Defibrotide for the treatment of hepatic veno‐occlusive disease: results of the European compassionate‐use study

Abstract

Summary. Severe hepatic veno-occlusive disease (VOD) is a recognized complication of autologous and allogeneic stem cell transplantation (SCT) that is often fatal. Defibrotide (DF) is a polydeoxyribonucleotide that has been found to have anti-thrombotic, anti-ischaemic and thrombolytic properties without causing significant anticoagulation. Preliminary studies have demonstrated activity for DF in the treatment of VOD, with minimal associated toxicity. In the present study, 40 patients who fulfilled established criteria for VOD were treated with DF on compassionate grounds in 19 European centres; 28 patients met risk criteria predicting progression of VOD and fatality or had evidence of multiorgan failure (MOF), and were defined as`poor-risk'. DF was commenced intravenously at a median of 14 d (range, 22 d to 53 d) post SCT at doses ranging from 10 to 40 mg/kg. The median duration of therapy was 18 d (range, 2±71 d). Twenty-two patients showed a complete response (CR) (bilirubin , 34´2 mmol/l and resolution of signs/symptoms of VOD and end-organ dysfunction) [CR 55%, confidence interval (CI) 40±70%] and 17 patients (43%) are alive beyond d 1100. Ten poor-risk patients showed a complete response (CR 36%, CI 21±51%). These results demonstrate that DF is an active treatment for VOD following SCT and a randomized trial is now underway in order to further evaluate its role.

Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies

“…These favorable results were confirmed in a subsequent European compassionate use trial by Chopra et al 9 In this study of 40 patients with established VOD treated with DF in 19 European transplant centers, 22 (55%) achieved a complete response and 17 (43%) survived to D þ 100. Among the 28 patients in this series who were considered to have severe VOD, characterized by the presence of MOF, the complete response rate after DF therapy was 36%.…”

“…Defibrotide (DF), a polydisperse oligonucleotide mixture that has protective effects on vascular endothelium, has demonstrated encouraging responses with little toxicity in multicenter phase I/II trials. [8][9][10][11] Recent studies have also demonstrated that DF is an effective agent for VOD prophylaxis after transplantation in patients at high risk for this complication. [12][13][14] …”

Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality from veno-occlusive disease

“…This finding is in keeping with previous reports suggesting that defibrotide can be administered with relative safety in this patient population. [8][9][10][11][12][13]17,18 Hyperbilirubinaemia was noted to be common in post allogeneic SCT in our series. Twenty-nine patients (50%) had a bilirubin X34 mmol/l although they failed to meet the Baltimore criteria.…”

“…Early phase trials of defibrotide in the treatment of moderate to severe VOD have shown promising results with minimal attributable toxicity, encouraging complete response rates (36-50%) and consistent improvements in day þ 100 survival (at 30-60% versus 410% expected). [8][9][10][11][12][13] Several studies have investigated various types of VOD prophylaxis. The role of prophylactic anticoagulation remains uncertain despite a recent meta-analysis.…”

Incidence and management of hepatic severe veno-occlusive disease in 273 patients in a single centre with defibrotide

“…6 Defibrotide, a single-stranded polydeoxyribonucleotide has anti-thrombotic, anti-inflammatory and anti-ischaemic properties and is recommended as the definitive treatment for VOD. [7][8][9][10] We report a single-centre experience based on case note review from over a 45-months period (January 2011 till September 2014) ( Table 1). A total of 273 allogeneic transplants were performed and VOD was diagnosed in 13.…”