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Richardson, Paul G., Marta Palomo, Nancy A. Kernan, Gerhard C. Hildebrandt, Nelson Chao, and Enric Carreras. "The importance of endothelial protection: the emerging role of defibrotide in reversing endothelial injury and its sequelae." Bone Marrow Transplantation 56, no. 12 (September 28, 2021): 2889–96. http://dx.doi.org/10.1038/s41409-021-01383-x.
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AbstractHepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), a potentially life-threatening complication of hematopoietic cell transplantation (HCT), results from prolonged sinusoidal endothelial cell activation and profound endothelial cell damage, with sequelae. Defibrotide, the only drug approved in the United States and Europe for treating VOD/SOS post-HCT, has European Commission orphan drug designation for preventing graft-versus-host disease (GvHD), associated with endothelial dysfunction. This endothelial cell protector and stabilizing agent restores thrombo-fibrinolytic balance and preserves endothelial homeostasis through antithrombotic, fibrinolytic, anti-inflammatory, anti-oxidative, and anti-adhesive activity. Defibrotide also preserves endothelial cell structure by inhibiting heparanase activity. Evidence suggests that downregulating p38 mitogen-activated protein kinase (MAPK) and histone deacetylases (HDACs) is key to defibrotide’s endothelial protective effects; phosphatidylinositol 3-kinase/Akt (PI3K/AKT) potentially links defibrotide interaction with the endothelial cell membrane and downstream effects. Despite defibrotide’s being most extensively studied in VOD/SOS, emerging preclinical and clinical data support defibrotide for treating or preventing other conditions driven by endothelial cell activation, dysfunction, and/or damage, such as GvHD, transplant-associated thrombotic microangiopathy, or chimeric antigen receptor T-cell (CAR-T) therapy-associated neurotoxicity, underpinned by cytokine release syndrome and endotheliitis. Further preclinical and clinical studies will explore defibrotide’s potential utility in a broader range of disorders resulting from endothelial cell activation and dysfunction.
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&NA;. "Defibrotide." Reactions Weekly &NA;, no. 538 (February 1995): 7. http://dx.doi.org/10.2165/00128415-199505380-00024.
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Palmer, Katharine J., and Karen L. Goa. "Defibrotide." Drugs 45, no. 2 (February 1993): 259–94. http://dx.doi.org/10.2165/00003495-199345020-00007.
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&NA;. "Defibrotide." Reactions Weekly &NA;, no. 1113 (August 2006): 9. http://dx.doi.org/10.2165/00128415-200611130-00028.
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Coccheri, Sergio, and Giovanna Biagi. "Defibrotide." Cardiovascular Drug Reviews 9, no. 2 (June 1991): 172–96. http://dx.doi.org/10.1111/j.1527-3466.1991.tb00410.x.
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Moore, Julie M., and John W. Avery. "Defibrotide." Arteriosclerosis, Thrombosis, and Vascular Biology 32, no. 3 (March 2012): 541–44. http://dx.doi.org/10.1161/atvbaha.111.242776.
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Baker, Danial E., and Kendra Demaris. "Defibrotide." Hospital Pharmacy 51, no. 10 (October 2016): 847–54. http://dx.doi.org/10.1310/hpj5110-847.
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Tappe, William, Saurabh Aggarwal, Ozlem Topaloglu, and Massimo Iacobelli. "A Meta-Analysis Evaluating the Incidence of Bleeding Events With Intravenous Defibrotide Treatment Outside the Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Setting." Clinical and Applied Thrombosis/Hemostasis 26 (January 1, 2020): 107602962093520. http://dx.doi.org/10.1177/1076029620935202.
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Defibrotide is approved to treat hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal/pulmonary dysfunction following hematopoietic cell transplantation (HCT) in adult and pediatric patients in the United States, and to treat severe hepatic VOD/SOS post-HCT in adult and pediatric patients aged >1 month in the European Union. The defibrotide prescribing information warns that defibrotide may increase bleeding risk in VOD/SOS patients. To broaden our understanding of the incidence of bleeding with defibrotide, we performed a meta-analysis of the published literature of defibrotide use outside of the post-HCT VOD/SOS setting. Of 1857 records identified, 125 reported on defibrotide; 23 contained data on bleeding events. The estimated overall incidence of bleeding events was 1% (95% confidence interval [CI]: 0%-2%) and 8% (95% CI: 3%-14%) in studies using intravenous defibrotide and studies with controls, respectively. The risk ratio for bleeding events with intravenous defibrotide versus controls was 0.36 (95% CI: 0.24-0.52; P < .00001) among studies with data on intravenous defibrotide and controls. This meta-analysis of defibrotide use outside of the post-HCT VOD/SOS setting suggests that the incidence of bleeding with defibrotide is lower than controls.
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Fareed, Jawed, Debra A. Hoppensteadt, Massimo Iacobelli, and Jeanine M. Walenga. "Defibrotide Does Not Cross-React with HIT Antibodies. Implications in the Management of HIT." Blood 108, no. 11 (November 16, 2006): 1054. http://dx.doi.org/10.1182/blood.v108.11.1054.1054.
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Abstract Defibrotide is a mammalian DNA derived antithrombotic and anti-ischemic agent that does not produce systemic anticoagulation. Heparin-induced thrombocytopenia (HIT) is an immune disease related to heparin exposure, in which patients are at risk of developing life- and limb-threatening thrombosis. Studies were performed to determine whether defibrotide cross-reacts with HIT antibodies. Sera from 141 clinically confirmed HIT patients were tested for platelet activation in the presence of defibrotide (1 – 100 μg/ml) and unfractionated heparin (1 – 100 μg/ml). 103 sera (73%) produced platelet aggregation and serotonin release activities with heparin. Only 4 samples (2%) showed a weak reactivity with defibrotide which was eliminated by heparinase treatment indicating heparin contamination in the patient sample. Further studies revealed that defibrotide does not complex with platelet factor 4 (PF4), and that prolonged incubation of defibrotide with platelet rich plasma does not mobilize PF4. Studies of patients treated with extended dosing of intravenous or oral defibrotide (n=270) demonstrated that HIT antibodies are not generated with defibrotide treatment. Studies carried out on the effect of purified IgG from HIT patients revealed that defibrotide blunts platelet activation and microparticle formation as measured by flow cytometry. These studies suggest that defibrotide may be a useful antithrombotic agent for the management of patients with HIT. Moreover, unlike heparin, defibrotide does not promote platelet activation, rather it is capable of suppressing the hypercoagulable state associated with HIT. Defibrotide is orally bioavailable and can be used for extended anticoagulant management of HIT patients.
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Park, Meerim, Hyeon Jin Park, Hyeon-Seok Eom, Jeong A. Park, Yeon Jung Lim, Jong Hyung Yoon, Hye Won Lee, Tak Yun, and Byung-Kiu Park. "Effects of Prophylactic Defibrotide for Veno-Occlusive Disease in Hematopoietic Stem Cell Transplantation." Blood 118, no. 21 (November 18, 2011): 4517. http://dx.doi.org/10.1182/blood.v118.21.4517.4517.
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Abstract Abstract 4517 Background: Defibrotide has recently been successfully used to treat veno-occlusive disease (VOD). We report the use of intravenous defibrotide for VOD prophylaxis in 49 patients who received hematopoietic stem cell transplantation (HSCT). This group was compared with a control group of 49 patients who underwent HSCT without defibrotide prophylaxis. Patients and methods: Data were collected retrospectively on 98 patients undergoing HSCT at the National Cancer Center, Goyang, Korea, between August 2005 and July 2008. During this period, defibrotide was randomly supplied to 49 patients free of charge by the compassionate use program. For 49 patients, VOD prophylaxis with 200 to 400 mg of defibrotide (25 mg/kg/day in children weighing less than 30 kg) administered intravenously 3 or 4 times daily was initiated from the start of conditioning and continued until 28 days post-HSCT. Results: VOD was diagnosed in 5 of 98 total patients (5.1%) at a median of 11 days post-HSCT (range: 10–14 days). VOD was graded as mild in 2 patients, moderate in 1, and severe in 2. The incidences of engraftment syndrome, thrombotic microangiopathy and VOD were not significantly different between the defibrotide group and the control group, although absolute incidences of each syndrome were lower in the defibrotide group. Patients who received prophylactic defibrotide showed earlier platelet engraftment (p<0.01) and lower activated prothrombin time (p=0.02) after HSCT. There was no day 100 treatment-related mortality (TRM) in the defibrotide group. Day 100 TRM occurred in two patients who did not receive defibrotide for VOD prophylaxis during allogeneic HSCT. Each patient was diagnosed with mild or severe VOD, and the direct causes of death were infection or VOD. Of the patients who were diagnosed with VOD, the overall survival at 100 days post HSCT was significantly higher in the defibrotide group compared to the control group (100% vs. 33.3 ± 27.2%, p<0.01). Defibrotide was well tolerated and was not discontinued in any patients. There was no grade 3 or 4 toxicity related to defibrotide or any worsening of clinical bleeding. Conclusions: Our data showed that the use of prophylactic defibrotide is safe and may have beneficial effects of defibrotide on hepatic endothelial damage following HSCT, with no TRM in defibrotide group. Considering there is no consensus on when to start treatment if a patient shows clinical features suggesting VOD, it could be important to use prophylactic defibrotide in advance for improved VOD outcomes. Disclosures: No relevant conflicts of interest to declare.
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Fareed, Jawed, Debra Hoppensteadt, Omer Iqbal, Josephine Cunanan, Vinod Bansal, Schuharazad Abro, and Rakesh Wahi. "Defibrotide Interactions with Newer Oral Anticoagulants and Antithrombotic Agents." Blood 120, no. 21 (November 16, 2012): 3411. http://dx.doi.org/10.1182/blood.v120.21.3411.3411.
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Abstract Abstract 3411 Defibrotide is a polydisperse mixture of porcine-derived single-stranded oligonucleotides which has been used for multiple clinical indications. Recent clinical trials of defibrotide indicate that this drug may provide benefits both for the treatment and prophylaxis of hepatic veno-occlusive disease (VOD) in hematopoietic stem cell therapy. In VOD it is believed that defibrotide exerts two distinct effects; 1. Endothelial cell protection and 2. Restoration of the thrombotic-fibrinolytic balance. Although antithrombotic in nature, defibrotide does not produce any systemic anticoagulant effects atthe selected dose of 25 mg/kg/day Conventional oral anticoagulants are routinely not used in veno-occlusive disease however heparin is often used in the management of these patients. More recently, newer oral anticoagulant drugs such as dabigatran, apixiban and rivaroxiban have been approved for the management of post orthopaedic surgical venous thrombosis and stroke prevention in atrial fibrillation. The current study was undertaken to investigate the effect of defibrotide on the anticoagulant and antiprotease effects of the newer oral anticoagulant drugs in the whole blood, plasma and platelet rich plasma based systems. Materials and Methods Native whole blood was drawn from 25 normal healthy individuals and supplemented with 100 μg/mL defibrotide and 250 ng/mL of each of the individual oral anticoagulant drugs alone and with defibrotide. Activated clotting time (ACT) measurements were made on a Hemachron instrument using celite ACT tubes. For the plasma based anticoagulant studies, a fixed concentration of defibrotide of 100 μg/mL was supplemented with defibrotide to pool plasma alone and with each of the individual oral anticoagulantagents in a concentration range of 0–1000 ng/mL. To investigate the effect of defibrotide on agonist induced platelet aggregation platelet rich plasma was prepared with varying amounts of defibrotide (0–100ug/ml). Such agonsits as ADP, epinephrine, collagen and arachodonic acid were used. To test the effects of newer oral anticoagulants, each agent was supplemented at 250–500ng/ml to the defibrotide enriched PRP (100ug/ml) and agonist induced aggregation studies were carried out in comparison to saline and defibrotide control. To test the effect of defibrotide on the conventional oral anticoagulant agents, plasma samples from patients with INR range of 1.5–3.0 were supplemented with 100ug/ml and the PT/INR was re-determined using Innovin® reagent. Results In the whole blood studies apixaban and rivaroxaban did not produce any prolongation of the whole blood ACT. However, dabigatran produced a modest increase in the ACT at 250 ng/mL. In the anticoagulant assays, supplementation of these agents did not result in any prolongation of the PT with defibrotide and newer oral anticoagulants. In the aPTT assay, the apixaban and rivaroxaban did not have any interaction, at a concentration greater than 500 ng/mL. Dabigatran shows a slight interaction in the aPTT assay. Defibrotide, did not produce any alterations of the effect on the agonist (ADP, epinephrine, collagen, arachidonic acid) induced aggregation of platelets in concentrations up to 100 μg/mL. Studies carried out where defibrotide at 100 μg/mL is combined with 250 ng/mL of each of the new anticoagulants does not show any modification of the aggregation responses. Defibrotide supplementation to anti-platelet therapy treated patient's blood collected did not result in any augmentation of the observed inhibitory responses. Defibrotide did not produce any changes in the PT/INR values of plasma samples collected from warfarin treated patients at concentrations of up to 100 μg/ml. Conclusions These studies indicate that in a concentration range of 0–1000 ng/mL the new anticoagulants do not exhibit any significant interactions with defibrotide. Since dabigatran exhibits some anticoagulant effect of its own, minor interactions with defibrotide may be observed. Based on the indications for the new oral anticoagulant drugs, their circulating levels and rapid clearance, it is unlikely that defibrotide will produce any interactions with these drugs. Disclosures: No relevant conflicts of interest to declare.
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Fareed, Jawed, Adrian Sonevytsky, Omer Iqbal, Walter P. Jeske, Massimo Iacobelli, and Debra Hoppensteadt. "Inhibition of Heparinase I by Defibrotide with Potential Clinical Implications." Blood 108, no. 11 (November 16, 2006): 1626. http://dx.doi.org/10.1182/blood.v108.11.1626.1626.
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Abstract Defibrotide represents a poly-deoxyribonucleotide derived antischemic and antithrombotic agent. Currently this agent is used for the management of transplantation associated with vascular complications. Defibrotide is a polyanionic electrolyte capable of releasing endogenous antithrombotic mediators such as (tissue factor pathway inhibitor (TFPI) and heparans. Co-administration of defibrotide with heparin has been shown to produce an augmentation of the effect of heparin and an increase in the biologic half-life. This may be due to the drug interactions or inhibition of endogenous heparin digesting enzyme by defibrotide. To test the hypothesis that defibrotide may inhibit heparin digesting enzymes such as heparinases (I–III), the effects of defibrotide were investigated on the digestion of unfractionated heparin. Unfractionated heparin was subjected to bacterial heparinase I (flavobacterion heparinicum) in an isolated biochemical systems where unfractionated heparin was used as a substrate at a fixed concentration of 750 μg/ml. Graded amounts of defibrotide in the range of 6.25–250 μg/ml were supplemented to this mixture. The degree of heparinase digestion of unfractionated heparin was determined by using high performance liquid chromatographic methods and computation of oligosaccharide profiles. Heparinase I was found to digest heparin (MW=15.2kDa) converting it to low molecular mass heparins (MW=4.1kDa). At concentrations of >125 μg/ml defibrotide produced an almost complete inhibition of heparinase I digestion. This inhibition of heparinase digestion was dependent on defibrotide concentration and the IC50 was found to be 12.5 μg/ml. These results suggest that polyelectrolytes such as defibrotide are capable of inhibiting heparin/heparan digestion enzymes. The observed potentiation of anticoagulant effect of heparin in patients treated simultaneously with defibrotide may partially be due to the inhibition of endogenous heparin digesting enzymes. Subsequent studies in primates have revealed that the anticoagulant effects of both unfractionated heparin and low-molecular mass heparins are potentiated by defibrotide as determined by AUC measurements for the circulating level of these agents. Thus, these interactions should be taken into account to optimize anticoagulant management where these drugs are used in a combination regimen.
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Fareed, Jawed, Debra Hoppensteadt, Josephine Cunanan, Walter Jeske, Cafer Adiguzal, He Zhu, Cinara Echart, and Massimo Iacobelli. "Prolonged Administration of Defibrotide Is Non-Immunogenic in Rats and Dogs." Blood 114, no. 22 (November 20, 2009): 4180. http://dx.doi.org/10.1182/blood.v114.22.4180.4180.
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Abstract Abstract 4180 Introduction Polyelectrolytes such as heparins and sulfated glycosaminoglycans are capable of interacting with endogenous proteins resulting in the generation of neoepitopes leading to the formation of antibodies such as the anti-heparin platelet factor 4 antibodies. Defibrotide represents a polyanionic, DNA derived antithrombotic/antiischemic drug which is currently used in the management of various blood and vascular disorders. Although defibrotide does not have the same protein binding profile as heparins, it mediates various cellular and plasmatic responses to produce its pharmacologic effects. The purpose of this study is to determine if the long term administration of defibrotide results in the generation of any antigenic responses in rats and dogs. Methods Individual groups of rats (n=24) and dogs (n=30) were administered intravenously with varying dosages of Defibrotide (0-4800 mg/kg/day in rats and 0-1600 mg/kg/day in dogs) for a 3 month period of time. At the end blood samples were drawn from each group and the collected sera were tested for the presence of anti-defibrotide, antiphospholipid and anti-heparin PF4 (HIT antibodies) using modified ELISA methods which utilized specific secondary antibodies (IgG-rat/dog conjugated to alkaline phosphatase) for the rat and dog plasmas. Blood samples collected from normal rats and dogs constituted the control group (n=30-40). Results Neither the rats nor the dogs treated with Defibrotide exhibited any generation of anti-defibrotide, HIT and antiphospholipid antibodies in all groups of animals tested. There was no significant difference (p>0.05) between the control and defibrotide treated animals. The average circulating levels of defibrotide were dose dependent. Conclusion Prolonged administration of defibrotide to rats and dogs did not result in the production of antibodies to the drug product. Moreover, there was no evidence for the generation of HIT and antiphospholipid antibodies in these studies. Therefore, unlike heparins, defibrotide administration to animals does not lead to the generation of antibodies. Disclosures: Echart: Gentium: Employment. Iacobelli:Gentium: Employment.
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Fareed, Jawed, Michael J. Moorman, Walter Jeske, and Debra Hoppensteadt. "Defibrotide Interaction With Newer Oral Anticoagulant and Antiplatelet Drugs." Blood 122, no. 21 (November 15, 2013): 4804. http://dx.doi.org/10.1182/blood.v122.21.4804.4804.
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Introduction Defibrotide represents a single stranded mammalian DNA derived agent originally developed for anti-thrombotic and anti-ischemic indications. Defibrotide is currently used to treat or prevent failure of normal blood flow (Veno-occlusive disease, VOD) in the liver of patients who had bone marrow transplants or received drugs such as oral estrogens and mercatopurine. Defibrotide is a polypharmocologic agent with multiple sites of actions, which include anti-inflammatory and vaso-facilitatory effects. The purpose of this investigation is to determine potential interactions of defibrotide and some of the newer oral anticoagulant drugs, such as dabigatran, apixaban and rivaroxaban and antiplatelet drugs such as ticagrelor. Materials & Methods Defibrotide (lot no. DV0601) was obtained in powder form from Gentium s.p.A (Villa Guardia, Italy). The active form of dabigatran was purchased from Selleckcham (Houston, TX). Apixaban and rivaroxaban were obtained commercially and were of synthetic origin. The effect of defibrotide on dabigatran, apixaban, rivaroxaban and ticagrelor, on agonists (epinephrine, ADP, collagen, arachidonic acid and 2.5U thrombin) was measured using platelet aggregation techniques. The platelet rich plasma collected from normal healthy donors (n=15) were also supplemented with each of the individual anticoagulant drugs, alone in a range of 0-1000 ng/ml and in combination with defibrotide at 50-250ug/ml. Such clotting times as the PT, aPTT and Heptest and thrombin generation studies were carried out. In addition, whole blood activated clotting time (celite) studies were carried out by supplementing each of the individual oral anticoagulant agents at 1ug/ml, alone and with defibrotide at 100ug/ml. Results Neither defibrotide nor the newer anticoagulants and ticagrelor produced any effects on the epinephrine, ADP, collagen and arachidonic acid induced aggregation of PRP (p>0.05). However, dabigatran at concentrations of >62.5ng/ml produced inhibition of thrombin induced aggregation, all of the other agents did not have any effect on thrombin. Defibrotide at a concentration 100 ug/ml did not alter the aggregation profile in anticoagulant supplemented PRP. In both the plasma and whole blood anticoagulant assays, dabigatran produced stronger anticoagulant effects (306+30sec) than both apixaban (145+12sec) and rivaroxaban(160+15sec). Defibrotide exhibited minimal effects (135+10sec). Ticagrelor did not have any anticoagulant effect. Defibrotide in combination with dabigatran produced modest augmentation of the anticoagulant responses (360+42sec), however, it had much weaker effects on rivaroxaban (168+18sec) and apixaban(152+14sec). All of the anticoagulants in the TGA produced varying degrees of inhibition of thrombin generation in the following order; dabigatran > rivaroxaban > apixaban. Ticagrelor did not produce any inhibition of thrombin generation. Defibrotide did not produce any effects on TGA at concentrations up to 100ug/ml. When combined with oral anticoagulants, it did not show any augmentation of rivaroxaban and apixaban; however, it enhanced dabigatrans inhibitory effects. Conclusions These results suggest that defibrotide itself has weak or negligible anticoagulant effects in the plasma and whole blood assays. All of the new oral anticoagulants produced varying degrees of assay dependent anticoagulant effects in plasma and whole blood systems. However defibrotide did not show any interactions with apixaban and rivaroxaban, it showed some augmentation of the anticoagulant responses of dabigatran. Ticagrelor did not exhibit any interactions with defibrotide. These studies demonstrate that unlike heparins, defibrotide exhibits minimal interactions with newer oral anticoagulant and antiplatelet drugs. Disclosures: No relevant conflicts of interest to declare.
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Fareed, Jawed, Omer Iqbal, Debra Hoppensteadt, Cafer Adiguzel, Massimo Iacobelli, and Jeanine M. Walenga. "Defibrotide Augments the Anticoagulant Actions of Heparin and Low Molecular Weight Heparins." Blood 112, no. 11 (November 16, 2008): 4086. http://dx.doi.org/10.1182/blood.v112.11.4086.4086.
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Abstract Defibrotide represents a polydeoxyribonucleotide derived antithrombotic and antiischemic drug, which has been used in the management of vascular disorders and is currently being developed in other clinical indications. Defibrotide is a polyelectrolyte-based agent with target effects on endothelium, platelets, and blood cells. In addition, the aptameric consensus sequences in the nucleotides exhibit inhibitory effects towards thrombin and related proteases. In the anticoagulant assays defibrotide exhibits relatively weak effects (<5 USP U/mg). These studies were undertaken to study whether there is an interaction between defibrotide and unfractionated heparin (UFH) in various systems of anticoagulation. The interaction of defibrotide with commercially available low molecular weight heparins (LMWHs), enoxaparin and dalteparin, was also studied. For the first investigation, to evaluate the effect of defibrotide on the anticoagulant effects of UFH, native whole blood freshly drawn from human volunteers (n = 20) was supplemented with UFH at a fixed concentration of 5 μg/mL (0.8 U/mL), and graded amounts of defibrotide were added in a concentration range of 12.5 – 100 μg/mL. The whole blood celite Activated Clotting Time test (ACT) and the thrombin generation markers fibrinopeptide A (FPA), thrombin-antithrombin complex (TAT), and prothrombin fragment 1.2 (F1.2) were measured. Parallel controls with saline were included. While defibrotide did not produce a significant prolongation of the ACT compared to saline (128 ± 9 s vs 132 ± 7 s), it produced a concentration-dependent increase in the heparinized whole blood leading to an almost doubling of the anticoagulant action of UFH (248 ± 19 s vs 418 ± 21 s). Additional studies carried out by varying the concentrations of the two agents also revealed supraadditive to synergistic effects. Defibrotide also augmented the inhibitory effects of UFH on thrombin generation markers in a concentration-dependent fashion. Similar studies carried out with the two LMWHs did not reveal a similar interaction in the anticoagulant assays such as the ACT; however, significant interactions between defibrotide and the LMWHs were observed in the thrombin generation studies. For the second investigation, studies were carried out using plasma samples collected from heparinized patients (aPTT of 50 – 100 s). These studies also revealed that supplementation of defibrotide augmented the anticoagulant effects of UFH in a concentration-dependent fashion. While defibrotide at 12.5 μg/mL did not significantly increase the aPTT of normal plasma, when supplemented to heparinized plasmas (n = 50 with aPTT of 64.6 ± 14.0 s) it produced a strong prolongation of the clotting time (96.1 ± 20.6 s). In the third investigation, animal models of thrombosis including the rat jugular vein clamping model, demonstrated an augmentation of the antithrombotic effects of intravenously administered UFH by defibrotide. However, no augmentation of the hemorrhagic effect was observed in the rat tail bleeding model. These studies demonstrate that defibrotide exhibits a strong anticoagulant interaction with UFH and to a lesser degree LMWH. While the combination of defibrotide and UFH exhibits enhanced anticoagulant/antithrombotic activities, it does not exhibit any alteration of the hemorrhagic profile. These studies clearly suggest that defibrotide can be combined with UFH to achieve a superior anticoagulant approach with better safety/efficacy profile.
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Tappe, William, Saurabh Aggarwal, Ozlem Topaloglu, and Massimo Iacobelli. "A Meta-Analysis Evaluating the Risk of Bleeding-Related Adverse Events with Defibrotide Treatment." Blood 134, Supplement_1 (November 13, 2019): 2016. http://dx.doi.org/10.1182/blood-2019-123686.
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Introduction: Defibrotide is approved for adult and pediatric patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT) in the United States and Canada and for patients aged >1 month with severe hepatic VOD/SOS post-HCT in the European Union. The recommended dose is 6.25 mg/kg every 6 hours given as a 2-hour intravenous (IV) infusion. Defibrotide has been shown in vitro to reduce endothelial cell (EC) activation and promote EC-mediated fibrinolysis. Post-HCT patients with VOD/SOS are often at a high risk for bleeding events. In a phase 3 study of patients with VOD/SOS post-HCT, rates of bleeding-related adverse events (AEs) with defibrotide were generally similar to matched historic controls (Richardson PG, et al. Blood. 2016;127[13]:1656-1665). To broaden our understanding of the risk of bleeding events associated with defibrotide treatment, this meta-analysis assessed the incidence and risk of bleeding-related AEs with defibrotide treatment in studies outside of the VOD/SOS and HCT setting, using published literature. Methods: PubMed and Embase were searched from database inception through July 24, 2018 for studies using defibrotide (controlled trials with ≥1 arm assessing an intervention of interest, observational/retrospective studies, retrospective or post hoc analyses, and case series with ≥10 patients). Studies of patients with VOD/SOS or HCT, case reports with <10 patients, and reviews were excluded. Publications were evaluated for the presence of data on endpoints of interest, which included any bleeding-related event and overall safety or efficacy summaries; all studies with available data were included in the analysis. Overall bleeding rate was estimated for defibrotide and controls using the Freeman-Tukey double arcsine transformation and random-effects modeling (Stata Software). The risk ratio of bleeding was calculated using the Mantel-Haenszel method and random-effects modeling (RevMan 5.3 Software). Overall bleeding rate and risk ratio of bleeding were calculated from studies that used the IV defibrotide formulation; studies using oral or intramuscular formulations were excluded from these calculations. Results: A total of 1,857 records were identified in the search; 124 studies reported on defibrotide and 19 contained data related to bleeding and were included in the analysis. Of the 19 included studies, 2 had >1,000 patients. An IV defibrotide formulation was used in 12 studies; the other 7 used intramuscular or oral delivery or more than one method of defibrotide administration. The most common indications were prevention of deep vein thrombosis (11 of 19) and treatment of thrombosis (3 of 19). Most studies (14 of 19) had 2 treatment arms; among these studies, heparin was the most common comparator (11 of 14). For the other 5 of 19 studies, 4 studies were single-arm and 1 study had 3 arms. The majority of studies (16 of 19) were conducted in adults; the other 3 studies did not specify patients' age. The most commonly administered defibrotide dose was 800 mg daily (14 of 19 studies). Bleeding rate and risk ratio of bleeding were calculated based upon data from the 12 studies that used IV defibrotide. Rates of bleeding events reported in the 12 studies with IV defibrotide ranged from 0% to 10% in individual studies and the estimated overall bleeding rate was 1% (95% confidence interval [CI]: 0.00-0.03). In 10 studies with control treatments (9 calcium heparin, 1 urokinase), rates of bleeding events ranged from 1% to 37%, with 7 studies having rates ≥10%. Across the 10 control studies, the estimated overall bleeding rate for controls was 11% (95% CI: 0.05-0.20). Among the 8 studies with available data on IV defibrotide and controls (7 calcium heparin, 1 urokinase), the risk ratio for bleeding events with IV defibrotide versus controls was 0.36 (95% CI: 0.24-0.52; P <0.00001; Figure). Conclusions: This meta-analysis of defibrotide use outside of the VOD/SOS setting suggests that the bleeding risk with defibrotide is low, and there is comparable risk of bleeding with defibrotide treatment versus controls such as heparin or urokinase. Important limitations of this analysis include variations in AE reporting across studies and the use of a defibrotide dose that is lower than the currently approved recommendation in the majority of studies. Disclosures Tappe: Jazz Pharmaceuticals: Employment, Equity Ownership. Aggarwal:Jazz Pharmaceuticals: Consultancy. Topaloglu:Jazz Pharmaceuticals: Consultancy. Iacobelli:Massimo Iacobelli: Consultancy. OffLabel Disclosure: The abstract describes a meta-analysis of defibrotide (indicated for VOD/SOS) in the non-VOD/SOS setting. As this analysis drew data from existing literature, no patients were administered defibrotide for off-label indications in the course of this analysis.
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Maher, Kristin N., Xu Han, Keith B. Neeves, Marvin T. Nieman, and Jorge Di Paola. "Modulation of Thrombin-Induced Platelet Activation By Defibrotide." Blood 134, Supplement_1 (November 13, 2019): 3614. http://dx.doi.org/10.1182/blood-2019-125945.
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Defibrotide is a mixture of single-stranded phosphodiester oligonucleotides 9-80 bases in length derived from mammalian tissue and it is the only medication that is FDA approved for the prevention and treatment of post-transplant veno-occlusive disease, also known as sinusoidal obstructive syndrome (VOD/SOS). The mechanism of action of defibrotide is not well understood. A better understanding of the molecular mechanism by which defibrotide prevents and reverses the microvascular occlusion seen in VOD/SOS will be critical in the development of novel therapeutics for VOD/SOS and other related disorders. Our central hypothesis is that single stranded phosphodiester oligonucleotide mixtures such as defibrotide alter thrombin-induced platelet and endothelial cell activation primarily via altered signaling through protease activated receptors (PARs). To determine the effect of defibrotide on thrombin-induced platelet activation we performed flow cytometry on washed platelets from humans and mice. Washed platelets were incubated with agonist (1 nM thrombin, 100 μM synthetic PAR1 agonist TRAP6, or 100 μM synthetic PAR4 agonist PAR4AP) in the presence or absence of 1 mg/mL of defibrotide. Fluorescent antibodies against P-selectin (anti-CD62P antibody) and against the high affinity conformation of the αIIβ3 receptor (PAC1 antibody for human samples and JON/A antibody for murine samples) were added to assess for inhibition of platelet activation by defibrotide. Fluorescent anti-PAR1 antibodies SPAN12 (which spans the canonical thrombin cleavage site) and WEDE15 (which binds at the hirudin-like domain) were also added to separate samples to assess whether defibrotide inhibits cleavage of the PAR1 N-terminal domain by thrombin. After twenty minutes of incubation at room temperature the samples were analyzed by flow cytometry. We calculated the geometric mean of the fluorescence intensity (MFI) for three replicate samples and data are shown as the fold change compared to the washed platelet control without addition of agonist or defibrotide. For thrombin-stimulated human platelets, both anti-CD62P binding (MFI fold over control 5.7 vs. 1.2) and PAC1 antibody binding (MFI fold over control 7.1 vs. 1.7) are significantly reduced in the presence of defibrotide (See Figure 1a). For thrombin-stimulated murine platelets there is a small decrease in anti-CD62P antibody binding (MFI fold over control 8.4 vs. 6.6), but no significant change in JON/A antibody binding (See Figure 1b). Binding of both anti-CD62P and PAC1 antibodies to human platelets stimulated with synthetic PAR agonists was unaffected by the presence of defibrotide (See Figure 1c). There is no significant difference in SPAN12 or WEDE15 binding in thrombin-stimulated platelets in the absence or presence of defibrotide. However, defibrotide alone does appear to interfere with WEDE15 binding in unstimulated platelets (See Figure 1d). In conclusion, we showed that defibrotide inhibits thrombin-induced human platelet activation at low concentrations of thrombin, as shown by a decrease in surface platelet activation markers measured by flow cytometry. This effect is much less pronounced under the same conditions if mouse platelets are used, supporting the hypothesis that defibrotide inhibits platelet activation by alteration of PAR1 receptor signaling, since PAR1 receptors are not present on mouse platelets. Defibrotide does not interfere with TRAP6-induced platelet activation, evidence against interference with the intracellular portion of the signaling pathway, since TRAP6 is a synthetic PAR1 agonist that binds directly into the ligand-binding pocket of the receptor, eliminating the need for cleavage of the PAR1 extracellular domain. The decrease in WEDE15 antibody binding to washed platelets seen with defibrotide alone suggests that the mechanism may involve alterations in the hirudin-like domain of the PAR1 receptor which is crucial for thrombin binding and cleavage site specificity. Ongoing studies including investigating the effect of defibrotide on peptide mimics of the extracellular N-terminal domain of the PAR1 receptor and the effect of defibrotide on the activation of endothelial cells will likely shed light on the exact mechanism of platelet response modulation by defibrotide and may provide new targets for treatment of the microvascular occlusion that characterizes VOD/SOS. Disclosures No relevant conflicts of interest to declare.
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Hasenkamp, Justin, Imme Conradi, Gerald Wulf, Wolfram Jung, Lorenz Truemper, and Bertram Glass. "Prevention of Veno-Occlusive Disease in Hematopoietic Stem Cell Transplantation Due to Defibrotide Prophylaxis." Blood 104, no. 11 (November 16, 2004): 1139. http://dx.doi.org/10.1182/blood.v104.11.1139.1139.
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Abstract Veno-occlusive disease (VOD) is a serious complication of intensive chemotherapy regimens used in hematopoietic stem cell transplantation (HSCT). Incidence ranges from 10–60% (Chopra et al., 2000). Despite numerous therapeutic attempts described such as rtPA, TIPS and defibrotide mortality remains 80% (Fried et al., 1996). Risk factors for developing VOD are previous high-dose chemotherapy, unrelated donor transplants and busulfan-based conditioning regimens. In face of the frequency and high mortality due to absence of effective therapeutic options there is need for prophylaxis. We incorporated defibrotide into the supportive regimen for high risk patients undergoing a HSCT with busulfan containing conditioning regimens. From 01/2003 to 08/2004 44 patients (median age 52y, 24 male) receiving a busulfan containing regimen for HSCT (2 autologous, 42 allogeneic, 23 unrelated donors) were treated prophylactically with defibrotide as 800mg/24h continuous infusion from start of conditioning chemotherapy up to day +21 (group 1). Underlying diseases were: 10 AML, 24 NHL, 3 HD, 6 MM, 1 CML. Median number of previous regimens were 3. 27 patients had high-dose chemotherapies followed by autologous HSCT as prior therapy. From 07/2001 to 12/2002 16 patients (median age 45y, 11 male) receiving busulfan-based conditioning for allogeneic HSCT (7 unrelated donors) received heparin (300IE/h) for prophylaxis of VOD and catheter related thrombosis (group 2). Disease entities were 7 AML, 7 NHL, 1 HD, 1 ALL. Median number of previous regimen was 3. 11 patients had high-dose therapies followed by autologous HSCT as prior therapy. While in the latter group 1/16 patients developed and finally died of VOD, 3/44 in the defibrotide group did so. Date of VOD diagnosis in the patient not prophylatically treated with defibrotide was day +13 after HSCT compared to day +21, +25 and +27 in patients who received defibrotide prophylaxis. There were no serious adverse events (e.g. bleeding) attributable to defibrotide. Overall incidence of VOD in both groups is low (6,8% group 1; 6,3% group 2). Although patients in group 1 were at high risk of VOD, no VOD occurred during the period of defibrotide prophylaxis. We conclude that defibrotide is save and efficient in prevention of VOD. Defibrotide delayed the onset of VOD beyond its application. However, with defibrotide prophylaxis late onset of VOD has to be encountered. The optimal application period has to be determined.
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Richardson, Paul G., Enric Carreras, Massimo Iacobelli, and Bijan Nejadnik. "The use of defibrotide in blood and marrow transplantation." Blood Advances 2, no. 12 (June 26, 2018): 1495–509. http://dx.doi.org/10.1182/bloodadvances.2017008375.
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Abstract Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of conditioning during hematopoietic stem cell transplantation (HSCT) or chemotherapy without HSCT, with a historically reported mean incidence of 13.7% post-HSCT. Typical symptoms of VOD/SOS may include hyperbilirubinemia, painful hepatomegaly, weight gain, and ascites. Defibrotide, a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotides, is currently the only therapy approved to treat hepatic VOD/SOS with pulmonary/renal dysfunction (ie, multiorgan dysfunction/multiorgan failure [MOD/MOF]) following HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the European Union. In preclinical and human studies, defibrotide has demonstrated profibrinolytic, antithrombotic, anti-inflammatory, and angio-protective actions, thus promoting an anticoagulant phenotype of the endothelium that protects and stabilizes the function of endothelial cells. In a phase 3, historically controlled, multicenter trial in adults and children with VOD/SOS and MOD/MOF (defibrotide: n = 102; controls treated before defibrotide availability: n = 32), defibrotide resulted in significantly greater day +100 survival following HSCT (38.2%) vs controls (25.0%; propensity analysis-estimated between-group difference: 23%; P = .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graft-versus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.
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Tekgunduz, Emre, Seval Akpinar, Sinem Civriz Bozdag, Aysegul Tetik, Serife Kocubaba, Murat Cinarsoy, Gamze Durgun, et al. "Effectiveness of Defibrotide in the Prevention of VOD Among Patients Receiving Allogeneic Hematopoetic Cell Transplantation: A Retrospective Single Center Experience." Blood 120, no. 21 (November 16, 2012): 4508. http://dx.doi.org/10.1182/blood.v120.21.4508.4508.
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Abstract Abstract 4508 Introduction: Hepatic venooclusive disease (VOD), is one of the major regimen related early complications of hematopoietic cell transplantation (HCT). The incidence of VOD ranges between 3% to 54% in different series. Mortality rates also differ according to severity of the disease and defibrotide treatment. We aimed to assess the impact of defibrotide prophylaxis on the incidence of VOD in our center by day 30 after allogeneic HST (allo-HCT). Material Method: We retrospectively analyzed 87 consecutive patients who had received allo-HCT with different diagnosis of hematological diseases in our transplantation unit between January 2009 and August 2012 in two groups acoording two VOD prophylaxis they received. The first (standard group; n: 59) and second (defibrotide group; n: 28) groups of patients were treated with allo-HST during January 2009-October 2011 and November 2011-August 2012 (n:28), respectively. Patient characteristics are summarized in Table 1. All of the patients had enoxaparin (as long as Plt ≥ 30000/mm3 and absence of bleeding), ursodeoxycolic acid and N-acetylsistein prophylaxis. Twenty eight of the patients in the second group received upfront defibrotide 10 mg/kg/day i.v between posttransplantation days 1 and 14 in addition to standard VOD prophylaxis approach. If the patients were diagnosed as VOD, defibrotide dose was increased to 25 mg/kg/day i.v in the prophylaxsis group. Fifty nine of the patients belonging to standard group did not have the opportunity to get defibrotide for prophylaxis or treatment due to drug supply. Diagnosis and classification of severity was defined according to Seattle criteria. None of the patients had hepatic biopsy for histopathological diagnosis mainly because of the thrombocytopenia/coagulopaty associated bleeding risk. Results: Nine of eighty seven (10%) patients diagnosed as VOD; only one of these patients was in the defibrotide group. Less patients were diagnosed as VOD in the defibrotide (8/59; 3.5%) compared to standard prophlaxis (1/28;13%) group (p=0,153). Number of patients who were diagnosed with mild/moderate/severe VOD were 2/3/4,respectively. The median day of VOD diagnosis was posttransplantation day 9(2–19). The median of maximum bilirubin level was 5 (2,1–24). Seven of nine (77%) patients died during the follow up. Eight patients in standard who were diagnosed with VOD could not be treated with the defibrotide as the drug was unavailable during this time period in our country. The only patient with VOD in second group received primary defibrotide prophylaxis and the dose of the drug was increased to treatment dosage when VOD was diagnosed. Venooclusive disease of the two alive patients resolved completely without defibrotide treatment. Hypoxemia and O2 requirement was observed in four patients. The median diuretic (furosemide; IV) requirement for weight gain of the patients was found to be lower for patients in defibrotide arm (160 mg; (0–4280 mg)) compared to standard prophylaxis arm (280 mg; (20–6500 mg)) (p=0,196). Discussion–Conclusion: There are several factors that can effect VOD incidence during allogeneic stem cell transplantation. Myeloablative conditioning, previous liver disease, poor performance status, and alternative donors are the variables with higher impact on VOD development. Our patient groups were not statistically different according to the conditioning regimen, number of transplantations and previous hepatic disease status. Zheng et al reported the incidence of VOD with or without defibrotide prophylaxis as 13,7% and 4.4%, respectively. Although our results are similar to this report we did not observed a significant difference in terms of VOD between the two groups. The majority of our patients had either moderate or severe disease and mortality was very high in the group without defibrotide prophylaxis; as a consequence of inability to reach to defibrotide. In conclusion, defibrotide seems to be a very promising agent to reduce VOD incidence by prophylactic usage. Disclosures: No relevant conflicts of interest to declare.
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Fareed, Jawed, Walter Jeske, Demetra Callas, Debra Hoppensteadt, and Jeanine Walenga. "Modulation of Endothelium by Heparin and Related Polyelectrolytes." Clinical and Applied Thrombosis/Hemostasis 2, no. 3 (July 1996): 200–208. http://dx.doi.org/10.1177/107602969600200310.
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The vascular endothelium is an important me diator of the hemostatic balance. In addition to shielding subendothelial tissue factor from flowing blood, endothe lial cells produce a number of substances which favor an antithrombotic state including TFPI and tPA. The ability of polyelectrolytes such as heparin and defibrotide to modulate endothelial function is examined using animal models and human studies. Like heparin, defibrotide is observed to increase plasma TFPI antigen levels. Addi tionally, defibrotide administration is observed to in crease plasma tPa antigen levels and to decrease PAI, TF and endothelin levels. Modulation of endothelial function by defibrotide may account for its beneficial effect in PAOD.
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Marubini, E., S. Coccheri, G. G. Nenci, and F. Violi. "Improvement of Walking Distance by Defibrotide in Patients with Intermittent Claudication." Thrombosis and Haemostasis 83, no. 05 (2000): 672–77. http://dx.doi.org/10.1055/s-0037-1613890.
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SummaryDefibrotide is an antithrombotic drug which enhances prostacyclin production and activates fibrinolytic system. The aim of this study was to investigate the improvement of walking distance in patients with intermittent claudication treated with defibrotide.DICLIS was a double blind, placebo-controlled study which included patients with walking distance autonomy at a standardized treadmill test ≤350 ≥100 meters. A total of 310 patients were randomly allocated to placebo (n = 101), defibrotide 800 mg/day (n = 104) or defibrotide 1200 mg/day (n = 105).During a one year follow-up, the Absolute Walking Distance (AWD) was measured six times (0, 30, 60, 90, 180, 360 days).Similar improvement in walking distance was found in the three groups until the 90th day; thereafter placebo group showed no further increase, while AWD continued to increase in the defibrotide groups. Between the 180th and 360th day visits, AWD was significantly higher (P <0.01) in patients given defibrotide than in patients given placebo. No difference in efficacy was observed between the two dosages of defibrotide. No differences in side effects were observed among the three groups.The results of the present trial suggest that long-term administration of defibrotide improves walking distance in patients with intermittent claudication. Abbreviations: DICLIS = Defibrotide Intermittent CLaudication Italian Study, AWD = Absolute Walking Distance, IC = Intermittent Claudication, PVD = Peripheral Vascular Disease, LVOCF = Last Valid Observation Carried Forward, ITT = Intention-To-TreatAppendix, please see p. 676.
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Hale, Gregory A., Renee M. Madden, Kimberly A. Kasow, Joseph Woodard, Wing H. Leung, Raymond C. Barfield, Usman Yusuf, Edwin M. Horwitz, and Rupert Handgretinger. "High Dose Defibrotide as Therapy for Pediatric Patients with Veno-Occlusive Disease of the Liver." Blood 108, no. 11 (November 16, 2006): 2963. http://dx.doi.org/10.1182/blood.v108.11.2963.2963.
Full textAbstract:
Abstract Veno-occlusive disease (VOD), is a life-threatening complication following autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and certain chemotherapy regimens. Presently, there is no effective treatment for this disorder, with potential therapies resulting in hemorrhage. In adults with VOD, defibrotide, an investigational agent consisting of a single strand polydexoyribonucleotide, has been shown to improve survival rates at doses up to 60 mg/kg/day. Even with this improvement, a significant proportion of patients with VOD still die of multi-system organ failure. However, there is limited published data in pediatric patients and no data on administering doses of defibrotide > 60 mg/kg/day to patients who do not respond at standard dosages. In 2003, we initiated a compassionate use prospective clinical trial studying defibrotide therapy for patients with VOD. All transplant patients had received heparin 100 units/kg/day as a continuous infusion for VOD prophylaxis. A diagnosis of VOD was made if either of the following criteria were met:Bilirubin ≥ 2 mg/dl with 2 of the following criteria --hepatomegaly, weight gain ≥ 5%, and ascites; orultrasonographic evidence of VOD. Defibrotide therapy was initiated at 10 mg/kg/day escalated every 24 hours by 10 mg/kg/day to 60 mg/kg/day over 6 days. Doses were administered intravenously at 6-hour intervals. Patients who did not have improvement in VOD at the maximum dose level were further escalated in 10 mg/kg/day increments to a maximum dose of 110 mg/kg/day. We enrolled 21 patients from August 2003 to July 2006. The median patient age, was 7.7 years (range, 0.5 to 21.6); 16 were male. Eighteen had received allogeneic HSCT (4 matched related, 6 unrelated, and 8 mismatched related donors), two had received autologous HSCT, and one was receiving chemotherapy for recurrent ALL. Diagnoses included ALL (n=5), AML (n=4), CML (n=1), NHL (n=2), JMML (n=1), neuroblastoma (n=4), Wilms’ tumor (n=1), and non-malignant disease (n=3). The non-HSCT patient had active disease at the time of enrollment. Of the 17 HSCT patients with malignancies, 5 had refractory/active disease, 5 were in CR1/CP1, 4 were in CR2, and 3 had PR. Five patients underwent second allogeneic HSCT. Thirteen patients had resolution of VOD at defibrotide doses ≤60 mg/kg/day. Eight patients required additional dose escalation: 70 mg/kg/day in 4 pts; 80 mg/kg/day in 2 pts; 100 mg/kg/day in 1 pt; and 110 mg/kg/day in 1 pt. VOD resolved in all but one. Only one patient died of VOD. Eight of 19 patients who have completed defibrotide therapy survive as outpatients with performance scores ≥ 90. Two other patients continue to receive defibrotide with resolving VOD--one who was treated at a maximum defibrotide dose of 70 mg/kg/day and the other at 110 mg/kg/day. Eleven patients expired--five of relapse, three of infection, and one each from graft failure, GVHD, and VOD. There were no defibrotide infusion-related adverse events. No unexpected adverse events related to the defibrotide occurred. Two of 3 patients with concomitant thrombotic microangiopathy at time of enrollment experienced resolution of the microangiopathy at a median of 14 days after initiating defibrotide. Defibrotide does improve survival for pediatric patients with VOD, that many patients with persistent VOD at standard doses will respond to higher doses of defibrotide, and that defibrotide can be safely administered at doses up to 110 mg/kg/day.
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Mountfort, Katrina, Mohamad Mohty, and Elisabeth Wallhult. "Defibrotide – A New Treatment Approach for Severe Veno-occlusive Disease." European Oncology & Haematology 11, no. 1 (2015): 11. http://dx.doi.org/10.17925/eoh.2015.11.01.11.
Full textAbstract:
Severe veno-occlusive disease (VOD) is a serious and life-threatening complication of haematopoietic stem cell transplantation (HSCT), for which the standard of care has until recently been supportive care. VOD is the result of a primary injury to sinusoidal endothelial cells and severe VOD is characterised by sinusoidal narrowing and occlusion, which leads to portal hypertension, multi-organ failure (MOF) and, ultimately, death. Defibrotide regulates multiple pathways involved in the pathological processes underlying VOD and is the first drug to be approved in Europe for the treatment of severe VOD. Defibrotide is indicated for the treatment of severe hepatic VOD in HSCT therapy in adults and infants aged over 1 month. A phase III study found significant increases in complete response (CR) and survival with defibrotide compared with historical controls. These data together with earlier studies and an ongoing expanded access protocol in a large patient cohort demonstrate improved outcomes with defibrotide in severe VOD and highlight the importance of treatment with defibrotide
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Uygun, Vedat, Gulsun Tezcan, Volkan Hazar, and Akif Yesilipek. "Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease in Children." Blood 108, no. 11 (November 16, 2006): 5263. http://dx.doi.org/10.1182/blood.v108.11.5263.5263.
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Abstract Veno-occlusive disease (VOD) of the liver is a major complication of allogeneic or autologous stem cell transplantation (HSCT), particularly after busulfan-based conditioning regimens. Clinically, VOD is characterized by fluid retention, weight gain, hyperbilirubinemia and painful hepatomegaly. Efficacy and safety of defibrotide for the treatment of VOD, especially in pediatric patients, has not been adequately confirmed or the results are still preliminary. This retrospective report describes experience with defibrotide in children with hepatic veno-occlusive disease (HVOD) following HSCT in a single institution. Materials and Method: Children who had undergone HSCT between April 2005–June 2006 and who received defibrotide for the treatment of HVOD during their admission were identified. Demographic data and clinical information of these patients were abstracted from their health records. Results: Eight children (median age: 4.5 years; range: 1–14 years) who underwent HSCT during the study period received defibrotide for the treatment of HVOD; 5 were boys and 3 were girls. Three patients underwent HSCT for hematologic malignancies, 2 for neuroblastoma, 1 for hemoglobinopathy, 1 for severe combined immunodeficiency (SCID) and 1 for fanconi aplastic anemia. Conditioning regimens included busulfan (16 mg/kg) in four, melphelan (140 mg/m2) in two and total body irradiation in 1 patient as being risk factors for HVOD. Two patients with neuroblastoma had undergone autologous HSCT, three patients had been transplanted from matched sibling donor and the other three were either unrelated donor or unrelated cord blood transplantation. HVOD was diagnosed on transplant day +4 to +19 (median: +12 ). The median initial defibrotide dose was 31.5 mg/kg/day (25–46 mg/kg/day). The median duration of defibrotide therapy was 27 days (1–46 days). Defibrotide was discontinued due to clinical improvement (5), gastrointestinal hemorrhage (2), death (1). Two patients in whom defibrotide was discontinued because of gastrointestinal hemorrhage died. The primary cause of death in these two children was: progressive HVOD and multiorgan failue following sepsis. As a result of this experience and under the light of literature, we believed that defibrotide is an effective treatment for children with HVOD and should be instituted in each children without delay in the event of at least one of the criteria for HVOD is established. But it is necessary to carry out further studies in larger group of patients with longer follow-up to validate the efficacy and safety of defibrotide.
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Richardson, Paul G., Nancy A. Kernan, Stephan A. Grupp, Paul L. Martin, Robert J. Soiffer, Richard Martin, Alison L. Hannah, and Kathleen F. Villa. "Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease: An Analysis of Clinical Benefit As Determined By Number Needed to Treat (NNT) to Achieve Complete Response and to Improve Survival." Blood 124, no. 21 (December 6, 2014): 2469. http://dx.doi.org/10.1182/blood.v124.21.2469.2469.
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Abstract Introduction: Hepatic veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplantation (HSCT) and, in severe cases, is associated with multi-organ failure and mortality rates exceeding 80% (Coppell et al. Biol Blood Marrow Transplant, 2010, p157-168). In the US there are currently no FDA-approved treatments for severe VOD. Defibrotide, an oligonucleotide with a mechanism of action that encompasses both restoration of the thrombo-fibrinolytic balance and endothelial cell protection, has recently been approved for the treatment of severe VOD following HSCT in the EU. The data presented are based on the primary and secondary endpoint analyses provided to the European Medicines Agency (EMA) that formed the basis of the defibrotide approval in the EU. Methods: A pivotal phase 3 study examined the efficacy and safety of defibrotide 25 mg/kg/day in patients with severe VOD (n=102) compared to historical controls (n=32) (Defibrotide Summary of Product Characteristics. Villa Guardia, Italy: Gentium SpA; 2013). The study’s primary endpoint was complete response (CR) (in terms of improvements in total bilirubin and resolution of multi-organ failure measured by renal and/or pulmonary dysfunction) by 100 days post-HSCT; secondary endpoints included survival 100 days and 180 days post-HSCT. We calculated the number needed to treat (NNT) with defibrotide to achieve one complete response and the NNT to prevent one death 100 days post-HSCT in patients with severe VOD compared to historical controls who did not receive defibrotide in order to evaluate how defibrotide compared to other novel and efficacious agents used for rare conditions in hemato-oncology. NNT is calculated as the reciprocal of the absolute risk reduction (1/ARR), where ARR is equal to the control minus experimental event rates (Laupacis et al, New Engl J Med, 1988, p1728-1733). Results: In the defibrotide trial, complete response by day 100 was achieved in 23.5% of the defibrotide-treated patients and 9.4% of the historical controls (P=0.013), which equated to an NNT of 7 (1/(0.235-0.094)) to achieve one complete response 100 days post-HSCT. Day 100 survival was 38.2% in the defibrotide group and 25.0% in the historical control group (P=0.034) (Defibrotide Summary of Product Characteristics. Villa Guardia, Italy: Gentium SpA; 2013). Therefore, the NNT to prevent one death in this study was 8 (1/(0.382-0.25)). To compare the NNTs in this analysis with those in other studies, a literature search was conducted, identifying a selected number of pediatric oncology clinical trials published within the previous 10 years each of which reported 5-year EFS rates (Sorrell et al, Cancer, 2012, p4806-4814; La et al, Int J Radiat Oncol Biol Phys, 2011, p1151-1157; Chou et al, Cancer, 2009, p5339-5348; Lange et al, Blood, 2008, p1044-1053; MacDonald et al, Cancer, 2005, p2862-2871). NNTs calculated from that review ranged from 5 to 50. Conclusion: The results of this pivotal Phase 3 trial showed improved complete response and survival in defibrotide-treated patients compared to historical controls who did not receive defibrotide for the treatment of severe VOD. The number needed to treat to achieve this benefit proved either comparable or lower than the NNT obtained for other widely-accepted and approved therapeutic medical interventions in hemato-oncology. Support: Jazz Pharmaceuticals Off-Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States. Disclosures Richardson: Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals Inc.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for veno-occlusive disease in the United States.. Martin:EUSA Pharma - an international division of Jazz Pharmaceuticals: Employment; Jazz Pharmaceuticals: Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership.
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Marsili, M., P. Lorenzi, M. Librenti, L. Doni, C. Benassai, E. Martini, L. P. Fabbri, S. Cinotti, M. Morfini, and S. Boncinelli. "Defibrotide in Extracorporeal Circulation on Healthy Rabbits." International Journal of Artificial Organs 12, no. 12 (December 1989): 749–54. http://dx.doi.org/10.1177/039139888901201203.
Full textAbstract:
Defibrotide, a partially depolymerized DNA fraction obtained from mammalian lung, was found to have significant antithrombotic and fibrinolytic activities. On the basis of this evidence defibrotide could be of clinical value during hemoperfusive treatment. The present study was designed to evaluate the biological tolerance of this technique in a model of extracorporeal circulation, using an original Silastic apparatus, with defibrotide (0.83 mg/kg–1/min–1 after a 50 mg/kg–1 bolus injection) and heparin (0.66 IU/kg–1/min–1 after a 400 IU/kg–1 bolus injection) in ten rabbits (Group 1) and heparin only in ten others (Group 2, control group). In this study defibrotide produced a significantly lower pressure inside the circuit compared to the control group and gave a protective effect against those pathological changes which appeared during extracorporeal circulation and that may be considered omens of a state of shock. However the use of defibrotide in addition to heparin seemed to have a poor effect on platelet and leukocyte count alterations during application of this technique.
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Ruggieri, M., D. Vicini, P. Mirando, G. P. Franceschetti, C. Sali, G. L. Picchio, P. Marandola, and L. Cocilovo. "Physical treatment and physical-drugs treatment of induratio penis plastica: Orgotein versus defibrotide versus only physical treatment. Our experience." Urologia Journal 61, no. 4 (August 1994): 259–61. http://dx.doi.org/10.1177/039156039406100404.
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Medical treatment of Induratio Penis Plastica consists of oral vitamin E and anti-inflammatory drugs in iontophoretic laser and ultrasonic treatment. The aim of this study is to compare the efficacy between iontophoretic, laser and ultrasonic treatment (physical treatment) and the same treatment plus orgotein and defibrotide. 10 patients undergoing only physical treatment, and 10 patients with orgotein or defibrotide. Iontophoretic, laser and ultrasonic treatment alone is not sufficient for pain to disappear. The association of an inexpensive drug, such as defibrotide, is necessary.
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Chalandon, Yves, Federico Simonetta, Carole Dantin, Aikaterini Koutsi, Anne-Claire Mamez, Yan Beauverd, Olga Tsopra, et al. "Efficient Prophylaxis with Defibrotide for Sinusoidal Obstruction Syndrome (SOS) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)." Blood 128, no. 22 (December 2, 2016): 2204. http://dx.doi.org/10.1182/blood.v128.22.2204.2204.
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Abstract Backgound : Sinusoidal obstruction syndrome [SOS, also known as hepatic veno-occlusive disease (VOD)] is frequent after HSCT and may have a mortality rate of up to 85%. Defibrotide has shown efficacy not only in the treatment of established SOS (Richardson et al. Blood 1998:92;737 and 2016:127;1656) but also in SOS prevention in children (prospective study: Corbacioglu et al. Lancet 2012:379;1301) as well as in adults (several retrospective studies). Patients and methods : Between 1999 and 2009, we gave defibrotide intravenously to 248 successive patients transplanted for hematological diseases starting at day -7 up to day +20 post-transplantation (dose range 800-2400 mg/d) in combination with heparin. We previously published the data of the 52 first patients compared to 52 historical controls who were transplanted just prior to the study period. We now expand the study with 196 additional patients treated successively with defibrotide prophylaxis while adding patients transplanted after 2010 when patients did not receive defibrotide as prophylaxis anymore (2011-2015) to the control group. The characteristics of patients are shown in Table 1. Results: Median follow-up for the study group was 10 (range 2-16) years and for the control group 2.7 (range 1-18) years. None of the 248 patients in the defibrotide group developed SOS (Baltimore criteria). The 100 day cumulative incidence (CI) of SOS was 0% in the defibrotide group as compared to 4.8% (95%CI 2.6-8%) in the control group, p=0.00046. The day 100 event free survival (EFS) where an event was defined as the 1st occurrence of one of the following: SOS, acute graft versus host disease (GvHD) ≥2, relapse or death, was not significantly different with 60% (95%CI 54%-66%) in the defibrotide group vs 53% (95%CI 47%-59%) in the controls, p=0.165, but the one year EFS was statistically different with 38% (95%CI 32%-44%) vs 28% (95%CI 22%-34%), p=0.00969. The 100 day CI of acute GVHD was not significantly different between the two groups [27% (95%CI 22%-33%) in the defibrotide group vs 29% (95%CI 24%-35%) in the control group, p= 0.707] while the 1 year acute GvHD CI was significantly reduced in the defibrotide group [31% (95%CI 25%-37%)] compared with the control group [42% (95%CI 36%-48%), p=0.026]. The one year overall survival (OS), relapse incidence (RI) and non-relapse mortality (NRM) were not statistically different being respectively 73% (95%CI 67%-78%) vs 65% (95%CI 59%-71%), p=0.0704, 32% (95%CI 27%-38%) vs 28% (95%CI 22%-34%), p=0.331 and 14% (95%CI 10%-18%) vs 19% (95%CI 14%-24%), p=0.148. Multivariate analysis, performed taking into account clinical factors known to influence the risk of SOS, confirmed the favorable impact of defibrotide on 100 day SOS CI [HR 7.5x10-7 (95%CI 1.8x10-7-3.2x10-6), p<0.00001] (Table 2). Conversely, multivariate analysis failed to confirm the impact of defibrotide on 1 year EFS or acute GvHD CI. Conclusion: To the best of our knowledge, this is the largest study on prophylaxis of SOS with defibrotide and it suggests that this drug has a potential benefit in the prevention of this liver complication. Our retrospective study needs to be confirmed in a prospective randomized trial. Table 1 Table 1. Table 2 Table 2. Disclosures No relevant conflicts of interest to declare.
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Echart, Cinara L., Barbara Graziadio, Simona Somaini, Laura I. Ferro, Paul G. Richardson, Jawed Fareed, and Massimo Iacobelli. "The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity." Blood Coagulation & Fibrinolysis 20, no. 8 (December 2009): 627–34. http://dx.doi.org/10.1097/mbc.0b013e32832da1e3.
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Pogliani, E. M., M. Salvatore, C. Fowst, R. Girardello, and C. Marelli. "Effects of a Defibrotide—Heparin Combination on Some Measures of Haemostasis in Healthy Volunteers." Journal of International Medical Research 17, no. 1 (January 1989): 36–40. http://dx.doi.org/10.1177/030006058901700105.
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In an open-study design five healthy volunteers were first given 2500 IU sodium heparin intravenously and then, after 72 h, another injection of the same dosage of sodium heparin followed immediately by 400 mg defibrotide intravenously. In two separate experiments, prothrombin time, activated partial prothrombin time, antithrombin III, tissue plasminogen activator, its inhibitor and plasma heparin levels were measured at baseline and after 15 min in one experiment, and at baseline and after 2 h in the other experiment. The most important finding was that an interaction exists between heparin and defibrotide on haemostatic activity: activated partial prothrombin time was increased three-fold in volunteers given the defibrotide—heparin combination compared with volunteers given heparin alone. This statistically and clinically significant effect was evident 15 min after administration of defibrotide–heparin and was still present after 2 h. Possible explanations for this effect are discussed briefly.
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Corbacioglu, Selim, Ansgar S. Schulz, Petr Sedlacek, Bernd Gruhn, Simone Cesaro, and Peter Bader. "Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplantation: Subanalysis Data from an Open-Label, Phase III, Randomized Trial." Blood 126, no. 23 (December 3, 2015): 4310. http://dx.doi.org/10.1182/blood.v126.23.4310.4310.
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Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of conditioning for hematopoietic stem cell transplantation (HSCT) and is associated with patient and transplant-related risk factors, such as prior therapies, underlying diagnoses, and conditioning regimen. Unpredictable in its occurrence and severity, VOD/SOS is clinically characterized by painful hepatomegaly, hyperbilirubinemia, ascites, and weight gain. Overall estimated prevalence is 14% post-HSCT, while rates in some high-risk populations (eg, osteopetrosis or prior gemtuzumab ozogamicin) are >60% (Wadleigh M et al. Blood. 2003;102:1578-82; Corbacioglu S et al. Bone Marrow Transplant. 2006;38:547-53). Evidence suggests that defibrotide stabilizes endothelial cells, with direct and endothelial-cell mediated restoration of the thrombo-fibrinolytic balance. Defibrotide is approved in the European Union for the treatment of severe hepatic VOD/SOS in patients receiving HSCT, and is available in the United States through an expanded-access study. In a previously reported randomized clinical trial, defibrotide prophylaxis for VOD/SOS in high-risk pediatric patients undergoing HSCT reduced the overall incidence of VOD/SOS by day +30 post-HSCT. Here we report novel subgroup analyses of VOD/SOS incidence from this trial in patients with specific VOD/SOS risk factors at baseline. Methods This was a phase 3, multicenter, open-label, randomized, controlled trial in patients aged <18 years, undergoing myeloablative conditioning before allogeneic or autologous HSCT, with ≥1 risk factor for VOD/SOS. VOD/SOS was diagnosed according to modified Seattle criteria plus >5% weight gain. Patients were randomized to standard care with or without defibrotide prophylaxis dosed at 25 mg/kg/day in 4 divided infusions of 6.25 mg/kg. Osteopetrosis was a stratification variable. Defibrotide began the same day as HSCT conditioning and continued for 30 days post-HSCT, or ≥14 days for patients discharged from hospital before day +30 post-HSCT. Control patients who developed VOD/SOS received defibrotide treatment. The primary endpoint was incidence of VOD/SOS at day +30 post-HSCT. Results The intent-to-treat population included 356 patients: 180 randomized to defibrotide prophylaxis and 176 in the control group. Mean (SD) age was 6.6 (5.3) years, and 40.7% of patients were female. Demographic and clinical characteristics, including VOD/SOS risk factors (Table), were well-matched in the defibrotide and control groups. The most common risk factors among all patients were conditioning with busulfan and melphalan (58%), preexisting liver disease (27%), and second myeloablative transplantation (13%). VOD/SOS occurred by day +30 post-HSCT in 22 (12%) patients in the defibrotide prophylaxis group vs 35 (20%) patients in the control group. For the stratification variable, osteopetrosis, rates of VOD/SOS were 14% in the defibrotide prophylaxis arm and 67% in the control arm (Table). Differences in rates of VOD/SOS were lowest for adrenoleukodystrophy (no cases) and prior abdominal irradiation (11% vs 13%, respectively) (Table). Conclusions Across risk-factor subgroups, the rate of VOD/SOS was lower in patients receiving defibrotide compared with controls (except adrenoleukodystrophy: no VOD/SOS in either group). In particular, rates of VOD/SOS by day +30 were reduced by ≥50% in the defibrotide arm vs the control arm among patients with osteopetrosis, hemophagocytic lymphohistiocytosis, second myeloablative transplantation, and prior gemtuzumab treatment. Although the total numbers of patients with these risk factors were small, these between-group differences are of clinical interest and should be further explored. Table. Risk Factor Defibrotide (n=180) Control (n=176) Total n VOD/SOS incidence (n=22; 12.2%) n (%*) Total n VOD/SOS incidence (n=35; 20.0%) n (%*) Adrenoleukodystrophy 1 0 (0) 1 0 (0) Osteopetrosis 7 1 (14) 6 4 (67) Prior abdominal irradiation 9 1 (11) 8 1 (13) Hemophagocytic lymphohistiocytosis 10 0 (0) 15 6 (40) Prior gemtuzumab 11 2 (18) 5 2 (40) Allogeneic HSCT for leukemia 17 2 (12) 11 2 (18) Second myeloablative transplantation 25 2 (8) 23 4 (17) Pre-existing liver disease 41 6 (15) 54 12 (22) Busulfan/melphalan conditioning 106 15 (14) 99 17 (17) *Percent of patients with VOD/SOS. Support: Jazz Pharmaceuticals Disclosures Corbacioglu: Gentium S.p.A.: Consultancy, Honoraria. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Bader:Amgen: Consultancy; Medac: Other: Institutional grants; Neovii: Other: Institutional grants; Riemser: Other: Institutional grants; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy.
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Filimberti, E., S. Cinotti, M. Salvadori, M. Amato, G. Longo, M. Nazzari, and M. Morfini. "Hemodialysis with Defibrotide: Effects on Coagulation Parameters." International Journal of Artificial Organs 15, no. 10 (October 1992): 590–94. http://dx.doi.org/10.1177/039139889201501004.
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In a crossover study conducted with eight uremic patients maintained on hemodialysis, the Authors compared the effects of heparin (100 IU/kg at the start of dialysis) and defibrotide (400 mg at the start, repeated at 2 hours of ongoing dialysis) on the parameters of blood coagulation (VIII:C, AT III, TAT, PC antigen and activity, PS, and FPA), each being assessed before dialysis and at 2, 3 and 4 hours of the ongoing procedure. Heparin-assisted dialysis resulted in a significant rise of VIII:C and AT III; with defibrotide, instead, there was evidence of thrombin activation (increased FPA and TAT). PC levels were raised with both dialysis modalities; however, PC activity and PS levels were increased only in defibrotide-assisted dialysis. There were no adverse reactions or evidence of fibrin formation. These results confirm the antithrombotic activity of defibrotide in the course of dialysis and indicate that this action is independent of thrombin neutralization.
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Kong, Seom Gim, Je-Hwan Lee, Young Tak Lim, Ji Hyun Lee, Hyeon-Seok Eom, Hyewon Lee, Do Young Kim, et al. "Influence of creatinine levels on survival in patients with veno-occlusive disease treated with defibrotide." Korean Journal of Internal Medicine 37, no. 1 (January 1, 2022): 179–89. http://dx.doi.org/10.3904/kjim.2021.178.
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Background/Aims: Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is one of the most fatal complications of hematopoietic cell transplantation (HCT), and defibrotide is the only curative drug. We conducted this study to confirm the survival rate of VOD/SOS patients diagnosed in Korea and assess the efficacy of defibrotide.Methods: Patients diagnosed with VOD/SOS after allogenic HCT between 2003 and 2020 were enrolled. We investigated day +100 survival rates and associated risk factors in patients who satisfied the modified Seattle criteria within 50 days of HCT.Results: A total of 110 patients satisfied the modified Seattle criteria, of which 65.5% satisfied the Baltimore criteria. Thirty-seven patients were treated with defibrotide. The day +100 survival rate of the 110 patients was 65.3%. The survival rates in patients who did not meet the Baltimore criteria and in those who did were 86.8% and 53.7%, respectively (p = 0.001). The day +100 survival rate of patients treated with defibrotide was 50.5%. Among the patients receiving defibrotide, those whose creatinine levels were more than 1.2 times the baseline had a significantly lower survival rate at 26.7% (p = 0.014). On multivariate regression analysis, the hazard ratio of satisfaction of the Baltimore criteria was 4.54 (95% confidence interval [CI], 1.69 to 12.21; p = 0.003). In patients treated with defibrotide, the hazard ratio was 8.70 (95% CI, 2.26 to 33.45; p = 0.002), when creatinine was more than 1.2 times the baseline on administration.Conclusions: The day +100 survival rate was significantly lower when the Baltimore criteria were satisfied, and when there was an increase in creatinine at the time of defibrotide administration.
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Laurence, Jeffrey, and Sonia Elhadad. "Defibrotide Inhibits Endothelial Cell Injury Induced By Plasmas of Patients with Thrombotic Microangiopathies." Blood 134, Supplement_1 (November 13, 2019): 3676. http://dx.doi.org/10.1182/blood-2019-124158.
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Introduction: Defibrotide is a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotide sodium salts derived from porcine intestinal mucosa. It is currently the only therapy FDA-approved to treat hematopoietic stem cell transplant (HSCT)-associated hepatic veno-occlusive disease (VOD) with multi-organ dysfunction. Its mechanisms of action are complex and incompletely understood. In vitro, defibrotide can: promote endothelial cell (EC) mitogenesis via interaction with basic fibroblast growth factor; inhibit platelet adhesion and aggregation; reduce calcineurin inhibitor-induced EC apoptosis; and block pro-inflammatory cytokine activity, in the absence of anticoagulant effects (Blood Adv 2018;2:1495-1509). Given the critical role of EC injury with impaired regulation of thrombo-fibrinolytic pathways in both transplant-associated VOD and thrombotic microangiopathies (TMA), defibrotide has been used off-label to treat TMAs post-allogeneic HSCT. Significant clinical responses occurred in the majority of cases not complicated by renal failure (Bone Marrow Transplant 2019;54:142-145). It is known that conditioning regimens for autologous HSCT involve activation of pro-inflammatory pathways in EC which can be blocked by defibrotide (Biol Blood Marrow Transplant 2011;17:497-506). We sought to determine whether clinically relevant concentrations of defibrotide could block activation of caspase 8 in EC, an early step in apoptotic injury, as induced by plasmas from patients with TMAs secondary to thrombotic thrombocytopenic purpura (TTP), cancer/chemotherapy, and allogeneic HSCT. Methods: We utilized plasmas from individuals with acute TMAs: 13 with TTP; 5 with an atypical hemolytic-uremic syndrome (HUS)-type of TMA in the setting of cancer chemotherapy, persisting after withdrawal of chemotherapy; and 10 with TMAs following alloHSCT, persisting after withdrawal of GvHD prophylaxis. The in vitro model system was previously published by our lab, documenting the ability of plasmas from acute TTP patients to activate caspase 8 in EC, followed by apoptotic EC death (Blood 2008;112:340-349). This effect was dependent on plasma-based proinflammatory cytokines capable of down-regulating EC cytoprotective factors. Briefly, 5 x 105 primary human neonatal microvascular endothelial cells of dermal origin were plated in 1ml culture medium/well of 12 well polystyrene plates (3.6cm2/well) pre-coated with 1% fibronectin. 2% (v/v) patient or control plasma was added, alone or with varying concentrations of defibrotide (0.5-10μg/ml), for 3hrs at 37ºC. Cells were then harvested and a commercial colorimetric kit (Millipore) was used to assess caspase 8 enzyme activity. Results: Initial dose-response curves showed a plateau effect for defibrotide-mediated inhibition of caspase 8 activation at 5μg/ml; subsequent experiments utilized that dose. To control for the possibility of direct inhibition of caspase 8 by defibrotide, we found that caspase 8 activity initiated by staurosporine (1μM) was unaffected by defibrotide (Fig.) >50% inhibition of caspase 8 was seen for 3/5 cancer/chemotherapy-linked TMA patient plasmas, 7/13 TTP plasmas, and 0/10 TA-TMA plasmas. >20% suppression of such activation was seen for 5/5 cancer/chemotherapy TMA plasmas, 12/13 TTP plasmas, and 4/10 TA-TMA plasmas. Representative examples are shown in the Fig., including defibrotide blocking caspase 8 activity induced by plasmas from a patient with cancer/chemotherapy linked TMA (patient 18) or TTP (patient 41), but not from another TTP patient (patient 17). Conclusions: Interventions with high degrees of therapeutic success are available for TMAs related to TTP and primary aHUS. However, TMAs complicate 20% of alloHSCT, and though half may resolve when GvHD immunoprophylaxis is discontinued, three year survival rates for those in whom the TMA persists are as low as 11%. Based on multiple case reports, defibrotide may represent an important resource in those cases, and in other TMAs refractory to conventional treatment. Further studies are required to see if defibrotide-mediated blockade of plasma-induced EC activation and injury which we demonstrate in vitro correlates with in vivo responses, and if the mechanism involves suppression of pro-inflammatory cytokine-mediated cell activation. Disclosures No relevant conflicts of interest to declare.
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Belcaro, G., and C. Marelli. "Treatment of Venous Lipodermatosclerosis and Ulceration in Venous Hypertension by Elastic Compression and Fibrinolytic Enhancement with Defibrotide." Phlebology: The Journal of Venous Disease 4, no. 2 (June 1989): 91–106. http://dx.doi.org/10.1177/026835558900400207.
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The value of elastic compression and defibrotide, a profibrinolytic and antithrombotic drug, in patients with venous hypertension, lipodermatosclerosis and ulceration was assessed in a cross-over trial. Elastic compression alone and in association with defibrotide (800 mg/day) were completed the study (18 were treated with the combined treatment in the first 3 months and 14 in the second period). We evaluated the decrease of the areas of liposclerosis and ulceration by computerized analysis of the areas. We also studied the decrease of leg circumference and subjective clinical improvement by an analogue scale line. Patients were also evaluated by laser-Doppler flowimetry, transcutaneous PO2 and PCO2 measurements, capillary permeability and fibrinolytic activity. Both forms of treatment were active in reducing the areas of liposclerosis and ulceration but combined treatment with defibrotide and elastic compression was significantly more effective in reducing both liposclerosis and ulceration, and in improving microcirculatory parameters and capillary permeability. The improvement in objective evaluation was comparable to the clinical improvement measured by the analogue score. The positive variation of all parameters studied was associated with a significant increase of fibrinolytic activity during the administration of defibrotide. No side effects were observed during this study. These results suggest that defibrotide treatment is effective in treating liposclerosis and ulceration in postphlebitic limbs with venous hypertension, improving both microcirculatory parameters and subjective symptoms.
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&NA;. "Walk further with defibrotide." Inpharma Weekly &NA;, no. 814 (November 1991): 14. http://dx.doi.org/10.2165/00128413-199108140-00039.
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FERRARESSO, MARIANO, PAOLO RIGOTTI, STANISLAW M. STEPKOWSKI, TING-CHAO CHOU, and BARRY D. KAHAN. "IMMUNOSUPPRESSIVE EFFECTS OF DEFIBROTIDE." Transplantation 56, no. 4 (October 1993): 928–33. http://dx.doi.org/10.1097/00007890-199310000-00029.
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Berti, F., F. Magni, and G. Rossoni. "Cardiovascular pharmacology of defibrotide." Pharmacological Research Communications 20 (September 1988): 37. http://dx.doi.org/10.1016/s0031-6989(88)80167-x.
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Artesani, M. C. "Anaphylactic shock to defibrotide." Allergy 61, no. 8 (August 2006): 1022. http://dx.doi.org/10.1111/j.1398-9995.2006.01086.x.
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Richardson, Paul G., Angela R. Smith, Brandon M. Triplett, Nancy A. Kernan, Stephan A. Grupp, Sally Arai, Joseph H. Antin, et al. "Updated Results from a Large, Ongoing, Treatment IND Study Using Defibrotide for Patients with Hepatic Veno-Occlusive Disease." Blood 124, no. 21 (December 6, 2014): 2470. http://dx.doi.org/10.1182/blood.v124.21.2470.2470.
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Abstract Background: Severe hepatic veno-occlusive disease (VOD, also referred to as sinusoidal obstruction syndrome) with associated multi-organ failure (MOF) is a life-threatening complication of hematopoietic stem cell transplant (HSCT) and has an associated mortality rate >80%. Defibrotide has been shown to have a protective effect on injured endothelium and to restore the thrombo-fibrinolytic balance. In severe VOD, defibrotide has improved complete response (CR) rates and survival at Day +100 post HSCT compared with historical controls, and has also been shown to have a favorable safety profile. In the EU, defibrotide is now approved for the treatment of severe hepatic VOD in HSCT therapy. It is indicated in adults, adolescents, children, and infants >1 month of age. In the USA, there are currently no approved therapies for this complication; however, defibrotide has been made available since 2007 through an expanded access protocol directed treatment IND (T-IND). The aim of the T-IND is to gather additional data on safety and efficacy of defibrotide in a broader patient population, including those with severe VOD/MOF post HSCT, non-severe VOD post HSCT, and VOD following chemotherapy in the non-HSCT setting. This is the largest prospective evaluation of defibrotide for the treatment of VOD. Here we provide an update on the safety of defibrotide from this ongoing study. Methods: The original T-IND protocol required patients to have a diagnosis of VOD by Baltimore criteria (total bilirubin ≥2.0 mg/dL with ≥2 of the following: hepatomegaly, ascites, or 5% weight gain) with MOF (either renal and/or pulmonary failure) following HSCT; the study was amended to allow inclusion of patients with non-severe VOD (defined as no MOF) occurring either post-HSCT or post-chemotherapy. Key exclusion criteria include clinically significant bleeding or the need for >1 vasopressor. Defibrotide was given as a 2-hour infusion at 6.25 mg/kg IV every 6 hours (25 mg/kg/d) with a recommended minimum treatment duration of 21 days. Results: The current interim safety analysis is based on 612 patients enrolled between December 2007 and December 2013 (including 99 in 2013) for whom safety data is available and who received ≥1 dose of defibrotide. Across the USA, over the course of the study approximately 86 centers were active to enroll patients. Median patient age was 12 years (range <0.1–69), with 24.2% aged <1 month to 2 years, 39.4% aged >2 to 18 years, 34.9% aged >18 to 65 years, and 1.2% aged >65 years. Patients were primarily male (55.8%) and predominantly white (65.6%). Overall, 454 patients (74.2%) reported ≥1 treatment emergent adverse events (AEs). Of these, 138 patients (22.5%) had AEs that investigators assessed as related (possibly, probably, or definitely) to study medication. Related AEs in >2.0% were pulmonary hemorrhage (4.7%), gastrointestinal hemorrhage (3.6%), epistaxis (3.1%), and hypotension (2.8%). Serious AEs (SAEs) were reported by 368 patients (60.1%). The majority of SAEs were assessed as not related to study treatment; 82 patients (13.4%) had an SAE at least possibly related to study treatment, most commonly pulmonary hemorrhage (3.9%) and gastrointestinal hemorrhage (2.9%). AEs leading to death occurred in 254 patients (41.5%); these AEs were deemed by the investigators to be possibly related to study medication in only 17 patients (2.8%). Previously reported efficacy data at D +100 in 425 patients evaluable for outcome have shown survival of 55% (by Kaplan-Meier estimate) for patients following HSCT, and survival of 62% (by Kaplan-Meier estimate) in 45 patients following chemotherapy (without HSCT), respectively. Conclusions: Defibrotide therapy in patients with VOD was generally well tolerated in this population, with manageable toxicity, and promising results seen in terms of response and survival. Safety results from prior studies, which have also been associated with a low incidence of defibrotide-associated toxicities, have proven very consistent with the favorable tolerability profile seen in this largest experience to date. Enrollment to the T-IND study continues; updated results will be presented at the meeting. Support:Jazz Pharmaceuticals Off-Label Use Defibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States. Disclosures Richardson: Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals Inc.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for veno-occlusive disease in the United States.. Antin:Dana-Farber Cancer Institute: Employment; Tempera: Consultancy; Enlivex: Consultancy. Lehmann:Dana Farber/Boston Children's Hospital: Employment. Bandiera:Gentium S.p.A.: Employment. Hume:Jazz Pharmaceuticals Inc.: Employment. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment. Study Group:Gentium S.p.A.: Employment.
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Richardson, Paul, Enric Carreras, Antonio Pagliuca, Robert Ryan, William Tappe, and Mohamad Mohty. "A Pooled Analysis of Survival By Defibrotide Timing of Initiation in Adults with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) Following Hematopoietic Stem Cell Transplant (HSCT)." Blood 132, Supplement 1 (November 29, 2018): 815. http://dx.doi.org/10.1182/blood-2018-99-113099.
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Abstract Introduction Hepatic VOD/SOS is a potentially life-threatening complication of HSCT or of nontransplant-associated high-dose chemotherapy. VOD/SOS associated with multi-organ dysfunction (MOD; eg, renal or pulmonary dysfunction) may be associated with >80% mortality. Defibrotide is approved to treat hepatic VOD/SOS with renal and/or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. Prior to US approval, defibrotide was available through an international compassionate-use program (CUP; 1998-2009) and an expanded-access protocol (T-IND; 2007-2016). Data for adults with VOD/SOS post-HSCT from the CUP and the T-IND were pooled to investigate whether the time to initiate defibrotide therapy after VOD/SOS diagnosis had an impact on Day +100 survival. Methods In both the CUP (N=710) and the T-IND (N=1137), defibrotide was used to treat hepatic VOD/SOS following HSCT or nontransplant-associated chemotherapy in pediatric and adult patients with or without MOD. Diagnosis of VOD/SOS was made using the Baltimore or modified Seattle criteria or was proven by biopsy (the CUP also allowed patients with hemodynamic, ultrasound, or histologic evidence of VOD/SOS to enroll). In the CUP cohort, the defibrotide median daily dose was 25 mg/kg/day administered for a median of 15 days; only patients who received 25 mg/kg/day were included in the analysis. In the T-IND, the defibrotide dose was 25 mg/kg/day for a recommended administration ≥21 days. In this analysis, adult patients (aged >18 years) from the CUP and the T-IND with VOD/SOS post-HSCT were pooled to examine Day +100 survival rates by time to start of defibrotide post-diagnosis. The first analysis examined patients who initiated defibrotide before/after Days 1, 2, 3, 4, 7, and 14 after VOD/SOS diagnosis, using Fisher's exact test, and the second examined starting defibrotide on a particular day: 0, 1, 2, 3, 4, 5, 6, 7, 8-14, and ≥15 (Cochran-Armitage test for trend across days). Results Of 534 pooled adult patients with VOD/SOS following HSCT who were treated with defibrotide 25 mg/kg/day and had reported time to dosing, 300 (56%) patients had MOD. Defibrotide treatment was initiated by Day 1 in 273 (51%) patients. In the analysis of treatment initiation before or after Days 1, 2, 3, 4, 7, and 14, earlier initiation of defibrotide showed numerically higher survival rates for all cut points (Day +100 survival before and after all cut points is provided in Table 1). Cochran-Armitage test for trend in the overall group suggested that Day +100 survival was higher with earlier initiation following diagnosis (nominal P=0.011; for patients with MOD, P=0.048; Table 2). Safety information for the CUP and T-IND were not pooled, as adverse events in the CUP were reported only if those events caused death in a consistent fashion. In all adult patients with post-HSCT VOD/SOS in the T-IND, treatment-related adverse events that occurred in ≥2% of adults were epistaxis and gastrointestinal hemorrhage (3.5% each), pulmonary hemorrhage (2.3%), and hematuria and hypotension (2.1% each). Conclusion: These results from the pooled post hoc analysis of adult patients with VOD/SOS post-HSCT from the CUP and T-IND studies suggest that earlier defibrotide initiation post-VOD/SOS diagnosis may improve Day +100 survival outcomes, although no specific day post-diagnosis provides a clinically meaningful cutoff for better outcome, suggesting that later intervention still retains value if therapy is not initiated sooner. Causes of treatment delay were not assessed. The safety profile for these patients was consistent with other defibrotide studies in VOD/SOS. Support: Jazz Pharmaceuticals. Disclosures Richardson: Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Carreras:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pagliuca:Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Tappe:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Mohty:Molmed: Consultancy; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau.
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Unal, Emel, Nurdan Tacyildiz, Gulsan Yavuz, Handan Dincaslan, Gulsah Tanyildiz, Erol Ayyildiz, and Muhit Ozcan. "Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Autologous, Non-Purged Peripheral Stem Cell Transplantation for High Risk Neuroblastoma Patients." Blood 124, no. 21 (December 6, 2014): 5910. http://dx.doi.org/10.1182/blood.v124.21.5910.5910.
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Abstract High-dose chemotherapy (HDC) represents the standard of treatment for high-risk neuroblastoma(NBL), hepatic veno-occlusive disease (VOD) is a common, 10-50% and serious complication of haematological stem cell transplantation (HSCT), with up to 90% mortality rates. We planned study to assess whether the use of prophylactic defibrotide in paediatric patients who were heavily treated with chemo-radiotherapy before transplant, and then underwent autologous HSCT. Seventeen patients who underwent autologous, unpurged peripheral stem cell transplantation PBSC with a high risk of developing VOD, between January 2003-July 2014, were given Defibrotide prophylaxis 25mg/kg/day for 30 days, commencing on -1 of conditioning regimen. All patients were stratified by INSS stage, age, N-MYC status. All were treated with six cycles of induction chemotherapy, myeloablative intensification, surgery for primary site, radiation therapy to the primary tumour site plus metastatic sites i.e bone metastases including skull. Meta-iodobenzylguanidin treatment as targeted radiotherapy was given on -21 prior to myeloablative chemotherapy. Oral 13-cis retinoic acid was employed on day +90 post-transplant. CD34+ cell mobilization and PBSC collection was carreid out after two-four cycles of induction cycles. Conditioning regimen and stem cell infusion was done following four-six weeks of last chemotherapy cycle, in order to reduce the toxicitiy. Conditioning regimen CEM consisted Carboplatin, Etoposide, Melfalan. There were no toxic deaths. All of the patients receieved antimicrobial prophylaxis and total parenteral nutrition support when was needed. Myeloid engraftment on day+13, erythroid engraftment on day+18 and thrombocyte engraftment was achieved on day +23. Defibrotide prophylaxis seems to reduce incidence of VOD and is well tolerated. VOD incidence and severity was reduced in the defibrotide group which suggests that defibrotide might be effective in preventing and treating VOD. Sufficiently powered randomised trials are now required to definitively test the role of defibrotide in this setting. Disclosures No relevant conflicts of interest to declare.
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Milone, G., M. Poidomani, S. Coppoletta, E. Mauro, E. Marturano, F. Crispi, A. Spadaro, A. Di Marco, and S. Leotta. "Defibrotide in Prevention of Liver Toxicity in Patients at High Risk of VOD after HSC Transplantation." Blood 112, no. 11 (November 16, 2008): 3275. http://dx.doi.org/10.1182/blood.v112.11.3275.3275.
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Abstract Defibrotide has been proposed as preventive treatment of Veno Occlusive Disease (VOD), data on its use are, however, limited and its effectiveness not yet demonstrated. We have administered Defibrotide as prevention of VOD in pts treated with HSC transplantation because of haematological malignancies, all patients were at high VOD risk because of hyper-ferritinemia (>800 ng/ml) or because not in CR of their underlying disease at time of transplant or being overweight (Actual BW>20% of Ideal BW) or because Hepatitis virus B or C sero-positive. 120 pts were treated with Defibrotide, 77 pts received allogeneic HSC tx and 43 autologous HSC tx, 105 received a myeloablative conditioning (55 pts it was based on busulfan) and 15 pts received a RIC. 48% of patients were affected with Acute leukemia, 23% with Lymphomas, 17% with Multiple Myeloma, 12% by other malignancies. Defibrotide was administered i.v. at dosage of 600 mg/d. from the day of conditioning was started to day +25 together with heparin at low dose (100 IU/Kg c.i.). RESULTS: after prophylaxis with Defibrotide a bilirubin value above 2.5 mg/dl during the first 30 days was observed in 16/120 pts (13%), 7/120 pts (5%) reached Seattle’s VOD criteria but had spontaneous resolution of liver toxicity, only 1 patient (0.8%) had a severe VOD and MOF. Overall survival at 3 years was 60% and it was 54% in allo-transplanted patients. We compared results with those obtained in a group of 78 pts treated by allogeneic or autologous transplants and who received low dose heparin only and not Defibrotide because they were considered at low risk of VOD. Percentage of pts who developed a bilirubin level > 2.5 mg/dl (p=0.12) and percentage of patients that reached criteria for VOD were not different (p= 0.08) in these two groups, numbers of red blood cell transfusions were comparable (p=0.07). When all the 198 studied patients were analyzed using logistic regression for factors important in the development of a bilirubinemia above 2.5 mg/dl we found to be important: use of MTX as prophylaxis of GVHD (P=0.004; Odds ratio 5,153), allogeneic transplant (P=0.007; Odds ratio 7,127) and baseline value of bilirubin (P=0.02; Odds Ratio 4,690). Conclusions: Use of Defibrotide in prophylaxis of VOD after HSC transplantation is safe and when employed in patients at high risk of VOD, it leads to an incidence of severe VOD below 1% with a frequency of liver toxicity equivalent to that found in patients having low risk features. To conclude on efficacy of Defibrotide in comparison to low dose heparin alone, a large randomised comparison is warranted.
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Dignan, Fiona L., Dorothy Gujral, Mark E. Ethell, Jennifer Treleaven, Gareth Morgan, and Michael Potter. "Prophylactic Defibrotide in Allogeneic Stem Cell Transplantation: Low Morbidity and Zero Mortality from Veno-Occlusive Disease." Blood 108, no. 11 (November 16, 2006): 2968. http://dx.doi.org/10.1182/blood.v108.11.2968.2968.
Full textAbstract:
Abstract Veno-occlusive disease (VOD) is a common complication following the intensive conditioning regimens used in stem cell transplantation (SCT). The reported incidence is between 10–60% and the clinical spectrum varies from mild, reversible disease to a severe disorder with a mortality rate approaching 100% by day 100 post SCT (McDonald et al. Ann Intern Med1993, 118, 255–267). Defibrotide has recently been shown to be effective in the treatment of severe VOD in several series (Chopra et al. Br J Haematol2000, 111, 1122–1129; Richardson et al. Blood2002, 100, 4337–4343). Only one report to date details the use of prophylactic defibrotide in the allogeneic SCT population. This study showed a significant reduction in VOD in patients treated with prophylactic defibrotide and heparin (Chalandon et al. Biol Blood Marrow Transplant2004, 10, 347–354). We report a retrospective review of the incidence of VOD in 58 adult patients who received defibrotide prophylaxis during allogeneic SCT from May 2004 to December 2005. Heparin was not used routinely. Patients received 5mg/kg of defibroide twice daily IV from day + 1 to day + 21. All patients were assessed daily by clinical examination including weight and abdominal girth and laboratory tests including liver function tests. The Baltimore criteria were used to diagnose VOD. If VOD was suspected then US of the liver with a doppler test was performed. No patients met the Baltimore criteria for VOD and no patients died of suspected VOD within 100 days of SCT. The transplant related mortality was 5/58 (8.6%) of patients. Three patients died of bronchopnemonia, one of E.Coli septicaemia and one of multi-organ failure secondary to infection. VOD was not felt to have contributed to the deaths of any of these patients. The dose of defibrotide was increased to 10mg/kg four times daily IV in 3 patients in whom VOD formed part of the differential diagnosis for deranged liver function tests but who did not meet the Baltimore criteria. None of these patients had a positive US scan. One of these patients had a liver biopsy suggestive of mild VOD but also showed features consistent with GVHD and viral infection. The liver function of the other two patients improved after hepatotoxic drugs were stopped. All of these patients were alive at 100 days post transplant with no features of VOD. Patients tolerated defibrotide well and the drug did not have to be discontinued in any patient. There were no cases of haemorrhagic complications attibutable to defibrotide. It seems unlikely that differences in clinical characteristics accounted for the low incidence of VOD as many of our patients had several high risk factors. Sixty-seven % (39/58) had received a transplant from an unrelated donor, 18/58 (31%) had received a previous transplant and 28/58 (48%) had received either cyclophosphomide or busulphan as part of their conditioning regimen. This review suggests that the use of prophylactic defibrotide may reduce the incidence of VOD following allogeneic SCT. Defibrotide may be effective without concurrent heparin but a randomised controlled trial would be useful to further investigate this issue.
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Pescador, Rodolfo, Roberto Porta, and Laura Ferro. "Defibrotide and Endothelial Cell Activation." Cardiovascular Drug Reviews 18, no. 4 (June 7, 2006): 304–11. http://dx.doi.org/10.1111/j.1527-3466.2000.tb00054.x.
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&NA;. "Defibrotide has benefits in AMI." Inpharma Weekly &NA;, no. 723 (February 1990): 8. http://dx.doi.org/10.2165/00128413-199007230-00019.
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Richardson, Paul G., Selim Corbacioglu, Vincent Trien-Vinh Ho, Nancy A. Kernan, Leslie Lehmann, Craig Maguire, Michelle Maglio, et al. "Drug safety evaluation of defibrotide." Expert Opinion on Drug Safety 12, no. 1 (December 10, 2012): 123–36. http://dx.doi.org/10.1517/14740338.2012.749855.
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Lazarus, Hillard M., and Keith R. McCrae. "SOS! Defibrotide to the rescue." Blood 112, no. 10 (November 15, 2008): 3924–25. http://dx.doi.org/10.1182/blood-2008-09-177246.
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Zhou, Quansheng, Xiaohong Chu, and Changgeng Ruan. "Defibrotide Stimulates Expression of Thrombomodulin in Human Endothelial Cells." Thrombosis and Haemostasis 71, no. 04 (1994): 507–10. http://dx.doi.org/10.1055/s-0038-1642468.
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SummaryCultured human umbilical vein endothelial cells were incubated with defibrotide at concentrations of 0, 5, 50 and 500 jxg/ml for 4 and 24 h respectively. Thrombomodulin activity and molecules on the surface of the cells were determined by chromogenic assay and radioimmunoassay, thrombomodulin antigen in endothelial cells and in conditioned medium of the cells was measured by immunoradioassay. Thrombomodulin mRNA within the cells was analysed by slot blot. After 24 h of incubation, the activity and molecules of thrombomodulin on the surface of endothelial cells, as well as the antigen and mRNA of thrombomodulin in the cells were significantly increased in a dose dependent manner. However, the level of thrombomodulin antigen in conditioned medium was about equal to that of the control. Our data indicate that defibrotide stimulates expression of thrombomodulin in human endothelial cells. These beneficial effects may play a role in antithrombotic activity of defibrotide.