ Jr, Quinn DI, et al. Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clin Cancer Res 2010; 16: 3028-34. [PMC free article: PMC2898710] [PubMed: 20484019]

  (Among 53 patients with refractory prostate cancer treated with siltuximab, clinical responses were infrequent and 1 patient developed ALT elevations above 5 times ULN).
• San-Miguel J, Bladé J, Shpilberg O, Grosicki S, Maloisel F, Min CK, Polo Zarzuela M, et al. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 2014; 123: 4136-42. [PMC free article: PMC4123433] [PubMed: 24833354]

  (Among 106 patients with refractory multiple myeloma treated with bortezomib, melphalan and prednisone, overall and progression-free survival was not different with the addition of siltuximab and side effects of neutropenia and thrombocytopenia were more common; no mention of ALT elevations or hepatotoxicity).
• Angevin E, Tabernero J, Elez E, Cohen SJ, Bahleda R, van Laethem JL, Ottensmeier C, et al. A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res 2014; 20: 2192-204. [PubMed: 24563479]

  (Among 84 patients with advanced solid tumors treated with escalating doses of siltuximab, hepatic function abnormalities were reported in 15% of patients, but details were not given).
• Voorhees PM, Manges RF, Sonneveld P, Jagannath S, Somlo G, Krishnan A, Lentzsch S, et al. A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. Br J Haematol 2013; 161: 357-66. [PMC free article: PMC5837861] [PubMed: 23432640]

  (Among 53 patients with refractory multiple myeloma treated with siltuximab with or without dexamethasone, frequent side effects included hepatic dysfunction [31%], enzyme elevations [16%] and one case of HBV reactivation [2%]; but no details provided).
• Garcia-Manero G, Gartenberg G, Steensma DP, Schipperus MR, Breems DA, de Paz R, Valcárcel D, et al. A phase 2, randomized, double-blind, multicenter study comparing siltuximab plus best supportive care (BSC) with placebo plus BSC in anemic patients with International Prognostic Scoring System low- or intermediate-1-risk myelodysplastic syndrome. Am J Hematol 2014; 89: E156-62. [PubMed: 24888488]

  (Among 76 patients with anemia due to myelodysplastic syndromes treated with siltuximab or placebo for 12 weeks, reduced red cell transfusion requirements occurred in 12% vs 4% and adverse events were frequent including “abnormal hepatic function” in 10% vs 12%; no details given).
• van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fosså A, Simpson D, et al. Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol 2014; 15: 966-74. [PubMed: 25042199]

  (Among 89 patients with Castleman disease treated with siltuximab or placebo [11 mg/kg every 3 weeks], durable tumor and symptomatic responses occurred in 34% vs 0% while side effects included pruritus [42% vs 12%], fatigue [34% vs 38%], edema [32% vs 23%], weight gain [21% vs 0%], abdominal pain, thrombocytopenia; no mention of ALT or hepatotoxicity).
• Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T, Goranova-Marinova V, et al. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol 2015; 90: 42-9. [PMC free article: PMC4737504] [PubMed: 25294016]

  (Among 281 patients with refractory multiple myeloma treated with siltuximab or placebo combined with bortezomib, addition of siltuximab was not associated with improved progression free survival, but was associated with increased rates of neutropenia and thrombocytopenia, and slight increases in ALT and AST were observed on day 1 of cycle 2 in both groups, “but mean values remained in the normal range throughout the randomized treatment phase”).
• Deisseroth A, Ko CW, Nie L, Zirkelbach JF, Zhao L, Bullock J, Mehrotra N, et al. FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease. Clin Cancer Res 2015; 21: 950-4. [PubMed: 25601959]

  (Review of the clinical trial results that were the basis for approval of siltuximab as therapy of Castleman disease; no mention of ALT elevations or hepatotoxicity).
• Siltuximab (Sylvant) for treatment of multicentric Castleman's disease. Med Lett Drugs Ther 2015; 57 (1459): e8 . [PubMed: 25555075]

  (Concise review of the mechanism of action, clinical efficacy, adverse effects and costs of siltuximab shortly after its approval in the US for Castleman disease mentions adverse events of rash, pruritus, weight gain, hyperuricemia and nasopharyngitis, but does not mention ALT elevations or hepatotoxicity).
• van Rhee F, Casper C, Voorhees PM, Fayad LE, van de Velde H, Vermeulen J, Qin X, 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: 30408-19. [PMC free article: PMC4745809] [PubMed: 26327301]

  (Among 19 patients with Castleman disease who responded to siltuximab in a controlled trial and were continued on therapy long term [11 mg/kg every 3 to 6 weeks for an average of 5 years], side effects decreased with prolonged therapy, but included “hepatobiliary disorders” in 42% during the first year, but none thereafter and no patient stopped therapy because of liver test abnormalities).
• Koff JL, Lonial S. Emerging treatments in Castleman disease - a critical appraisal of siltuximab. Biologics 2016; 10: 9-15. [PMC free article: PMC4734738] [PubMed: 26869762]

  (Review of Castleman disease and its therapy including use of siltuximab; no mention of ALT elevations or hepatotoxicity).