Defibrotide reduces procoagulant activity and increases fibrinolytic properties of endothelial cells

Falanga, Anna; Vignoli, Alfonso; Marchetti, Marina; Barbui, Tiziano

doi:10.1038/sj.leu.2403004

Cited by 110 publications

(108 citation statements)

References 40 publications

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“…[7][8][9][10][11] Preclinical data suggest that defibrotide stabilizes endothelial cells by reducing endothelial-cell activation and by protecting endothelial cells from further damage, resulting in the restoration of the thrombo-fibrinolytic balance. [12][13][14][15][16] The primary objective of this phase 3 study was to demonstrate the efficacy of defibrotide 25 mg/kg per day in patients with hepatic VOD/ SOS with MOF. Efficacy was assessed as the primary end point of difference of survival rate at day 1100 post-HSCT between the 2 groups, as well as the secondary end points of difference of complete response (CR) by day 1100 post-HSCT and survival at day 1180 post-HSCT in patients receiving defibrotide vs historical controls.…”

Section: Introductionmentioning

confidence: 99%

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

Richardson

Riches

Kernan

et al. 2016

Blood

272

252

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Key Points• Defibrotide improves day 1100 survival and CR in patients with VOD and MOF compared with a historical control.• The historical control selection methodology offers a novel approach for investigation of a life-threatening orphan disease.Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n 5 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day 1100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8; P 5 .0109, using a propensityadjusted analysis). Observed day 1100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6; P 5 .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day 1100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as

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Section: Introductionmentioning

confidence: 99%

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

Richardson

Riches

Kernan

et al. 2016

Blood

272

252

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“…DF is a polydisperse mixture of 90% single-stranded polydesoxyribonucleotides with anti-thrombotic, anti-ischemic, and pro-fibrinolytic functions. [1][2][3][4] This mixture is obtained by controlled depolymerization of porcine mucosal DNA and has a mean molecular weight of 16-20 KD. DF is well tolerated and the only therapeutic option in severe hepatic veno-occlusive disease in the course of allogeneic stem cell transplantation (SCT).…”

Section: Introductionmentioning

confidence: 99%

Defibrotide: An endothelium protecting and stabilizing drug, has an anti-angiogenic potential in vitro and in vivo

Koehl¹,

Geissler²,

Iacobelli³

et al. 2007

Cancer Biology & Therapy

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Defibrotide (DF) is a polydisperse mixture of 90% single-stranded oligonucleotides with anti-thrombotic and anti-apoptotic functions. DF is used in the treatment of endothelial complications in the course of allogeneic stem cell transplantation. Recent preclinical evidence suggests that DF might also have anti-neoplastic properties. In the present study we hypothesized that DF might inhibit tumors via an anti-angiogenic effect. The anti-angiogenic potential of DF was tested in vitro using human microvascular endothelial cells forming vessel structures across a layer of dermal fibroblasts. Our results show that pharmacologic DF concentrations (100 mg/ml) significantly reduced vessel formation in this assay. Similarly, DF blocked sprouting from cultured rat aortic rings. In vivo, angiogenesis in a human gastric tumor (TMK1) implanted in dorsal skin-fold chambers (in nude mice) was inhibited by i.v. application of 450 mg/kg DF. Notably, due to its short half-life, DF was most effective when given on a daily basis. Although the precise mechanism of DF remains to be elucidated, initial Western blots show that DF reduces phosphorylation-activation of p70S6 kinase, which is a key target in the PI3K/Akt/mTOR signaling pathway linked to endothelial cell and pericyte proliferation and activation. However, in vitro data suggest that DF acts independently of vascular endothelial growth factor. Taken together, our data suggest that while DF is known for its endothelium-protecting function in SCT, it also inhibits formation of new blood vessels, and thus should be considered for further testing as an adjuvant anti-cancer agent, either alone, or in combination with other drugs.

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“…In preclinical studies, DF exerted a protective effect on injured microvasculature. [14][15][16][17][18] Early retrospective clinical trials of DF in mostly adult patients who fulfilled criteria for severe VOD based on the presence of MOF demonstrated encouraging responses. 19,20 A singlearm cohort study 21 and a prospective randomized trial of mostly adult patients with severe VOD confirmed these findings, clearly indicating efficacy of DF in the treatment of severe VOD.…”

Section: Introductionmentioning

confidence: 99%

Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide

Corbacioglu

Hönig

Lahr

et al. 2006

Bone Marrow Transplant

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Malignant infantile osteopetrosis (MIOP) is a rare hereditary disorder of osteoclast function, which can be reversed by hematopoietic stem cell transplantation (SCT). We observed a high incidence of hepatic veno-occlusive disease (VOD) in transplanted patients and explored the prevention of this complication by using defibrotide (DF) as a prophylaxis. Twenty children with MIOP were consecutively transplanted in our center between 1996 and 2005. Eleven of these patients were transplanted between 1996 and 2001 and experienced an overall incidence of VOD of 63.6% (7/11). VOD was severe in three patients and one patient succumbed to VOD-related multi-organ failure. Owing to this very high incidence of VOD, DF prophylaxis was initiated in nine patients consecutively transplanted between 2001 and 2005. In this group, only one patient (11.1%) was diagnosed with moderate VOD. We report here a very high risk in patients with MIOP to develop VOD after transplantation. Prophylactic DF was implemented in our current transplant protocol and reduced the VOD rate significantly in this high-risk population.

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Defibrotide reduces procoagulant activity and increases fibrinolytic properties of endothelial cells

Cited by 110 publications

References 40 publications

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

Defibrotide: An endothelium protecting and stabilizing drug, has an anti-angiogenic potential in vitro and in vivo

Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide

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