OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 27 December 2017

Abbreviations used: HCT, hematopoietic cell transplantation; SOS, sinusoidal obstruction syndrome (which was formerly called veno-occlusive disease: VOD).

• Zimmerman HJ. Heparin. Drugs used in cardiovascular disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 641-3.

  (Textbook of hepatotoxicity published in 1999 before availability of defibrotide).
• Weitz JI. Blood coagulation and anticoagulant, thrombolytic, and antiplatelet drugs. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 849-76.

  (Textbook of pharmacology and therapeutics).
• Richardson PG, Elias AD, Krishnan A, Wheeler C, Nath R, Hoppensteadt D, Kinchla NM, et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 1998; 92: 737-44. [PubMed: 9680339]

  (Among 19 patients with severe SOS after HCT [bilirubin 11.7 to 54.4 mg/dL] who were treated with defibrotide, 8 had an initial response and 5 were long term survivors; side effects included nausea, hypotension, bleeding, and abdominal cramping, and serious adverse events were common, but "a causative temporal relationship to any grade 3 or 4 toxicity with defibrotide could not be shown).
• Chopra R, Eaton JD, Grassi A, Potter M, Shaw B, Salat C, Neumeister P, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol 2000; 111: 1122-9. [PubMed: 11167751]

  (Among 40 patients with SOS after HCT treated with defibrotide [10 to 40 mg/kg daily] for 2-53 [median=14] days, 22 [55%] had complete resolution and 17 [43%] were long term survivors, response not correlating with daily or total dose; "defibrotide was safely administered with no significant side effects").
• Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D, Elias AD, et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002; 100: 4337-43. [PubMed: 12393437]

  (Among 88 patients with severe SOS after HCT treated with defibrotide [5 to 60 mg/kg/day for 1-139 days], complete resolution occurred in 36% and therapy was "without significant toxicity").
• DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Seminars Liver Dis 2002; 22: 27-41. [PubMed: 11928077]

  (Review of the clinical features, pathophysiology and management of SOS, formerly known as veno-occlusive disease, which appears to be due to toxic injury to sinusoidal endothelial cells which undergo necrosis, detachment and release into sinusoids with subsequent obstruction, collagen formation and obliteration of central [hepatic] veins).
• Kornblum N, Ayyanar K, Benimetskaya L, Richardson P, Iacobelli M, Stein CA. Defibrotide, a polydisperse mixture of single-stranded phosphodiester oligonucleotides with lifesaving activity in severe hepatic veno-occlusive disease: clinical outcomes and potential mechanisms of action. Oligonucleotides 2006; 16: 105-14. [PubMed: 16584299]

  (Review of the clinical features, pathogenesis and therapy of SOS focusing upon defibrotide, its structure, proposed mechanisms of action, clinical efficacy and safety: "in general no significant side effects occurred").
• Richardson PG, Soiffer RJ, Antin JH, Uno H, Jin Z, Kurtzberg J, Martin PL, et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant 2010; 16: 1005-17. [PMC free article: PMC2956581] [PubMed: 20167278]

  (Among 149 patients with severe SOS after HCT treated with defibrotide [25 or 40 mg/kg/day] for 2-85 [median = 19] days, resolution occurred in 49% and 43%, and adverse events were common [~90%] but only 3% were attributed to therapy [hypotension, hemorrhage], none of which were liver related).
• Richardson PG, Ho VT, Giralt S, Arai S, Mineishi S, Cutler C, Antin JH, et al. Safety and efficacy of defibrotide for the treatment of severe hepatic veno-occlusive disease. Ther Adv Hematol 2012; 3: 253-65. [PMC free article: PMC3627330] [PubMed: 23606935]

  (Review of safety and efficacy of defibrotide as therapy of severe SOS; mentions that in most studies there was "no significant toxicity").
• Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, Boelens JJ, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet 2012; 379 (9823): 1301-9. [PubMed: 22364685]

  (Among 356 children undergoing myeloablation and HCT who were given prophylaxis with defibrotide or were not treated, SOS rates were somewhat less with treatment [12% vs 20%], but overall survival was the same; adverse event rates were also similar in the two groups including hemorrhage and gastrointestinal complaints; no mention of ALT elevations or hepatotoxicity).
• Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Mar 31; 127 (13): 1656-65. [PMC free article: PMC4817309] [PubMed: 26825712]

  (Among 102 adults with severe SOS after HCT treated with defibrotide [25 mg/kg] for 1-58 [median = 21.5] days, resolution by 100 days occurred in 25.5% compared to 12.5% in a matched, historical control group and adverse event rates were also similar).
• Strouse C, Richardson P, Prentice G, Korman S, Hume R, Nejadnik B, Horowitz MM, et al. Defibrotide for treatment of severe veno-occlusive disease in pediatrics and adults: an exploratory analysis using data from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant 2016; 22: 1306-12. [PMC free article: PMC4914048] [PubMed: 27108694]

  (In a retrospective analysis of 8341 patients who underwent HCT between 2008 and 2011 enrolled in an international database, 3.2% developed SOS, which was severe in 1.2% and included 41 defibrotide treated patients who were compared to 55 untreated subjects and had slightly, but not statistically significantly better survival [39% vs 31%], lower rates of graft-vs-host disease [23% vs 38%], but no differences in engraftment rates or other measures of safety).
• Corbacioglu S, Carreras E, Mohty M, Pagliuca A, Boelens JJ, Damaj G, Iacobelli M, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: final results from the International Compassionate-Use Program. Biol Blood Marrow Transplant 2016; 22: 1874-82. [PubMed: 27397724]

  (Among 710 patients treated with defibrotide in an international compassionate use study, the 100+ day survival rate was 54% and adverse events were those largely due to multiorgan failure and graft vs host disease, while severe bleeding events occurred in 55 patients [8%] and were fatal in 37 [5%]).
• Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, Arai S, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood 2016; 127: 1656-65. [PMC free article: PMC4817309] [PubMed: 26825712]

  (Among 102 patients with severe SOS after HCT treated with defibrotide, the 100+ daily survival was 38% which compared favorably to historical control rates [25%] while adverese event rates, including bleeding, were similiar).