Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease and Multiorgan Failure after Stem Cell Transplantation: A Multicenter, Randomized, Dose-Finding Trial

Richardson, 2001, Hepatic veno-occlusive disease following hematopoietic stem cell transplantation, Acta Haematol, 106, 57, 10.1159/000046590 McDonald, 1984, Veno-occlusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors, Hepatology, 4, 116, 10.1002/hep.1840040121 Blostein, 1992, A comparison of clinical criteria for the diagnosis of veno-occlusive disease of the liver after bone marrow transplantation, Bone Marrow Transplant, 10, 439 Lee, 1999, Veno-occlusive disease of the liver after busulfan, melphalan, and thiotepa conditioning therapy: incidence, risk factors, and outcome, Biol Blood Marrow Transplant, 5, 306, 10.1016/S1083-8791(99)70006-6 Carreras, 1998, Blood, 92, 3599 McDonald, 1993, Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients, Ann Intern Med, 118, 255, 10.7326/0003-4819-118-4-199302150-00003 McCune, 2007, Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality, Biol Blood Marrow Transplant, 13, 853, 10.1016/j.bbmt.2007.03.012 Reiss, 2002, Hepatic veno-occlusive disease in blood and bone marrow transplantation in children and young adults: incidence, risk factors, and outcome in a cohort of 241 patients, J Pediatr Hematol Oncol, 24, 746, 10.1097/00043426-200212000-00013 DeLeve, 2002, Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease), Semin Liver Dis, 22, 27, 10.1055/s-2002-23204 Shulman, 1994, Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms, Hepatology, 19, 1171, 10.1002/hep.1840190515 Shulman, 1987, Hepatic veno-occlusive disease after bone marrow transplantation: immunohistochemical identification of the material within occluded central venules, Am J Pathol, 127, 549 McCune, 2009, Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy, Clin Pharmacol Ther, 85, 615, 10.1038/clpt.2009.27 Tay, 2007, Systematic review of controlled clinical trials on the use of ursodeoxycholic acid for the prevention of hepatic veno-occlusive disease in hematopoietic stem cell transplantation, Biol Blood Marrow Transplant, 13, 206, 10.1016/j.bbmt.2006.09.012 Bearman, 1997, Treatment of hepatic veno-occlusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients, Blood, 89, 1501, 10.1182/blood.V89.5.1501 Bearman, 1993, A phase I/II study of prostaglandin E1 for the prevention of hepatic veno-occlusive disease after bone marrow transplantation, Br J Haematol, 84, 724, 10.1111/j.1365-2141.1993.tb03152.x Haussmann, 2006, Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of preemptive antithrombin III replacement and combined antithrombin III/defibrotide therapy, Haematologica, 91, 795 Eissner, 2002, Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide, Blood, 100, 334, 10.1182/blood.V100.1.334 Bracht, 1994, Isolation and identification of aptamers from defibrotide that act as thrombin antagonists in vitro, Biochem Biophys Res Commun, 200, 933, 10.1006/bbrc.1994.1539 Coccheri, 1988, Acute effects of defibrotide, an experimental antithrombotic agent, on fibrinolysis and blood prostanoids in man, Eur J Clin Pharmacol, 35, 151, 10.1007/BF00609244 Berti, 1990, Defibrotide, by enhancing prostacyclin generation, prevents endothelin-1–induced contraction in human saphenous veins, Prostaglandins, 40, 337, 10.1016/0090-6980(90)90099-H Zhou, 1994, Defibrotide stimulates expression of thrombomodulin in human endothelial cells, Thromb Haemost, 71, 507, 10.1055/s-0038-1642468 Falanga, 1999, Defibrotide (DF) modulates tissue factor expression by microvascular endothelial cells, Blood, 94, 146a Falanga, 2000, Impact of defibrotide on the fibrinolytic and procoagulant properties of endothelial cell macro- and micro-vessels, Blood, 96, 53a Benimetskaya, 2008, Angiogenesis alteration by defibrotide: implications for its mechanism of action in severe hepatic veno-occlusive disease, Blood, 112, 4343, 10.1182/blood-2008-04-149682 Mitsiades, 2009, Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias, Clin Cancer Res, 15, 1210, 10.1158/1078-0432.CCR-08-1270 Richardson, 1998, Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population, Blood, 92, 737 Chopra, 2000, Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study, Br J Haematol, 111, 1122, 10.1046/j.1365-2141.2000.02475.x Richardson, 2002, 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, 100, 4337, 10.1182/blood-2002-04-1216 Corbacioglu, 2004, Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention, Bone Marrow Transplant, 33, 189, 10.1038/sj.bmt.1704329 Bulley, 2007, Defibrotide for the treatment of hepatic veno-occlusive disease in children, Pediatr Blood Cancer, 48, 700, 10.1002/pbc.20934 Bearman, 1993, Veno-occlusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation, J Clin Oncol, 11, 1729, 10.1200/JCO.1993.11.9.1729 Rowlings, 1997, IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade, Br J Haematol, 97, 855, 10.1046/j.1365-2141.1997.1112925.x Cheuk, 2007, Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation, Bone Marrow Transplant, 40, 935, 10.1038/sj.bmt.1705835 Eber, 2007, Favorable response of pediatric stem cell recipients to human protein C concentrate substitution for veno-occlusive disease, Pediatr Transplant, 11, 49, 10.1111/j.1399-3046.2006.00612.x Schlegel, 1998, Hepatic veno-occlusive disease in pediatric stem cell recipients: successful treatment with continuous infusion of prostaglandin E1 and low-dose heparin, Ann Hematol, 76, 37, 10.1007/s002770050358 Rajvanshi, 2002, Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy, Blood, 99, 2310, 10.1182/blood.V99.7.2310 Cutler, 2008, Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation, Blood, 112, 4425, 10.1182/blood-2008-07-169342 Platzbecker, 2009, Graft-versus-host disease prophylaxis with everolimus and tacrolimus is associated with a high incidence of sinusoidal obstruction syndrome and microangiopathy: results of the EVTAC trial, Biol Blood Marrow Transplant, 15, 101, 10.1016/j.bbmt.2008.11.004 Cutler, 2005, Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation, Biol Blood Marrow Transplant, 11, 551, 10.1016/j.bbmt.2005.04.007 Tanikawa, 2000, Predictive markers for hepatic veno-occlusive disease after hematopoietic stem cell transplantation in adults: a prospective single-center study, Bone Marrow Transplant, 26, 881, 10.1038/sj.bmt.1702624 Pihusch, 2005, Diagnosis of hepatic veno-occlusive disease by plasminogen activator inhibitor-1 plasma antigen levels: a prospective analysis in 350 allogeneic hematopoietic stem cell recipients, Transplantation, 80, 1376, 10.1097/01.tp.0000183288.67746.44 Carreras, 2007, Defibrotide for the treatment of veno-occlusive disease post SCT: preliminary results of EU compassionate use program in 332 patients confirms promising activity and manageable toxicity, Blood, 110, 189a, 10.1182/blood.V110.11.613.613 Al Beihany, 2008, Successful treatment of hepatic veno-occlusive disease after myeloablative allogeneic hematopoietic stem cell transplantation by early administration of a short course of methylprednisolone, Bone Marrow Transplant, 41, 287, 10.1038/sj.bmt.1705896 Ringden, 2000, N-acetylcysteine for hepatic veno-occlusive disease after allogeneic stem cell transplantation, Bone Marrow Transplant, 25, 993, 10.1038/sj.bmt.1702387 Corbacioglu, 2006, Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide, Bone Marrow Transplant, 38, 547, 10.1038/sj.bmt.1705485 Dignan, 2007, Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality from veno-occlusive disease, Bone Marrow Transplant, 40, 79, 10.1038/sj.bmt.1705696 Bonini, 2007, Defibrotide low-dose continuous infusion from day +1 until day +21 after allogeneic stem cell transplantation as prophylaxis of veno-occlusive disease (VOD) of the liver: a single-center experience, Blood, 110, 307b, 10.1182/blood.V110.11.4927.4927 Qureshi, 2008, Defibrotide in the prevention and treatment of veno-occlusive disease in autologous and allogeneic stem cell transplantation in children, Pediatr Blood Cancer, 50, 831, 10.1002/pbc.21425 Corbacioglu, 2008, Update on the phase II/III study of the incidence and outcome of VOD with the prophylactic use of defibrotide in pediatric stem cell transplantation (VOD-DF Study), Bone Marrow Transplant, 41, S34 Corbacioglu, 2009, The prospective study on the incidence and outcome of VOD with the prophylactic use of defibrotide in paediatric stem cell transplantation has completed enrolment: update on the VOD-DF study, Bone Marrow Transplant, 43, S34 Richardson, 2007, Blood, 110, 189a, 10.1182/blood-2006-08-036947 Richardson, 2009, Defibrotide (DF) in the treatment of severe hepatic veno-occlusive disease (VOD) with multi-organ failure (MOF) following stem cell transplantation (SCT): results of a phase 3 study utilizing a historical control, Blood, 114, 272a, 10.1182/blood.V114.22.654.654