Defibrotide

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Paul G. Richardson - One of the best experts on this subject based on the ideXlab platform.

  • Defibrotide real world management of veno occlusive disease sinusoidal obstructive syndrome after stem cell transplant
    Blood Advances, 2021
    Co-Authors: Mary Nauffal, Paul G. Richardson, Corey Cutler, Joseph H. Antin, Robert J Soiffer, Haesook T Kim, Sarah Nikiforow, Mahasweta Gooptu, John Koreth, Rizwan Romee
    Abstract:

    Hepatic veno-occlusive disease or sinusoidal obstructive syndrome (VOD/ SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Defibrotide is the only FDA-approved medication for the management of severe VOD/ SOS after HSCT. We report our center's experience with commercially available Defibrotide as treatment for patients with VOD/SOS. We retrospectively identified 28 cases of VOD/ SOS, based on the European Society for Blood and Marrow Transplantation criteria, from March 2016 through June 2019. The median day of VOD/ SOS onset was 25 days (range, 8 to 69) and Defibrotide was initiated on day of diagnosis in 71% of patients. Complete resolution of VOD/ SOS occurred in 75% of patients. Day +100 survival was 64% for all HSCT patients and 53% for those with very severe VOD/ SOS. Response rates and survival were similar in patients with VOD/SOS after myeloablative or reduced intensity chemotherapy HSCT. Therapy related adverse events were mild and included hematuria (43%), epistaxis (18%) and hypotension (11%). Severe hemorrhagic adverse events occurred in 2 patients (pulmonary and upper gastrointestinal hemorrhage; 7%) and both in the setting of progressive VOD/SOS. Early diagnosis, prompt initiation of Defibrotide, and minimizing dosing interruptions may be key to successful treatment of VOD/ SOS.

  • the importance of endothelial protection the emerging role of Defibrotide in reversing endothelial injury and its sequelae
    Bone Marrow Transplantation, 2021
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Marta Palomo, Gerhard C Hildebrandt, Nelson J Chao, Enric Carreras
    Abstract:

    Hepatic 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.

  • analysis of time to complete response after Defibrotide initiation in patients with hepatic veno occlusive disease sinusoidal obstruction syndrome after hematopoietic cell transplantation
    Biology of Blood and Marrow Transplantation, 2021
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Angela R Smith, Leslie Lehmann, Robert J Ryan, Stephan A Grupp
    Abstract:

    ABSTRACT Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of Defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with Defibrotide. The time to Defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin 21 days). Taken together, these results highlight the importance of continued Defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.

  • pooled analysis of day 100 survival for Defibrotide treated patients with hepatic veno occlusive disease sinusoidal obstruction syndrome and ventilator or dialysis dependence following haematopoietic cell transplantation
    British Journal of Haematology, 2020
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Robert J Soiffer, Angela R Smith, Leslie Lehmann, William Tappe, Robert J Ryan, Stephan A Grupp
    Abstract:

    For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst Defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from Defibrotide.

  • systematic review of Defibrotide studies in the treatment of veno occlusive disease sinusoidal obstruction syndrome vod sos
    Bone Marrow Transplantation, 2019
    Co-Authors: Paul G. Richardson, Kathleen F Villa, Saurabh Aggarwal, Ozlem Topaloglu, Selim Corbacioglu
    Abstract:

    Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) conditioning or high-dose nontransplant chemotherapy. VOD/SOS with multi-organ dysfunction (MOD) is associated with a mortality rate of > 80%. Defibrotide (25 mg/kg/day) is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post HSCT in the United States and to treat severe hepatic VOD/SOS in patients > 1 month of age in the European Union. A random effects model was used for pooling data from 17 systematically chosen Defibrotide studies. For patients in these reports (n = 2598), and those in the subset of 10 reports of patients treated with ~ 25 mg/kg/day (n = 1691), estimated Day + 100 survival rates were 54% and 56%, respectively. Among those patients treated with ~ 25 mg/kg/day, estimated Day + 100 survival was 44% among patients with MOD and 71% in patients without MOD; survival was 41% and 70%, respectively, for the population of patients receiving any dose of Defibrotide. Safety results were not pooled owing to differences in reporting methodology but were generally consistent with the known tolerability profile of Defibrotide. This analysis provides the largest assessment of survival in patients treated with Defibrotide for VOD/SOS with or without MOD.

Stephan A Grupp - One of the best experts on this subject based on the ideXlab platform.

  • analysis of time to complete response after Defibrotide initiation in patients with hepatic veno occlusive disease sinusoidal obstruction syndrome after hematopoietic cell transplantation
    Biology of Blood and Marrow Transplantation, 2021
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Angela R Smith, Leslie Lehmann, Robert J Ryan, Stephan A Grupp
    Abstract:

    ABSTRACT Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of Defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with Defibrotide. The time to Defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin 21 days). Taken together, these results highlight the importance of continued Defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.

  • pooled analysis of day 100 survival for Defibrotide treated patients with hepatic veno occlusive disease sinusoidal obstruction syndrome and ventilator or dialysis dependence following haematopoietic cell transplantation
    British Journal of Haematology, 2020
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Robert J Soiffer, Angela R Smith, Leslie Lehmann, William Tappe, Robert J Ryan, Stephan A Grupp
    Abstract:

    For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst Defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from Defibrotide.

  • final results from a Defibrotide treatment ind study for patients with hepatic veno occlusive disease sinusoidal obstruction syndrome
    British Journal of Haematology, 2018
    Co-Authors: Nancy A Kernan, Sally Arai, Joseph H. Antin, Stephan A Grupp, Angela R Smith, Brandon M Triplett, Leslie Lehmann, Tsiporah B Shore, Nancy Bunin, Massimo Iacobelli
    Abstract:

    Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life‐threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi‐organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded‐access treatment programme (T‐IND; {"type":"clinical-trial","attrs":{"text":"NCT00628498","term_id":"NCT00628498"}}NCT00628498). In the completed T‐IND, the Kaplan–Meier estimated Day +100 survival for 1000 patients with documented Defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7–61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of Defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8–71·6%) and 47·1% (95% CI, 42·3–51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier Defibrotide initiation was also associated with higher Day +100 survival. The safety profile of Defibrotide in the completed T‐IND study was similar to previous reports.

  • final analysis of day 100 survival by prior hematopoietic stem cell transplant type from an expanded access study of Defibrotide for hepatic veno occlusive disease sinusoidal obstruction syndrome
    Blood, 2017
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Robin Hume, Angela R Smith, Brandon M Triplett, Leslie Lehmann, William Tappe, Robert J Ryan, Stephan A Grupp
    Abstract:

    Abstract Background Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is an unpredictable, life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT) and has an estimated overall incidence of 13.7% post-HSCT. VOD/SOS with multi-organ dysfunction (MOD, sometimes referred to as multi-organ failure) may be associated with >80% mortality. In the United States (US), Defibrotide is approved for the treatment of adult and pediatric patients with hepatic VOD/SOS and renal or pulmonary dysfunction following HSCT, and it is approved in the European Union for treatment of severe hepatic VOD/SOS after HSCT therapy in patients older than 1 month. Prior to US approval, Defibrotide was made available through an expanded-access protocol (T-IND). The present post hoc analysis of final data from the T-IND investigates Day +100 survival in groups of patients receiving autologous or allogeneic transplant. Methods Patients received Defibrotide 25 mg/kg/day in 4 divided doses, and treatment was recommended for ≥21 days. The original eligibility criteria were VOD/SOS by biopsy or Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of: hepatomegaly, ascites, ≥5% weight gain) post-HSCT, with MOD (renal and/or pulmonary); the protocol was amended to include also patients after chemotherapy without HSCT (off label), patients without MOD (off label), and patients with VOD/SOS per modified Seattle criteria (≥2 of: bilirubin >2 mg/dL, hepatomegaly, or ≥5% weight gain [in this study]). Results From 2007 to 2016, 1000 post-HSCT patients were enrolled and received Defibrotide. Of these, 843 (52% pediatric; 48% adult) patients received allografts (450 of whom had MOD), and 155 (82% pediatric; 18% adult) received autografts (61 had MOD) (Table); 2 had unknown graft types. Acute leukemias were most common in the allograft group, and neuroblastoma was most common in the autograft group. Kaplan-Meier estimated survival rate at Day +100 in the allograft group was 55% (95% confidence interval [CI]: 52%-58%) overall, 47% (95% CI: 43%-52%) for those with MOD, and 64% (95% CI: 59%-69%) for those without MOD (Figure). Kaplan-Meier estimated survival rate at Day +100 in the autograft group was 80% (95% CI: 72%-85%) overall, 67% (95% CI: 53%-77%) for those with MOD, and 88% (95% CI: 80%-93%) for those without MOD (Figure). Adverse events (AEs) occurred in 74% of allograft patients (in 77% of the MOD subgroup) and 53% of autograft patients (in 64% of the MOD subgroup). Hemorrhage and hypotension were more common post-allograft (31% and 13%, respectively) than post-autograft (17% and 7%). Treatment-related AEs (TRAEs), as determined by investigators, occurred in 21% of allograft patients (22% with MOD) and 20% of autograft patients (30% with MOD); most common (≥2%, either transplant group) were pulmonary hemorrhage (allograft, 5%; autograft, 3%), gastrointestinal hemorrhage (allograft, 3%; autograft, 1%), and epistaxis (allograft, 2%; autograft, 2%). TRAEs leading to discontinuation were more frequent post-allograft (13%) than post-autograft (10%); most common (≥2%) were pulmonary hemorrhage (allograft, 4%; autograft, 3%) and gastrointestinal hemorrhage (allograft, 2%; autograft, 0.6%). TRAEs leading to death occurred in 3% of the allograft group and 0.6% of the autograft group; most common (≥1%) was pulmonary hemorrhage (allograft, 1%; autograft, 0.6%). Conclusion In this post hoc analysis of T-IND transplant groups, Day +100 survival rates in both allograft and autograft patients with VOD/SOS, with and without MOD, were consistent with prior Defibrotide studies. Taken together, the current results support the overall efficacy and safety profile of Defibrotide in patients with VOD/SOS after either allogeneic or autologous HSCT. For both allogeneic and autologous transplant groups, the higher survival rates in the subgroups of patients without vs those with MOD (reinforced by 95% CIs that did not cross) indicate that further study is warranted to determine the impact of treatment earlier in the course of VOD/SOS. Support: Jazz Pharmaceuticals. Download : Download high-res image (153KB) Download : Download full-size image Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees. Kernan: Gentium: Other: NAK received grants from Gentium during the conduct of the study, and her research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA008748; the content is solely the responsibility of the author . Ryan: Celator/Jazz: Employment, Equity Ownership. Hume: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Tappe: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Grupp: Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy; University of Pennsylvania: Patents & Royalties; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant.

  • treatment of hepatic veno occlusive disease sinusoidal obstruction syndrome vod sos post hematopoietic stem cell transplantation hsct in patients with neuroblastoma final data from the Defibrotide expanded access program
    Blood, 2017
    Co-Authors: Stephan A Grupp, Robin Hume, Brandon M Triplett, William Tappe, Robert J Ryan, Araz Marachelian, Sonata Jodele, Paul G. Richardson
    Abstract:

    Background VOD/SOS is a potentially life-threatening complication of HSCT conditioning, with a reported mean incidence of 13.7%. VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved for treatment of hepatic VOD/SOS with renal/pulmonary dysfunction post-HSCT in the United States and for treating severe hepatic VOD/SOS post-HSCT in the European Union. The Defibrotide expanded-access program (T-IND) was designed to provide access to Defibrotide prior to its approval in the US and to collect data on safety and efficacy. There are few published data on survival of patients with neuroblastoma who develop VOD/SOS. Here, Day +100 post-HSCT survival and safety are analyzed post hoc for the subgroup of patients in that study with a primary disease of neuroblastoma. Methods The T-IND was the largest prospective study of Defibrotide. The original protocol required VOD/SOS diagnosis by Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of: hepatomegaly, ascites, ≥5% weight gain) or biopsy, post-HSCT, with evidence of MOD. The study was amended to also include patients without MOD (off label), with VOD/SOS per modified Seattle criteria (≥2 of: bilirubin >2 mg/dL, hepatomegaly, or ≥5% weight gain [in this study]), and/or with VOD/SOS following chemotherapy without HSCT (off label). Patients received Defibrotide 25 mg/kg/d in 4 divided doses (6.25 mg/kg q6h), which was recommended for ≥21 days. Results This post hoc analysis of final data is based on 1154 patients enrolled from 2007-2016 who received ≥1 dose of Defibrotide, including 571 patients with MOD. The primary diseases affecting 5% or more of the safety population at baseline were acute myelogenous leukemia, 24.2% (n=279); acute lymphocytic leukemia, 24.2% (n=279); and neuroblastoma, 9.6% (n=111). Among patients with neuroblastoma, 106 had received HSCT and 5 had chemotherapy without HSCT. In the post-HSCT subgroup, 64 (60.4%) were male and 42 (39.6%) were female, median age was 3 years (range 1-17 years), with 7.6% aged 0-23 months, 90.6% aged 2-11 years, 0.9% aged 12-16 years, and 1 (0.9%) patient was aged >16 years at HSCT. At Day +100 post-HSCT, survival data were available for 105 of the 106 neuroblastoma patients treated with Defibrotide with documented VOD/SOS, 43 with MOD and 62 without MOD. Of these patients, 103 had autologous transplants and 2 had allogeneic transplants. Kaplan-Meier estimated Day +100 survival for the total neuroblastoma group was 87.2% (95% confidence interval [CI], 79.0%-92.4%; Fig). For the MOD subgroup, Kaplan-Meier estimated Day +100 survival was 78.4% (95% CI, 62.6%-88.2%), and for the subgroup without MOD, 93.5% (95% CI, 83.6%-97.5%). For comparison, in the subgroup aged ≤16 years of the overall HSCT population (n=570; 127 autologous), Kaplan-Meier estimated Day +100 survival was 67.9% (95% CI, 63.8%-71.6%; Fig;Richardson PG et al. European Hematology Association 2017. Abstract P748). Adverse events (AEs) occurred in 45.3% (48/106) of neuroblastoma patients, with serious AEs in 23.6% (25/106; most common: multi-organ failure, 4.7% [5/106]). AEs leading to discontinuation developed in 17.0% (18/106) (most common: pulmonary hemorrhage, 2.8% [3/106]); death occurred in 10.4% (11/106) (>2%: multi-organ failure, 4.7% [5/106]; veno-occlusive disease, 2.8% [3/106]). Treatment-related AEs, as assessed by the investigators and of any severity, occurred in 17.0% (18/106) of neuroblastoma patients (most common: pulmonary hemorrhage, 2.8% [3/106]). Conclusions There are few data on VOD/SOS outcomes in patients with neuroblastoma. This post hoc analysis of final data from the Defibrotide expanded-access study found Kaplan-Meier estimated Day +100 survival of 87.2% in the comparatively large group of patients with a primary disease of neuroblastoma and VOD/SOS following HSCT (primarily autologous). Day +100 Kaplan-Meier estimated survival rates were 78.4% and 93.5% in the neuroblastoma groups with and without MOD, respectively. The Day +100 safety profile for the neuroblastoma subgroup in the expanded-access program was consistent with prior Defibrotide studies and analyses of the overall HSCT population in this study. These findings provide supportive evidence for, and warrant additional studies into, the clinical utility of Defibrotide for treatment of VOD/SOS in patients receiving HSCT for this common pediatric solid tumor. Support: Jazz Pharmaceuticals. Disclosures Grupp: University of Pennsylvania: Patents & Royalties; Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant. Ryan: Celator/Jazz: Employment, Equity Ownership. Hume: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Tappe: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Richardson: Oncopeptides AB: Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding.

Nancy A Kernan - One of the best experts on this subject based on the ideXlab platform.

  • the importance of endothelial protection the emerging role of Defibrotide in reversing endothelial injury and its sequelae
    Bone Marrow Transplantation, 2021
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Marta Palomo, Gerhard C Hildebrandt, Nelson J Chao, Enric Carreras
    Abstract:

    Hepatic 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.

  • analysis of time to complete response after Defibrotide initiation in patients with hepatic veno occlusive disease sinusoidal obstruction syndrome after hematopoietic cell transplantation
    Biology of Blood and Marrow Transplantation, 2021
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Angela R Smith, Leslie Lehmann, Robert J Ryan, Stephan A Grupp
    Abstract:

    ABSTRACT Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of Defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with Defibrotide. The time to Defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin 21 days). Taken together, these results highlight the importance of continued Defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.

  • pooled analysis of day 100 survival for Defibrotide treated patients with hepatic veno occlusive disease sinusoidal obstruction syndrome and ventilator or dialysis dependence following haematopoietic cell transplantation
    British Journal of Haematology, 2020
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Robert J Soiffer, Angela R Smith, Leslie Lehmann, William Tappe, Robert J Ryan, Stephan A Grupp
    Abstract:

    For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst Defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from Defibrotide.

  • incidence of post hematopoietic stem cell transplantation hsct veno occlusive disease sinusoidal obstruction syndrome vod sos without hyperbilirubinemia at diagnosis and efficacy of Defibrotide in an expanded access program
    Blood, 2018
    Co-Authors: Selim Corbacioglu, Nancy A Kernan, William Tappe, Antonio Pagliuca, Robert O Ryan, Paul G. Richardson
    Abstract:

    Introduction Hepatic VOD/SOS is a progressive, potentially life-threatening complication early post-HSCT, or of nontransplant chemotherapy. VOD/SOS diagnosis has been based on Baltimore (≤21 days post-HSCT and bilirubin ≥2 mg/dL plus ≥2 of: hepatomegaly, ascites, weight gain ≥5%) or modified Seattle (≤20 days post-HSCT and ≥2 of: bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, weight gain [>5% in Defibrotide studies]) criteria. Recent European Society of Blood and Marrow Transplantation (EBMT) VOD/SOS guidelines require elevated bilirubin only for adults diagnosed ≤21 days post-HSCT (the literature suggests bilirubin 21 days post-HSCT) or pediatric patients (~30% of pediatric patients present with anicteric VOD/SOS [ie, bilirubin 1 month in the European Union. This post hoc analysis examines incidence of VOD/SOS without elevated bilirubin, and survival in Defibrotide-treated, post-HSCT patients in the T-IND program (2007-2016). Methods Prior to US approval, Defibrotide was available through the T-IND expanded-access program. The original protocol required VOD/SOS post-HSCT diagnosed per Baltimore criteria (which require hyperbilirubinemia) or biopsy, and multi-organ dysfunction (MOD). The protocol was amended to include patients without MOD (2009) and with VOD/SOS per modified Seattle criteria (which do not require hyperbilirubinemia; 2012). Patients received Defibrotide 25 mg/kg/day (6.25 mg/kg q6h) recommended for ≥21 days. Results Of 991 patients in the T-IND with VOD/SOS post-HSCT and recorded bilirubin level at diagnosis, 190 (19%) had bilirubin 16 years (13% of all post-HSCT adult patients with recorded bilirubin [n=427]). Diagnosis by Day +21 post HSCT (ie, not late onset) was recorded for 135/190 (71%) patients with bilirubin In the overall post-HSCT group treated with Defibrotide in the T-IND (n=1000; with and without elevated bilirubin at diagnosis, including 9 patients without bilirubin measurement at diagnosis), Kaplan-Meier estimated Day +100 survival was 58.9% (95% confidence interval [CI], 55.7%-61.9%). Kaplan-Meier estimated Day +100 survival was 85.6% (95% CI, 79.7%-89.9%) for the 190 patients with bilirubin Conclusions: In the T-IND, 19% of post-HSCT patients with VOD/SOS had bilirubin Support: Jazz Pharmaceuticals. Disclosures Corbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Kernan:National Cancer Institute: Research Funding. Pagliuca:Jazz Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity9s 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. Richardson:Karyopharm: Membership on an entity9s Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity9s Board of Directors or advisory committees; Janssen: Membership on an entity9s Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding.

  • Defibrotide for the treatment of hepatic veno occlusive disease sinusoidal obstruction syndrome following nontransplant associated chemotherapy final results from a post hoc analysis of data from an expanded access program
    Pediatric Blood & Cancer, 2018
    Co-Authors: Nancy A Kernan, Paul G. Richardson, Joseph H. Antin, Robin Hume, Angela R Smith, Brandon M Triplett, Leslie Lehmann, Yoav H Messinger, Wei Liang, William Tappe
    Abstract:

    Background Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant-associated chemotherapy. Following HSCT, VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Prior to US approval, Defibrotide was available to treat VOD/SOS through an expanded-access treatment (T-IND) program. A post hoc analysis of nontransplant-associated VOD/SOS patients treated with Defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented. Procedure Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received Defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended). Results Of the 1,154 patients in the T-IND, 137 had nontransplant-associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan-Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan-Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment-related adverse events occurred in 26.8%. Conclusions In this post hoc analysis of 82 patients initiating Defibrotide within 30 days of starting chemotherapy, Kaplan-Meier estimated survival was 74.1% at 70 days after Defibrotide initiation. Safety profile was consistent with prior Defibrotide studies.

Leslie Lehmann - One of the best experts on this subject based on the ideXlab platform.

  • analysis of time to complete response after Defibrotide initiation in patients with hepatic veno occlusive disease sinusoidal obstruction syndrome after hematopoietic cell transplantation
    Biology of Blood and Marrow Transplantation, 2021
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Angela R Smith, Leslie Lehmann, Robert J Ryan, Stephan A Grupp
    Abstract:

    ABSTRACT Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of Defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with Defibrotide. The time to Defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin 21 days). Taken together, these results highlight the importance of continued Defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.

  • pooled analysis of day 100 survival for Defibrotide treated patients with hepatic veno occlusive disease sinusoidal obstruction syndrome and ventilator or dialysis dependence following haematopoietic cell transplantation
    British Journal of Haematology, 2020
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Robert J Soiffer, Angela R Smith, Leslie Lehmann, William Tappe, Robert J Ryan, Stephan A Grupp
    Abstract:

    For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst Defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from Defibrotide.

  • Defibrotide for the treatment of hepatic veno occlusive disease sinusoidal obstruction syndrome following nontransplant associated chemotherapy final results from a post hoc analysis of data from an expanded access program
    Pediatric Blood & Cancer, 2018
    Co-Authors: Nancy A Kernan, Paul G. Richardson, Joseph H. Antin, Robin Hume, Angela R Smith, Brandon M Triplett, Leslie Lehmann, Yoav H Messinger, Wei Liang, William Tappe
    Abstract:

    Background Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant-associated chemotherapy. Following HSCT, VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Prior to US approval, Defibrotide was available to treat VOD/SOS through an expanded-access treatment (T-IND) program. A post hoc analysis of nontransplant-associated VOD/SOS patients treated with Defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented. Procedure Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received Defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended). Results Of the 1,154 patients in the T-IND, 137 had nontransplant-associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan-Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan-Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment-related adverse events occurred in 26.8%. Conclusions In this post hoc analysis of 82 patients initiating Defibrotide within 30 days of starting chemotherapy, Kaplan-Meier estimated survival was 74.1% at 70 days after Defibrotide initiation. Safety profile was consistent with prior Defibrotide studies.

  • final results from a Defibrotide treatment ind study for patients with hepatic veno occlusive disease sinusoidal obstruction syndrome
    British Journal of Haematology, 2018
    Co-Authors: Nancy A Kernan, Sally Arai, Joseph H. Antin, Stephan A Grupp, Angela R Smith, Brandon M Triplett, Leslie Lehmann, Tsiporah B Shore, Nancy Bunin, Massimo Iacobelli
    Abstract:

    Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life‐threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi‐organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded‐access treatment programme (T‐IND; {"type":"clinical-trial","attrs":{"text":"NCT00628498","term_id":"NCT00628498"}}NCT00628498). In the completed T‐IND, the Kaplan–Meier estimated Day +100 survival for 1000 patients with documented Defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7–61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of Defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8–71·6%) and 47·1% (95% CI, 42·3–51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier Defibrotide initiation was also associated with higher Day +100 survival. The safety profile of Defibrotide in the completed T‐IND study was similar to previous reports.

  • final analysis of day 100 survival by prior hematopoietic stem cell transplant type from an expanded access study of Defibrotide for hepatic veno occlusive disease sinusoidal obstruction syndrome
    Blood, 2017
    Co-Authors: Paul G. Richardson, Nancy A Kernan, Robin Hume, Angela R Smith, Brandon M Triplett, Leslie Lehmann, William Tappe, Robert J Ryan, Stephan A Grupp
    Abstract:

    Abstract Background Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is an unpredictable, life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT) and has an estimated overall incidence of 13.7% post-HSCT. VOD/SOS with multi-organ dysfunction (MOD, sometimes referred to as multi-organ failure) may be associated with >80% mortality. In the United States (US), Defibrotide is approved for the treatment of adult and pediatric patients with hepatic VOD/SOS and renal or pulmonary dysfunction following HSCT, and it is approved in the European Union for treatment of severe hepatic VOD/SOS after HSCT therapy in patients older than 1 month. Prior to US approval, Defibrotide was made available through an expanded-access protocol (T-IND). The present post hoc analysis of final data from the T-IND investigates Day +100 survival in groups of patients receiving autologous or allogeneic transplant. Methods Patients received Defibrotide 25 mg/kg/day in 4 divided doses, and treatment was recommended for ≥21 days. The original eligibility criteria were VOD/SOS by biopsy or Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of: hepatomegaly, ascites, ≥5% weight gain) post-HSCT, with MOD (renal and/or pulmonary); the protocol was amended to include also patients after chemotherapy without HSCT (off label), patients without MOD (off label), and patients with VOD/SOS per modified Seattle criteria (≥2 of: bilirubin >2 mg/dL, hepatomegaly, or ≥5% weight gain [in this study]). Results From 2007 to 2016, 1000 post-HSCT patients were enrolled and received Defibrotide. Of these, 843 (52% pediatric; 48% adult) patients received allografts (450 of whom had MOD), and 155 (82% pediatric; 18% adult) received autografts (61 had MOD) (Table); 2 had unknown graft types. Acute leukemias were most common in the allograft group, and neuroblastoma was most common in the autograft group. Kaplan-Meier estimated survival rate at Day +100 in the allograft group was 55% (95% confidence interval [CI]: 52%-58%) overall, 47% (95% CI: 43%-52%) for those with MOD, and 64% (95% CI: 59%-69%) for those without MOD (Figure). Kaplan-Meier estimated survival rate at Day +100 in the autograft group was 80% (95% CI: 72%-85%) overall, 67% (95% CI: 53%-77%) for those with MOD, and 88% (95% CI: 80%-93%) for those without MOD (Figure). Adverse events (AEs) occurred in 74% of allograft patients (in 77% of the MOD subgroup) and 53% of autograft patients (in 64% of the MOD subgroup). Hemorrhage and hypotension were more common post-allograft (31% and 13%, respectively) than post-autograft (17% and 7%). Treatment-related AEs (TRAEs), as determined by investigators, occurred in 21% of allograft patients (22% with MOD) and 20% of autograft patients (30% with MOD); most common (≥2%, either transplant group) were pulmonary hemorrhage (allograft, 5%; autograft, 3%), gastrointestinal hemorrhage (allograft, 3%; autograft, 1%), and epistaxis (allograft, 2%; autograft, 2%). TRAEs leading to discontinuation were more frequent post-allograft (13%) than post-autograft (10%); most common (≥2%) were pulmonary hemorrhage (allograft, 4%; autograft, 3%) and gastrointestinal hemorrhage (allograft, 2%; autograft, 0.6%). TRAEs leading to death occurred in 3% of the allograft group and 0.6% of the autograft group; most common (≥1%) was pulmonary hemorrhage (allograft, 1%; autograft, 0.6%). Conclusion In this post hoc analysis of T-IND transplant groups, Day +100 survival rates in both allograft and autograft patients with VOD/SOS, with and without MOD, were consistent with prior Defibrotide studies. Taken together, the current results support the overall efficacy and safety profile of Defibrotide in patients with VOD/SOS after either allogeneic or autologous HSCT. For both allogeneic and autologous transplant groups, the higher survival rates in the subgroups of patients without vs those with MOD (reinforced by 95% CIs that did not cross) indicate that further study is warranted to determine the impact of treatment earlier in the course of VOD/SOS. Support: Jazz Pharmaceuticals. Download : Download high-res image (153KB) Download : Download full-size image Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees. Kernan: Gentium: Other: NAK received grants from Gentium during the conduct of the study, and her research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA008748; the content is solely the responsibility of the author . Ryan: Celator/Jazz: Employment, Equity Ownership. Hume: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Tappe: Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Grupp: Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy; University of Pennsylvania: Patents & Royalties; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant.

Selim Corbacioglu - One of the best experts on this subject based on the ideXlab platform.

  • systematic review of Defibrotide studies in the treatment of veno occlusive disease sinusoidal obstruction syndrome vod sos
    Bone Marrow Transplantation, 2019
    Co-Authors: Paul G. Richardson, Kathleen F Villa, Saurabh Aggarwal, Ozlem Topaloglu, Selim Corbacioglu
    Abstract:

    Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) conditioning or high-dose nontransplant chemotherapy. VOD/SOS with multi-organ dysfunction (MOD) is associated with a mortality rate of > 80%. Defibrotide (25 mg/kg/day) is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post HSCT in the United States and to treat severe hepatic VOD/SOS in patients > 1 month of age in the European Union. A random effects model was used for pooling data from 17 systematically chosen Defibrotide studies. For patients in these reports (n = 2598), and those in the subset of 10 reports of patients treated with ~ 25 mg/kg/day (n = 1691), estimated Day + 100 survival rates were 54% and 56%, respectively. Among those patients treated with ~ 25 mg/kg/day, estimated Day + 100 survival was 44% among patients with MOD and 71% in patients without MOD; survival was 41% and 70%, respectively, for the population of patients receiving any dose of Defibrotide. Safety results were not pooled owing to differences in reporting methodology but were generally consistent with the known tolerability profile of Defibrotide. This analysis provides the largest assessment of survival in patients treated with Defibrotide for VOD/SOS with or without MOD.

  • incidence of post hematopoietic stem cell transplantation hsct veno occlusive disease sinusoidal obstruction syndrome vod sos without hyperbilirubinemia at diagnosis and efficacy of Defibrotide in an expanded access program
    Blood, 2018
    Co-Authors: Selim Corbacioglu, Nancy A Kernan, William Tappe, Antonio Pagliuca, Robert O Ryan, Paul G. Richardson
    Abstract:

    Introduction Hepatic VOD/SOS is a progressive, potentially life-threatening complication early post-HSCT, or of nontransplant chemotherapy. VOD/SOS diagnosis has been based on Baltimore (≤21 days post-HSCT and bilirubin ≥2 mg/dL plus ≥2 of: hepatomegaly, ascites, weight gain ≥5%) or modified Seattle (≤20 days post-HSCT and ≥2 of: bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, weight gain [>5% in Defibrotide studies]) criteria. Recent European Society of Blood and Marrow Transplantation (EBMT) VOD/SOS guidelines require elevated bilirubin only for adults diagnosed ≤21 days post-HSCT (the literature suggests bilirubin 21 days post-HSCT) or pediatric patients (~30% of pediatric patients present with anicteric VOD/SOS [ie, bilirubin 1 month in the European Union. This post hoc analysis examines incidence of VOD/SOS without elevated bilirubin, and survival in Defibrotide-treated, post-HSCT patients in the T-IND program (2007-2016). Methods Prior to US approval, Defibrotide was available through the T-IND expanded-access program. The original protocol required VOD/SOS post-HSCT diagnosed per Baltimore criteria (which require hyperbilirubinemia) or biopsy, and multi-organ dysfunction (MOD). The protocol was amended to include patients without MOD (2009) and with VOD/SOS per modified Seattle criteria (which do not require hyperbilirubinemia; 2012). Patients received Defibrotide 25 mg/kg/day (6.25 mg/kg q6h) recommended for ≥21 days. Results Of 991 patients in the T-IND with VOD/SOS post-HSCT and recorded bilirubin level at diagnosis, 190 (19%) had bilirubin 16 years (13% of all post-HSCT adult patients with recorded bilirubin [n=427]). Diagnosis by Day +21 post HSCT (ie, not late onset) was recorded for 135/190 (71%) patients with bilirubin In the overall post-HSCT group treated with Defibrotide in the T-IND (n=1000; with and without elevated bilirubin at diagnosis, including 9 patients without bilirubin measurement at diagnosis), Kaplan-Meier estimated Day +100 survival was 58.9% (95% confidence interval [CI], 55.7%-61.9%). Kaplan-Meier estimated Day +100 survival was 85.6% (95% CI, 79.7%-89.9%) for the 190 patients with bilirubin Conclusions: In the T-IND, 19% of post-HSCT patients with VOD/SOS had bilirubin Support: Jazz Pharmaceuticals. Disclosures Corbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Kernan:National Cancer Institute: Research Funding. Pagliuca:Jazz Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity9s 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. Richardson:Karyopharm: Membership on an entity9s Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity9s Board of Directors or advisory committees; Janssen: Membership on an entity9s Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding.

  • pooled analysis of Defibrotide studies in the treatment of veno occlusive disease sinusoidal obstruction syndrome vod sos after hematopoietic stem cell transplantation hsct or chemotherapy without hsct
    Blood, 2017
    Co-Authors: Paul G. Richardson, Kathleen F Villa, Saurabh Aggarwal, Ozlem Topaloglu, Selim Corbacioglu
    Abstract:

    Background VOD/SOS is an unpredictable, potentially life-threatening complication of conditioning regimens for HSCT or of chemotherapy without HSCT. VOD/SOS with multi-organ dysfunction (MOD; typically defined as renal and/or pulmonary dysfunction) may be associated with survival of 20%-30% (Coppell et al. Biol Blood Marrow Transplant. 2010;16[2]:157-168. Richardson et al. Blood. 2016;127[13]:1656-1665. Strouse et al. Biol Blood Marrow Transplant . 2016;22[7]:1306-1312). For adult and pediatric patients, Defibrotide (25 mg/kg/day in 4 divided doses) is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States, and to treat severe hepatic VOD/SOS post-HSCT in patients over 1 month of age in the European Union. The overall efficacy and safety of Defibrotide treatment in adult and pediatric patients with VOD/SOS have been reported in controlled and uncontrolled studies, including a large expanded-access study and a historically controlled phase 3 trial. Reported here is a pooled Day +100 survival analysis of available data from Defibrotide studies in patients with VOD/SOS with or without MOD. Methods A title or abstract search of PubMed, Embase, and relevant 2017 congresses was performed for "Defibrotide" in the treatment of VOD/SOS. Prospective and retrospective studies, post-HSCT and post-chemotherapy without HSCT, were included in the analysis, but case reports of fewer than 10 patients were excluded. Citations were reviewed for relevance to this analysis, and the resulting studies were divided into subgroups to analyze data for patients with and without MOD. A random effects model was used for pooling data for efficacy. Interstudy heterogeneity was assessed with Cochran9s Q-test. The percentage of total variation across studies due to heterogeneity was evaluated by the I2 measure. Safety was also evaluated. Results The literature review identified 606 publications and abstracts; 581 were excluded for relevance. This yielded 25 records (16 manuscripts, 9 abstracts), which were further refined by exclusion of 8 reports that were post hoc analyses, reviews, duplicates, case reports, or a prevention trial. Of the remaining 17, 10 records included data for 2239 patients, nearly all of whom were treated with ~25 mg/kg/day, including 6 that specified patients with MOD (1177 patients), 2 of which also specified patients without MOD (495 patients), and 4 where MOD status was not reported (Table). The other 7/17 studies included off-label dosages or the dosage was not reported. Estimated Day +100 survival for patients receiving Defibrotide ~25 mg/kg/day across all studies was 56% (95% confidence interval [CI], 49%-62%; Figure). Pooled subgroup results showed estimated Day +100 survival rates of 42% (95% CI, 34%-49%) in the MOD subgroup; and 66% (95% CI, 61%-70%) in the no MOD subgroup (Figure). Safety results were not pooled for these studies due to differences in safety reporting methodology, but results of individual studies were generally consistent with the safety profile found in the phase 3 historically controlled trial in VOD/SOS patients with MOD (Richardson et al. Blood. 2016;127[13]:1656-1665). The trial reported that all but 1 of the 102 Defibrotide treated patients and all 32 HC patients experienced ≥1 AE. Hypotension was the most frequent AE (39% for Defibrotide, 50% for controls), and common hemorrhagic AEs, which included pulmonary alveolar and gastrointestinal hemorrhage, occurred in 64% of Defibrotide-treated patients and 75% of controls. Related AEs in the Defibrotide arm included hemorrhagic events and hypotension. Conclusion In this pooled analysis of studies of Defibrotide given primarily at the approved dose of 25 mg/kg/day for the treatment of VOD/SOS, estimated Day +100 survival was 56% in the 2239 patients with or without MOD. As expected, survival in patients with VOD/SOS without MOD was greater at Day +100 (66%) than in patients with VOD/SOS with MOD (42%). Safety results in the individual studies were generally consistent with the known safety profile of Defibrotide. Support: Jazz Pharmaceuticals. Disclosures Richardson: Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Oncopeptides AB: Membership on an entity9s Board of Directors or advisory committees. Aggarwal: Novel Health Strategies: Employment, Other: Funding from Jazz Pharmaceuticals. Topaloglu: Novel Health Strategies: Employment, Other: Funding from Jazz Pharmaceuticals. Villa: Jazz Pharmaceuticals: Employment, Other: stock options. Corbacioglu: Jazz Pharmaceuticals: Consultancy, Honoraria.

  • Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation.
    Expert review of gastroenterology & hepatology, 2017
    Co-Authors: Selim Corbacioglu, Paul G. Richardson
    Abstract:

    ABSTRACTIntroduction: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a complication that is typically associated with conditioning for hematopoietic stem cell transplantation (HSCT). In patients with concomitant multi-organ dysfunction, mortality may be >80%. Recently, the European Society for Blood and Marrow Transplantation established separate criteria for diagnosis and severity of VOD/SOS for adults and children, to better reflect current understanding of the disease.Areas covered: This review provides an overview of post-HSCT hepatic VOD/SOS and Defibrotide, including its pharmacological, clinical, and regulatory profile. In children and adults following HSCT, Defibrotide is approved for the treatment of hepatic VOD/SOS with concomitant renal or pulmonary dysfunction in the United States and for the treatment of severe hepatic VOD/SOS in the European Union. Day +100 survival rates with Defibrotide are superior to those of historical controls receiving best supportive care...

  • Defibrotide for the treatment of hepatic veno occlusive disease sinusoidal obstruction syndrome with multiorgan failure
    International Journal of Hematologic Oncology, 2017
    Co-Authors: Paul G. Richardson, Amrita Krishnan, Stephan A Grupp, Antonio Pagliuca, Selim Corbacioglu
    Abstract:

    Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening and unpredictable complication of hematopoietic stem cell transplantation (HSCT). Characterized by a prothrombotic-hypofibrinolytic state, VOD/SOS typically presents with hyperbilirubinemia, ascites, weight gain and painful hepatomegaly; VOD/SOS with multiorgan failure may be associated with >80% mortality. Treatment has been mainly supportive. However, Defibrotide is now approved in the USA for treatment of hepatic VOD/SOS with renal or pulmonary dysfunction following HSCT and in the European Union for treatment of severe hepatic VOD/SOS post-HSCT. In vitro evidence suggests Defibrotide may restore thrombotic-fibrinolytic balance at the endothelial level and protect endothelial cells. Defibrotide has demonstrated significant reduction in VOD/SOS-related mortality and resolved VOD/SOS-related symptoms, with a manageable safety profile.

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