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ctt-journal > Corbacioglu et al. (Abstract)

Corbacioglu et al. (Abstract)

Cellular Therapy and Transplantation (CTT), Vol. 3, No. 12
doi: 10.3205/ctt-2011-No12-abstract76

© The Authors. This abstract is provided under the following license: Creative Commons Attribution 3.0 Unported

Abstract accepted for "5th Raisa Gorbacheva Memorial Meeting Hematopoietic Stem Cell Transplantation in Children and Adults", Saint Petersburg, Russia, September 18–20, 2011

Preliminary Program

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The vascular endothelial implications of Defibrotide for VOD and GvHD

Selim Corbacioglu, Christina Peters*, Giorgio Dini*

(*on behalf of the PDWP of the EBMT)

Chair Pediatric Hematology, Oncology and Stem Cell Transplantation Children's Hospital Regensburg University of Regensburg Regensburg, Germany

Correspondence: Selim Corbacioglu, MD, Chair Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital Regensburg University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany, Email: selim.corbacioglu@spam is badklinik.uni-regensburg.de


Veno-occlusive disease (VOD) is a rare but in its severe form one of the most significant complications after stem cell transplantation. Defibrotide (DF) is a polydisperse oligonucleotide with a protective effect on endothelial cells in vitro. The VOD-DF trial assessed the benefit of DF in the prevention of the incidence, morbidity and mortality of veno-occlusive disease (VOD) as well as the incidence of graft versus host disease (GvHD) in children. The inclusion criteria were patients less than18 years with myeloablative SCT and high-risk criteria for VOD. The patients were prospectively randomized to the control arm (no prophylactic DF) or to receive DF 25mg/kg/day IV from the start of conditioning until D+30 post SCT. All patients diagnosed with VOD received DF for treatment.

The final sample size of 360 patients was recruited between 2006 and 2009. Of these, 24% infants, 52% children, and 23% adolescents received in 69% allogeneic, in 31% autologous transplants. Prophylactic DF reduced the incidence (12% vs. 20%; competing risk p=0.049), the morbidity and mortality of VOD. Mortality was significantly higher in patients with VOD at Day+100 than in those without VOD (25% vs. 6%, respectively; p<0.0001) and confirmed retrospective analyses of a four-times increased mortality due to VOD. Of 28 patients from both treatment arms with severe VOD (MOF), 19 (68%) survived to Day+100 and 9 (32%) died. Of 26 patients from both treatment arms with mild to moderate VOD, 23 (88%) survived to Day+100, and three (12%) died. These three patients were in the control arm. Therefore the mortality in the group of patients with mild and moderate disease who did not receive VOD prophylaxis by Day+100 was 20% (3 of 15).

DF also reduced significantly the incidence (47% vs. 65%; p=0.005) and severity of acute GvHD (aGvHD) by D+100 (p=0.003) in the allogeneic transplanted patients. Similar results were found when excluding grade I GvHD (p=0.013 for incidence; p=0.017 for severity). Concomitant medications were balanced between treatment arms, with the exception of the category of corticosteroids. Overall corticosteroid use was 48% in the control group and 37% in the DF group (p=0.0363). Corticosteroids were prescribed predominantly for aGVHD (76% vs. 22% in patients without GvHD; p<.0001), and were used significantly less in patients receiving DF prophylaxis, which reflects the lower incidence of aGVHD in the DF arm. Neither the incidence of chronic GvHD nor the graft-versus-leukemia effect (GvL) were affected by DF. SAEs were experienced by 61% and 59% respectively, in both arms. This prospective randomized Phase II/III study clearly demonstrates the efficacy and safety of DF in preventing aGvHD in pediatric patients and confirms the endothelial protective effect of DF observed in vitro. The clinical observation of the reduction of the incidence and severity of aGvHD was corroborated by significantly reduced steroid use in particular in patients with diagnosed aGvHD. The observations made with DF could reflect a paradigm shift of our approach to the prevention of GvHD through protection of the primary target and trigger organ, the endothelium, rather than manipulation of the global immune system.

Keywords: defibrotide, stem cell transplantation, VOD, veno-occlusive disease, children, GvHD, prevention