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

Corbacioglu, Selim; Cesaro, Simone; Faraci, Maura; Valteau-Couanet, Dominique; Gruhn, Bernd; Rovelli, Attilio; Boelens, Jaap J.; Hewitt, Annette; Schrum, Johanna and Schulz, Ansgar S., et al. (2012) In The Lancet 379(9823). p.1301-1309
Abstract
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... (More)
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. (Less)
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@article{2a855cee-c9cc-4dac-9e79-f95de4de6ace,
  abstract     = {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.},
  author       = {Corbacioglu, Selim and Cesaro, Simone and Faraci, Maura and Valteau-Couanet, Dominique and Gruhn, Bernd and Rovelli, Attilio and Boelens, Jaap J. and Hewitt, Annette and Schrum, Johanna and Schulz, Ansgar S. and Mueller, Ingo and Stein, Jerry and Wynn, Robert and Greil, Johann and Sykora, Karl-Walter and Matthes-Martin, Susanne and Fuehrer, Monika and O'Meara, Anne and Toporski, Jacek and Sedlacek, Petr and Schlegel, Paul G. and Ehlert, Karoline and Fasth, Anders and Winiarski, Jacek and Arvidson, Johan and Mauz-Koerholz, Christine and Ozsahin, Hulya and Schrauder, Andre and Bader, Peter and Massaro, Joseph and D'Agostino, Ralph and Hoyle, Margaret and Iacobelli, Massimo and Debatin, Klaus-Michael and Peters, Christina and Dini, Giorgio},
  issn         = {1474-547X},
  language     = {eng},
  number       = {9823},
  pages        = {1301--1309},
  publisher    = {Elsevier Limited},
  series       = {The Lancet},
  title        = {Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial},
  url          = {http://dx.doi.org/10.1016/S0140-6736(11)61938-7},
  volume       = {379},
  year         = {2012},
}