Articles www.thelancet.com Vol 379 April 7, 2012 1301 Lancet 2012; 379: 1301–09 Published Online February 23, 2012 DOI:10.1016/S0140- 6736(11)61938-7 See Comment page 1277 *Authors contributed equally on behalf of the Pediatric Disease Working Party of the European Blood and Marrow Transplantation Group University of Regensburg, Regensburg, Germany (Prof S Corbacioglu MD); University of Padova, Padova, Italy (S Cesaro MD); G Gaslini Institute, Genoa, Italy (M Faraci MD, Prof G Dini MD); Institut Gustave Roussy, Villejuif, France (D Valteau-Couanet MD); University Hospital of Jena, Jena, Germany (B Gruhn MD); University of Milano Bicocca, Monza, Italy (A Rovelli MD); University Medical Center, Utrecht, Netherlands (J J Boelens MD); Great Ormond Street Hospital, London, UK (A Hewitt BSc); University of Hamburg-Eppendorf, Hamburg, Germany (J Schrum MD); University Children’s Hospital, Ulm, Germany (A S Schulz MD, Prof K-M Debatin MD); University Children’s Hospital, Tübingen, Germany (I Müller MD); Schneider Children’s Medical Center, Petach-Tikva, Israel (J Stein MD); Royal Manchester Children’s Hospital, Manchester, UK (R Wynn FRCPath); University Children’s Hospital, Heidelberg, Germany (J Greil MD); Medical School Hannover, Hanover, Germany (Prof K-W Sykora MD); St Anna Children’s Hospital, Vienna, Austria (Prof S Matthes-Martin MD, Prof C Peters MD); University Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial Selim Corbacioglu, Simone Cesaro, Maura Faraci, Dominique Valteau-Couanet, Bernd Gruhn, Attilio Rovelli, Jaap J Boelens, Annette Hewitt, Johanna Schrum, Ansgar S Schulz, Ingo Müller, Jerry Stein, Robert Wynn, Johann Greil, Karl-Walter Sykora, Susanne Matthes-Martin, Monika Führer, Anne O’Meara, Jacek Toporski, Petr Sedlacek, Paul G Schlegel, Karoline Ehlert, Anders Fasth, Jacek Winiarski, Johan Arvidson, Christine Mauz-Körholz, Hulya Ozsahin, Andre Schrauder, Peter Bader, Joseph Massaro, Ralph D’Agostino, Margaret Hoyle, Massimo Iacobelli, Klaus-Michael Debatin, Christina Peters*, Giorgio Dini* Summary Background Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting. Methods In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948. Findings Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference –7·7%, 95% CI –15·3 to –0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. Interpretation Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT. Funding Gentium SpA, European Group for Blood and Marrow Transplantation. Introduction Hepatic veno-occlusive disease—also known as sinus- oidal obstruction syndrome—is a common and potentially fatal toxic outcome after haemopoietic stem- cell transplantation (HSCT). 1–3 In the disease, sinusoidal endothelial cells and hepatocytes are damaged with progressive venular occlusion and subsequent hepato- cellular necrosis. Clinical signs and symptoms of veno- occlusive disease include hepatomegaly, right upper quadrant pain, ascites, fluid retention, jaundice, weight gain, and hyperbilirubinemia. 4 Veno-occlusive disease usually develops by 30 days after transplantation. 2 Mean incidence of veno-occlusive disease is 14% (range 0–60%). 5 Well-established risk factors are younger age, 6 hepatic inflammation, 4 previous abdominal irradi- ation, 6 hepatic fibrosis or cirrhosis, 1,2,7,8 and repetitive transplantations with myeloablative conditioning regi- mens. 4 A particular risk of veno-occlusive disease arises with treatment with busulfan 9,10 and gemtuzumab ozogamicin. 11 Incidence of veno-occlusive disease is highest in children, 9,12,13 and rates are affected by presence of osteopetrosis, neuroblastoma, and inherited haemo- phagocytic lymphohistiocytosis. 14–16 Veno-occlusive disease severity ranges from mild to severe, which is defined by the presence of multiorgan failure and is associated with more than 85% mortality by 100 days. 4,5,17 Veno-occlusive disease has no approved prophylaxis or treatment. Defibrotide has protective effects on activated endo- thelial cells. Preclinical studies showed that defibrotide protects these cells against chemotherapy-induced death and activation, 18 and downregulates gene expression, protein concentrations, and activity of endothelial cell-triggers such as heparanase 19 (which are associated with increased risk of acute graft-versus- host disease after HSCT 20 ). Defibrotide reduces