Journal Article

Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial

Iacobelli, Massimo, Sykora, Karl-Walter, Schlegel, Paul G, Ozsahin, Hulya, Bader, Peter, D'Agostino, Ralph, Boelens, Jaap J, Greil, Johann, Peters, Christina, Arvidson, Johan, Gruhn, Bernd, Müller, Ingo, Matthes-Martin, Susanne, Mauz-Körholz, Christine, Sedlacek, Petr, Valteau-Couanet, Dominique, Rovelli, Attilio, Massaro, Joseph, Schrauder, Andre, Dini, Giorgio, Winiarski, Jacek, Hoyle, Margaret, Schulz, Ansgar S, Hewitt, Annette, Schrum, Johanna, Führer, Monika, O'Meara, Anne, Stein, Jerry, Faraci, Maura, Ehlert, Karoline, Wynn, Robert, Fasth, Anders, Corbacioglu, Selim, Cesaro, Simone, Toporski, Jacek, Debatin, Klaus-Michael

2012

Overview

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. 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. 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. 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. Gentium SpA, European Group for Blood and Marrow Transplantation.

• Publisher: Elsevier Ltd,Elsevier,Elsevier Limited
• Subject: Abdomen / Adolescent / adverse effects / Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Bilirubin / Bilirubin - blood / Biological and medical sciences / blood / blood groups / Bone marrow, stem cells transplantation. Graft versus host reaction / Child / Child, Preschool / Clinical Medicine / Clinical trials / complications / disease control / drug therapy / epidemiology / Female / Fibrinolytic Agents / Fibrinolytic Agents - therapeutic use / Gene expression / General aspects / Graft vs Host Disease / Graft vs Host Disease - epidemiology / Hematopoietic Stem Cell Transplantation / Hematopoietic Stem Cell Transplantation - adverse effects / Hepatic Veno-Occlusive Disease / Hepatic Veno-Occlusive Disease - drug therapy / Hepatic Veno-Occlusive Disease - epidemiology / Hepatic Veno-Occlusive Disease - prevention & control / Hospitals / Humans / Incidence / Infant / Infusions / Infusions, Intravenous / Internal Medicine / Intravenous / intravenous injection / Klinisk medicin / Male / Medical and Health Sciences / Medical sciences / Medicin och hälsovetenskap / Morbidity / Mortality / Multiple Organ Failure / Multiple Organ Failure - epidemiology / patients / Pediatrics / Pediatrik / Polydeoxyribonucleotides / Polydeoxyribonucleotides - therapeutic use / Preschool / prevention & control / Prevention and actions / Prophylaxis / Public health. Hygiene / Public health. Hygiene-occupational medicine / randomized clinical trials / Renal Insufficiency / Renal Insufficiency - epidemiology / Reviews / risk / Risk analysis / Risk factors / Side effects / therapeutic use / Transfusions. Complications. Transfusion reactions. Cell and gene therapy / Transplantation