Defibrotide: A Review of Its Use in Severe Hepatic Veno-Occlusive Disease Following Haematopoietic Stem Cell Transplantation

Abstract

Defibrotide (Defitelio(®)) was recently approved in the EU for the treatment of severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstructive syndrome, in haematopoietic stem cell transplantation (HSCT) therapy. It is indicated in adults, adolescents, children and infants over 1 month of age. Defibrotide is also available in the US via an expanded-access protocol. Defibrotide is thought to protect endothelial cells and restore the thrombo-fibrinolytic balance in VOD. In a multicentre, phase III trial, the complete response rate by day +100 (primary endpoint) was significantly higher, and mortality at day +100 was significantly lower, in patients with severe hepatic VOD and multiorgan failure following HSCT who received intravenous defibrotide 6.25 mg/kg every 6 h than in a group of historical controls. The efficacy of defibrotide in severe hepatic VOD following HSCT was also supported by findings from a phase II dose-finding study, compassionate-use data and information provided from an independent transplant registry. Intravenous defibrotide was generally well tolerated in patients with severe hepatic VOD following HSCT, and was not associated with an increased risk of haemorrhagic adverse events. In conclusion, defibrotide is the only agent approved (in the EU) for use in severe hepatic VOD following HSCT and represents a useful advance in the treatment of this condition.

Pharmacological Activity and Clinical Use of PDRN

“…DNA derived drugs might have relevant therapeutic effects in a clinical setting. In this context, there are two drugs named PDRN (polydeoxyribonucleotide) and defibrotide that share the same “natural” source: DNA (Altavilla et al, 2009; Keating, 2014). However, they differ in DNA origin, molecular weight, and manufacturing procedures; as a consequence, they have different pharmacological properties, mechanism(s) of action and, eventually, clinical effects.…”

“…The positive effect on wound healing and angiogenesis is a characteristic feature of PDRN that is not shared by other DNA-derived drugs that have different DNA origin, molecular weight and manufacturing process. In fact, defibrotide (Keating, 2014) inhibits angiogenesis (Table 1). This observation led us to speculate that the eventual approval of a DNA containing drug biologically equivalent to the registered PDRN (i.e., a PDRN bioequivalent drug) should be considered with extreme caution.…”

Independent risk factors and long-term outcomes for acute kidney injury in pediatric patients undergoing hematopoietic stem cell transplantation: a retrospective cohort study

“…AKI was reported to occur in 20 to 84% of pediatric patients undergoing HSCT [2][3][4]. AKI after HSCT has multifactorial etiologies with prerenal, renal, and postrenal mechanisms, including conditioning chemotherapy, total body irradiation (TBI), nephrotoxic medications, sepsis, sinusoidal obstruction syndrome (SOS), thrombotic microangiopathy (TMA), and graft-versus-host disease (GVHD) [5][6][7]. With advances in supportive care, the prevalence of post-HSCT AKI had decreased over the past several years [8][9][10][11][12].…”

Veno-occlusive disease nurse management: development of a dynamic monitoring tool by the GITMO nursing group

“…Therapy with a combination of heparin and recombinant tissue plasminogen activator has shown responses in 30% of patients, but it is associated with an increased risk of haemorrhage and poor overall survival [ 17 , 22 – 23 ]. Currently, the only drug approved by the European Medicines Agency (EMA) for the treatment of severe VOD is defibrotide [ 24 ]. Defibrotide has also been used in prevention with encouraging results [ 25 , 26 , 27 , 28 ], although high-quality randomised, controlled studies are needed to define the ideal prophylactic regimen [ 29 ].…”