Treatment Of Hepatic Veno-occlusive Disease Research Articles

The changes in the diagnostics and treatment of hepatic veno-occlusive disease in children

The changes in the diagnostics and treatment of hepatic veno-occlusive disease in children

Role of endothelial-microparticles and the tissue factor pathway in ginsenoside Rb1-mediated prevention of umbilical vein endothelial cell injury.

Hepatic veno-occlusive disease (VOD) is a life-threatening complication of hematopoietic stem cell transplantation, which urgently requires effective prevention and treatment. Endothelial damage is recognized as the first event in patients with hepatic VOD. However, the mechanism by which endothelial injury induces thrombosis in hepatic VOD is still not clear. In the present study, monocrotaline (MCT) was used to induce endothelial cell injury in EA.hy926 cells to imitate in vitro hepatic VOD. MCT significantly increased apoptosis in EA.hy926 endothelial cells and the secretion of endothelial microparticles (EMPs) which can be used to reflect the level of endothelial injury. Additionally, MCT significantly enhanced the expression of soluble tissue factor (TF) and EMP-bound TF protein, suggesting that EMPs may participate in the development of hepatic VOD by regulating coagulation. Ginsenoside Rb1, a major constituent and effective ingredient of Panax ginseng, was found to significantly decrease MCT-induced endothelial injury and release of EMPs. Moreover, Ginsenoside Rb1 decreased soluble TF released by EA.hy926 cells and EMP-bound TF protein induced by MCT. These data suggest that ginsenoside Rb1 may serve as a potent prophylactic and/or as a treatment of hepatic VOD by protecting endothelial cells and preventing microthrombosis induced by endothelial injury.

Efficacy and Safety of Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

Defibrotide has been approved in several geographic jurisdictions for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) for years. However, available data on efficacy and safety for its use in VOD are contrasting. We performed a meta-analysis to evaluate the efficacy and safety of defibrotide in the treatment of hepatic VOD/SOS post-hematopoietic stem cell transplantation (HSCT). PubMed and Embase were searched for studies regarding the efficacy and safety of defibrotide in VOD patients. Survival rate at day + 100 post-HSCT (D + 100 SR), as well as the prognosis, comprising complete response (CR), adverse events including ≥1 adverse event (≥1 AE), hemorrhage, and serious adverse events (SAEs), were pooled using a random effect model. Sixteen studies involving 3,002 participants were included. Pooled estimates for overall D + 100 SR as well as rate of CR, ≥1 AE, hemorrhage, SAEs in VOD patients post-HSCT were 58% (95% CI: 54-62%), 57% (95% CI: 45-68%), 65% (95% CI: 54-75%), 16% (95% CI: 5-27%), 53% (95% CI: 51-55%), respectively, and were 44% (95% CI: 39-48%), 39% (95% CI: 28-50%), 88% (95% CI: 71-100%), 42% (95% CI: 30-55%), 58% (95% CI: 52-64%), respectively, in severe VOD (sVOD) patients. Hemorrhage and hypotension were the most common AEs. Current evidence suggests that defibrotide improves the D + 100 SR and CR in VOD/sVOD patients following HSCT. However, the results of this review/meta-analysis were mainly based on data from observational studies, potentially subject to selection bias. Consequently, higher quality randomized control trials and larger prospective cohort studies are warranted.

OP-02 - The prophylaxis and the treatment of hepatic veno-occlusive disease after pediatric hematopoetic stem cell transplantation: our single-centre experience

OP-02 - The prophylaxis and the treatment of hepatic veno-occlusive disease after pediatric hematopoetic stem cell transplantation: our single-centre experience

The importance of early intervention in the treatment of hepatic veno-occlusive disease.

Antonio Pagliuca is Professor of hematopoietic stem cell transplantation at King’s College London (UK) and medical director at King’s College Hospital where, until last year, he had been the transplant director for the past 24 years. He also has roles within NHS England as national clinical lead for regenerative medicine and is a trustee on both the Anthony Nolan trust (London, UK) and Leukemia UK (London, UK).Here he speaks to Commissioning Editor Jennifer Straiton and discusses the interim results of the DEFIFrance study, recently presented at the European Society for Blood and Marrow Transplant (EBMT), which looked at the real-world use of the European Society for Blood and Marrow Transplant severity grading criteria. The study investigates the use of defibrotide as a treatment of patients with post-transplant hepatic veno-occlusive disease and demonstrates how it can benefit from early intervention.

The experience of hematopoietic stem cell transplantation in primary immunodeficiencies in the Russian Children's Clinical Hospital

Primary immunodeficiencies (PID) include a group of congenital diseases, many of which are associated with a high risk of developing life-threatening infectious and non-infectious complications. Many of PIDs require hematopoietic stem cell transplantation (HSCT), which can lead to a complete cure of the disease. The article presents more than 20 years of experience in conducting HSCT with PID in the Russian Children's Clinical Hospital for the period from 1997 to 2018. 88 HSCTs were performed in 80 patients (64 boys and 16 girls) with various PIDs: severe combined immune deficiency (SCID, n = 34), hemophagocytic lymphohistiocytosis (HLH, n = 12), chronic granulomatous disease (CGD, n = 11), Wiskott–Aldrich syndrome (WAS, n = 10), congenital agranulocytosis (n = 4), hyper IgM syndrome type 1 (n = 3), Nijmegen breakage syndrome (n = 2), lymphoproliferative syndrome (n = 2), Chediak–Higashi syndrome (n = 1), leukocyte adhesion deficiency (n = 1). Оverall survival (OS) and event-free survival (EFS) after HSCT with PID was 63.1% and 49.3%. OS after HSCT with SCID was 65.5%, EFS – 48.4%. The article presents the results of HSCT taking into account the type of HSCT, the source of hematopoietic stem cells (HSC) and the type of graft manipulation, conditioning regimen. Growth of positive results of HSCT in patients with PID in recent years is associated with the improvement of accompanying therapy (improving the quality of infection control, the introduction of new drugs for the prevention and treatment of hepatic veno-occlusive disease); technology application TcRα+β+/CD19+ depletion at haploidentical transplantation; optimization of conditioning regimens; successes in the prevention and treatment of the graftversus- host disease (antithymocyte globulin and rituximab administration during the period of conditioning, post-transplant administration of cyclophosphamide at haploidentical HSCT). The study was approved by the Independent Ethics Committee of Russian Children's Clinical Hospital.

Treatment of hepatic veno-occlusive disease in children with N-acetylcysteine.

In our institution, hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) has been treated with N-acetylcysteine (NAC) since 2008-a loading dose of 150mg/kg, followed by 12 doses of 70mg/kg 6 hourly. Nine children were diagnosed with hepatic VOD/SOS. Hepatic VOD/SOS occurred in seven children after stem cell transplantation and two were receiving chemotherapy for Wilms tumor. Their clinical severity was classified as moderate in two and severe in seven by the European Society for Blood and Marrow Transplantation criteria. All children recovered and were discharged from 4 to 16days after diagnosis. No side effects were observed. Intravenous NAC is an effective treatment for hepatic VOD/SOS.

Interventions for treatment of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation

Reason for withdrawal from publication Authors made no progress with the review within the last 12 months.

Prophylactic Treatment of Hepatic Veno-occlusive Disease During Stem Cell Transplantation.

Prophylactic Treatment of Hepatic Veno-occlusive Disease During Stem Cell Transplantation.

Computed tomography findings of hepatic veno-occlusive disease caused by Sedum aizoon with histopathological correlation.

This study investigated the value of computed tomography (CT) in the diagnosis and treatment of hepatic veno-occlusive disease (HVOD) caused by Sedum aizoon (SA). The clinical manifestations, treatment results, imaging findings, and histological findings of the liver were analyzed in 39 patients with HVOD caused by SA. Hepatomegaly, liver dysfunction, abdominal effusion, and geographic density changes on liver CT scans were found in all 39 patients. The pathological findings of histological liver examination included swelling and point-like necrosis of liver cells, significant expansion and congestion of the sinuses, endothelial swelling, and wall thickening with incomplete lumen occlusion of small liver vessels. CT geographic density changes were confirmed by histological examination of the liver in 18 patients. Sixteen patients with small amounts of ascites that started within 4 weeks of treatment recovered completely or significantly improved after symptomatic and supportive treatment. However, only 43.75% of the patients with larger amounts of ascites improved following symptomatic and supportive treatment. In conclusion, liver CT examination is a valuable, safe, and noninvasive tool for the diagnosis of HVOD caused by SA. In selected cases, liver CT examination may replace liver biopsy and histological analysis.

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: An Update from the International Compassionate Use Program in 710 Patients

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: An Update from the International Compassionate Use Program in 710 Patients

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: An Update from the International Compassionate Use Program in 710 Patients

▪Introduction: Hepatic veno-occlusive disease (VOD; also called sinusoidal obstruction syndrome) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Severe VOD (sVOD) is usually characterized by multi-organ failure (MOF) and >80% mortality. sVOD may develop in a substantial number of high risk patients (pts) and is often unpredictable. Defibrotide is an oligonucleotide that protects endothelial cells from transplant-induced damage and restores the thrombotic-fibrinolytic balance. Defibrotide is now approved in the EU for the treatment of severe hepatic VOD in HSCT. We report here the final results of a large, international compassionate use program (CUP), open from 1998-2009.Methods: Defibrotide was provided on a compassionate basis or via single pt emergency-use requests (collectively, the CUP) to 312 sites in Europe, the US, Asia and the Middle East. There was no protocol; however, eligibility data, defibrotide use, safety and outcome data were requested using case record forms. In the US, pts were required to meet Baltimore criteria for VOD and have MOF. At all other sites, pts who met Seattle criteria for VOD, ultrasound, or histological criteria were eligible. The program included pts diagnosed with VOD as a complication of HSCT as well as chemo-/radiotherapy. Defibrotide was recommended to be administered IV in 4 divided doses daily, each dose infused over 2 hours. The initial dosing recommendations were 10 mg/kg/day with incremental dose increases of 10 mg/kg every 24 to 48 hours to a maximum daily dose of 60 mg/kg, depending on tolerability and response to treatment. Following results of a US Phase 2 study, the dose recommendation was 25 mg/kg/day. Duration of treatment was at the discretion of the investigator. Reported data included adverse events (AEs) and survival at Day+100 post HSCT or chemo-/radiotherapy.Results: Enrollment data were provided for 1129 pts. Safety and outcome data (submitted voluntarily) were provided for 710 pts reported to have received ≥1 dose of defibrotide (433 male [61%]). Of these, 628 (89%) developed VOD following HSCT (499 [71%] allogeneic; 112 [16%] autologous; 17 [2%] other/missing) and 79 (11%) developed VOD following chemo-/radiotherapy alone; information on the index event that led to VOD was missing for 3 pts. The median age was 25 (range, 0.2-70) years; 303 (43%) were <18 years.In the 710 pts, median time to onset of VOD from HSCT or start of chemo-/radiotherapy was 13 days. A total of 623 (88%) had bilirubin >2 mg/dL, 584 (82%) had weight gain >5%, 548 (77%) had hepatomegaly, 477 (67%) had ascites, 455 (64%) had right upper quadrant pain, and 292 (41%) had MOF. Per Bearman criteria or MOF, 429 (60%) had sVOD.The median daily dose of defibrotide was 25 mg/kg given for a median of 15 days. The most common doses were 25 or 40 mg/kg/day (498 of 638 pts with dosing information, 78%).AEs were reported in 378 pts (53%); most were serious (364/710, 51%) and fatal (350/710, 49%). Causes of death were generally reported as AEs, hence the most common new or worsening AEs were recorded as MOF (n=144 [20%], all fatal) and VOD (n=79 [11%], 78 fatal). Among the other AEs, sepsis (n=49 [7%], 48 fatal) was the most common. Incidence of serious AEs and fatalities was generally similar across dose subgroups. At least one hemorrhage event was reported by 85 (12%) pts (55 serious, including 37 fatal), most commonly gastrointestinal (n=33, 5%) or respiratory (n=24, 3%). Central nervous system (CNS) hemorrhage was reported in 10 pts (1%). Respiratory tract hemorrhage was highest in the 60/80 mg/kg/day dose group (9%) vs lower doses (<5%), but gastrointestinal and CNS hemorrhages were similar across dose groups (4%-6% and 0%-2%, respectively). Sixty three (9%) pts withdrew due to an AE, most due to hemorrhage (n=50, 7%), which was primarily gastrointestinal (n=22, 3%).Across all doses in the 710 pts evaluated, the Kaplan-Meier (KM) estimate of survival at Day+100 was 54%. Figure shows KM estimated survival by dose group; in the 25 mg/kg/day subgroup (the approved EU dose) it was 58% at Day+100.Conclusions: This large compassionate-use experience demonstrated that defibrotide was generally well tolerated and AEs were typical for this population. The overall KM estimated survival rate of 54% at Day+100 is consistent with prior studies. Results from subgroup analyses support the 25 mg/kg/day dosing as an optimal approach.Support: Jazz Pharmaceuticals [Display omitted] DisclosuresCorbacioglu:Gentium: Consultancy, Honoraria. Off Label Use: Defibrotide is an investigational treatment for veno-occlusive disease in the United States.. Carreras:Gentium S.p.A.: Expert Testimony Other, Research Funding, Speakers Bureau. Mohty:Gentium S.p.A./Jazz Pharmaceuticals Inc.: Honoraria, Research Funding. Pagliuca:Gentium S.p.A.: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Ballabio:Jazz Pharmaceuticals Inc.: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals Inc.: Employment. Bandiera:Gentium S.p.A.: Employment. Finetto:Gentium S.p.A.: Employment. Richardson:Gentium S.p.A.: Membership on an entity’s Board of Directors or advisory committees; Jazz Pharmaceuticals Inc.: Research Funding.

Updated Results from a Large, Ongoing, Treatment IND Study Using Defibrotide for Patients with Hepatic Veno-Occlusive Disease

▪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 PharmaceuticalsOff-Label UseDefibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States. DisclosuresRichardson: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.

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

▪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 PharmaceuticalsOff-Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States. DisclosuresRichardson: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.

Risk-Benefit Trade-Off of Pediatric-Inspired Versus Hyper-CVAD Protocols for Philadelphia Negative Acute Lymphocytic Leukemia (ALL) in Adolescents and Young Adults: A Modeling Analysis

BackgroundAlthough treatment outcomes for childhood acute lymphocytic leukemia (ALL) have dramatically improved in recent years, treatment outcomes in adolescents and young adults (AYA, ages 16-39) have remained inferior due to unfavorable cytogenetic features associated with increasing age and differences in treatment for this population. Pediatric-inspired protocols include L-asparaginase for induction and intensification phases, which are thought to be less tolerable and to lead to increased adverse events in adults. As a result, they are not widely used in the AYA population. Although non-comparative studies suggest improved survival in AYA patients treated with pediatric-inspired protocols, the long-term risk-benefit profile of treating AYAs with a pediatric-inspired ALL protocol is unknown. We utilized an exploratory decision-analytic approach to model the survival and quality-adjusted survival of a pediatric-inspired protocol versus hyper-CVAD, a widely utilized adult protocol, in AYA patients with Philadelphia negative ALL.MethodsPatient outcomes were simulated using a 6-state Markov model including complete response (CR), no CR, first relapse, second CR, second relapse, and death. Hyper-CVAD protocol outcomes were modeled by fitting a Weibull distribution to the progression free survival curve of AYA patients from a single-center study of 288 patientsa; we utilized comparable patient data from a retrospective study of 85 patients treated with a pediatric-inspired regimenb to estimate a relative progression difference (HR = 0.51), and used this estimate to model survival for pediatric-inspired protocol patients. We estimated health state utilities (quality of life) based on treatment stage, and assumed the pediatric protocol had a 0.10 disutility compared to hyper-CVAD prior to the maintenance phase of treatment. Our analysis compared total life years and quality-adjusted life years (QALYs) between treatment protocols at 1 year, 5 years, and 10 years. [Display omitted] ResultsTreatment with the pediatric-inspired protocol led to a 0.04 increase in life years but a 0.01 decrease in QALYs at 1 year. By years 5 and 10, the pediatric-inspired protocol resulted in 0.18 and 0.24 increases in life years and 0.25 and 0.32 increases in QALYs, respectively, relative to hyper-CVAD. The lower quality of life associated with the induction and intensification phases of pediatric treatment was largely offset by more favorable progression-free survival and overall survival in comparison to hyper-CVAD.TableOutcomePediatricHyper-CVADDifference1 YearLife Years0.8150.7740.041QALYs0.5070.513-0.0065 YearsLife Years1.8821.6330.250QALYs1.3621.1790.18210 YearsLife Years2.1201.8020.318QALYs1.5641.3240.241ConclusionsOur exploratory analysis suggests Philadelphia negative AYA patients treated with a pediatric-inspired protocol experience a decrease in QALYs versus hyper-CVAD during the initial stages of treatment for ALL. However, the pediatric protocol leads to an increase in life years throughout all treatment stages and an increase in QALYs in the long-term following the initial stages of treatment. Ongoing work will incorporate treatment and adverse event costs to estimate the cost-effectiveness of pediatric-inspired versus hyper-CVAD protocols.a Kantarjian H. et al. Cancer 2004; 2788-801.b Storring JM, et al. BJH 2009; 76-85.Analysis support: This analysis was supported by Jazz Pharmaceuticals. DisclosuresGuzauskas:Jazz Pharmaceuticals: Consultancy. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States.. Vanhove:Jazz Pharmaceuticals: Employment, Equity Ownership. Veenstra:Jazz Pharmaceuticals: Consultancy.

Results of a Large Prospective Study On the Use of Defibrotide (DF) in the Treatment of Hepatic Veno-Occlusive Disease (VOD) in Hematopoietic Stem Cell Transplant (HSCT). Early Intervention Improves Outcome – Updated Results of a Treatment IND (T-IND) Expanded Access Protocol

AbstractAbstract 738 Background:Given the life-threatening nature of severe VOD (sVOD) and associated multi-organ failure (MOF) and that there are no currently approved therapies for this condition, DF has been made available since 2007 in the USA through a prospective T-IND. The aim of the T-IND is to gather additional data on safety and response to DF in a broader patient (pt) population including those with sVOD/MOF and those with non-severe VOD. To date this is the largest prospective evaluation of DF for the treatment of sVOD/MOF in pts undergoing HSCT and pts who developed VOD following chemotherapy (non-HSCT pts). Here we provide an update on the efficacy and safety of DF in pts undergoing HSCT. Methods:The original T-IND protocol required pts 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, and was amended to allow inclusion of pts with non-severe VOD (defined as no MOF). Key exclusion criteria included clinically significant bleeding or the need for >1 vasopressor. Complete response (CR) was defined as bilirubin <2 mg/dL plus resolution of MOF (if applicable). Mortality was assessed at Day +100 (D+100) in all pts. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d) with recommended treatment duration of at least 21 days (d). Results:The current interim analysis is based on 333 VOD pts enrolled between December 2007 and September 2011 at 68 centers, 305 of which had undergone HSCT (274 allogeneic HSCT, 82%). Median age was 16 years (range 0.1–70), 55% were male and 18% had undergone multiple HSCTs (>1 HSCT). Overall, 220 pts had severe disease at study entry. The most common diagnosis was leukemia (29% AML; 22% ALL; 4 other), with conditioning of CY (69%), BU (45%) and TBI (39%), respectively. Median onset of VOD was 16 d post-HSCT. Overall, 30% (90/305) of HSCT pts achieved CR and 50% (Kaplan-Meier estimate) survived to D+100. In HSCT pts with sVOD, CR was 26% and D+100 survival was 45%. For the HSCT pts with non-severe VOD, CR and D+100 survival was 39% and 65%, respectively. In the T-IND, 155 pts matched the entry criteria for the original phase III trial and were compared to the phase III historical controls (HCs) who did not receive DF. Results showed a statistically improved outcome in CR (29% vs 9%, p=0.0019) and D+100 survival (49% vs 25%, p=0.0016) compared with HCs. In all pts, delay of >2 d (vs ≤2 d) in the start of DF after VOD diagnosis resulted in reduced CR (20% vs 34%, p=0.0195) and survival (Kaplan-Meier estimate) (37% vs 56%, p=0.0118). Children (≤16 years) as compared to adults had higher CR rates (33% vs 26%, p=0.187) and survival (56% vs 44%, p=0.0277). Toxicity proved generally manageable: 21% of pts experienced a total of 92 related AEs, primarily consisting of hemorrhage (18%) and hypotension (4%). Hemorrhage included pulmonary bleeding (6%), GI hemorrhage (4%), epistaxis (2%) and hematuria (2%), with 2% of pts experiencing life threatening hemorrhage in which a possible relationship with DF could not be ruled out. Similar to the observation of decreased GvHD in other studies, the incidence of all grade GvHD in the allogeneic HSCT pts was 8%. Conclusions:DF therapy in sVOD/MOF pts achieved significantly improved outcomes compared to HCs. Based on the results of this large cohort of pts, early treatment with DF (i.e. within 2 d of VOD diagnosis) is recommended, and consistently improved outcomes are seen in pts who have not yet progressed to sVOD. Generally, DF was well-tolerated and as with prior studies, there was a low incidence of DF-associated toxicities. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after HSCT. Outcomes in children appear to be even better than in adults, supporting the importance of this agent in the pediatric population in particular. In addition, low rates of GvHD were seen and this is an area in which further studies are planned. Enrollment to the T-IND study continues. Disclosures:Richardson:Gentium: Advisory committee Other. Hannah:Gentium: Consultancy. Hume:Gentium: Employment. Tudone:Gentium: Employment. Heringa:Gentium: Employment. Study Group:Gentium: Employment.

Evaluation of Defibrotide (DF) in the Treatment of Hepatic Veno-Occlusive Disease (VOD) in Non-Stem Cell Transplant (non-SCT) Chemotherapy Patients (pts): Results From the Treatment IND (T-IND) Expanded Access Protocol and the Compassionate Use Program (CUP).

AbstractAbstract 3041 Background:Given the potentially life-threatening nature of hepatic VOD, the lack of approved treatments for this disease and the increasing evidence indicating that DF leads to improved outcome, DF has been made available on a compassionate use basis for almost a decade and more recently via prospective expanded access programs. Although VOD is most frequent in pts post-SCT, it can be induced by chemotherapy alone. The CUP and T-IND have collected safety and outcome information from a broader pt population (n=1129 and n=333, respectively), including non-SCT pts who developed both non-severe and severe (sVOD) after chemotherapy. Demographics and results from this non-SCT population from the CUP and from an interim analysis of the T-IND are presented. Methods:CUP pts met VOD diagnosis with at least two of the following criteria: bilirubin >2mg dL, hepatomegaly and/or ascites or an unexplained weight gain of >5%. The T-IND pts met similar criteria but required the presence of elevated bilirubin with two other criteria. Pts had non-severe and sVOD, with sVOD defined as multi-organ failure (MOF; including renal or pulmonary failure in the T-IND or additionally CNS dysfunction in the CUP). Key exclusion criteria included clinically significant bleeding/severe coagulopathy or hemodynamic instability. DF was given at 25 mg/kg/d IV (in the CUP, dosing ranged 10–80 mg/kg/day, with median dosing 25 mg/kg/d) for a minimum of 14–21 days. Complete response (CR) was defined as bilirubin <2 mg/dL plus resolution of MOF (if applicable). Mortality was assessed at Day +100 (D+100) in all pts. Results:The current analysis is based on a total of 89 pts who developed VOD after chemotherapy (chemo) alone: 61 pts in the CUP and 28 pts in the T-IND. Pts were enrolled in CUP between December 1998 and March 2009; median age was 14 years (range 0.2–65) and 66% were male. In the T-IND the chemo pts were enrolled from December 2009 to September 2011; median age was 8 years (range 0.2–58) and 50% were male. The most common diagnosis was ALL (36% and 32%) and AML (30% and 25%) in the CUP and T-IND, respectively. Vincristine, cytarabine and cyclophosphamide were the most frequent chemotherapeutic agents associated with VOD, and with the exception of cyclophosphamide, their prior exposure was relatively similar between arms: pts in the CUP and in the T-IND, respectively, were treated with vincristine (31% and 46%), cytarabine (25% and 39%), and cyclophosphamide (16% and 61%). Median onset of VOD after chemotherapy was 19 days and 16 days in the CUP and T-IND, respectively, and sVOD was present in 46% and 50% of pts at study entry in the CUP and T-IND, respectively.Overall, 53% (47/89) of pts achieved CR, with 53% (25/47) of pts with non-severe VOD achieving CR and 52% (22/42) of pts with sVOD achieving CR. Overall, 68% and 67% of pts were alive at D+100 (Kaplan-Meier estimate) in the CUP and T-IND, respectively, 65% and 69% of pts with non-severe VOD were alive at D+100 in the CUP and T-IND, respectively, and 72% and 64% of pts with sVOD alive at D+100 in the CUP and T-IND, respectively. When VOD outcomes were compared to the SCT population of the T-IND (Richardson PG, et al. Blood [ASH Annual Meeting Abstracts] 2011;118:487), CR was 43% in non-SCT pts vs 30% in SCT and survival was 68% vs 50%, respectively.Toxicity proved generally manageable: 24% of pts experienced a total of eight related AEs, primarily consisting of hemorrhage (21%) and hypotension (3%). Hemorrhage included pulmonary bleeding (7%), epistaxis (7%) and GI hemorrhage (3%). Conclusions:Demographic and outcome data for VOD, a frequent and life-threatening complication of SCT, has been documented from a population of 89 pts following intensive chemotherapy alone. These pts were most frequently diagnosed with ALL and AML and recipients of vincristine, cytarabine or cyclophosphamide-based chemotherapy. The use of DF for VOD, which has been shown to improve CR and survival in SCT pts, is also associated with better outcomes in pts who have not undergone transplant. Generally, DF was well-tolerated and as with prior studies, there was a low incidence of DF-associated toxicities. The use of DF in VOD following intensive chemotherapy without SCT appears promising, but more research in this predominantly pediatric patient population is needed. Enrollment to the T-IND study for this important subgroup of pts continues. Disclosures:Richardson:Gentium: Advisory committee Other. Tudone:Gentium: Employment. Sardella:Gentium: Employment. Bandiera:Gentium: Employment. Heringa:Gentium: Employment. Niederwieser:Gentium: Speakers Bureau. Study Group:Gentium: Employment.

Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation

Hepatic veno-occlusive disease (VOD) is a serious complication of stem cell transplantation in children. VOD is characterized by rapid weight gain, hepatomegaly, hyperbilirubinemia and ascites. The pathogenesis of VOD is thought to involve chemotherapy and radiation-induced damage to the sinusoidal endothelium, resulting in endothelial injury, microthrombosis, subendothelial damage and cytokine activation. These processes lead to concomitant progressive hepatocellular dysfunction and subsequent fluid retention and renal impairment. Severe VOD is typically associated with multiorgan failure and high mortality. A number of possible strategies for the prevention and/or treatment of VOD in children have been investigated. The most promising agent to date is defibrotide, a novel polydeoxyribonucleotide with fibrinolytic properties but no major bleeding risk. Numerous studies, including Phase II/III trials, have shown clinical benefit in pediatric patients with the use of defibrotide treatment and prophylaxis. This review discusses VOD in children and focuses on therapeutic options, including defibrotide, in this patient population.

Defibrotide (DF) in the Treatment of Hepatic Veno-Occlusive Disease (VOD) in Stem Cell Transplant (SCT) and Non-SCT Patients (Pts): Early Intervention Improves Outcome - Updated Results of a Treatment IND Expanded Access Protocol

Abstract 487 Background: Given the life-threatening nature of severe VOD (sVOD) and multi-organ failure (MOF), DF was made available in the US through a prospective treatment IND protocol (T-IND) to gather additional safety and response data from SCT patients (pts) with sVOD who were not eligible for a pivotal Phase 3 trial. Following completion of this Phase 3 trial, the T-IND protocol has continued and been amended to include pts who would have met eligibility criteria for the completed phase 3 trial, as well as pts with non-severe VOD and non-SCT pts who develop VOD after chemotherapy (chemo). This is the largest prospective evaluation of DF for the treatment of sVOD/MOF post SCT and non-SCT pts to date. Methods: Pts were initially required 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) that followed SCT. Following treatment of 104 pts, an amendment expanded eligibility criteria to include pts with VOD after chemo and pts with non-severe VOD (defined as no MOF). Key exclusion criteria included clinically significant bleeding or >1 pressor to maintain BP. CR was defined as bilirubin Results: This interim analysis is based on 269 pts enrolled between December 2007 and March 2011 at 67 centers. Nearly all pts (n=251) had undergone SCT (with allogeneic SCT in 225, 90%); 18 developed VOD after chemo alone. Of the 269 cases of VOD, 200 were severe at study entry, with 25% (66/269) of all pts dialysis dependent and 31% (83/269) ventilator dependent. Median age was 16 years (range 0.1 – 70); 55% were male. In the SCT pts, the most common diagnosis was leukemia (29% AML; 22% ALL; CML 3%; 4% other), with conditioning of CY (71%), BU (46%) and TBI (38%) respectively; 18% had undergone multiple SCTs (>1 SCT). Median onset of VOD was 15 d post-SCT. When presenting after chemo alone (n=18), median onset of VOD was 16 d after the first dose, most frequently after CY (61%), cytarabine (44%) and vincristine (39%), and for treatment of leukemia (AML 33%, ALL 33%, other 6%). Overall mean number of days of DF administration in all pts was 22 (range 1–88).Of 269 pts, 32% (85/269) achieved a CR and 50% [ by Kaplan-Meier estimate] survived to D+100. In the subgroup of SCT pts, 31% (78/251) achieved CR and 50% survived to D+100; 134 pts met entry criteria for the original Phase 3 trial and comparison to the Phase 3 historical control showed a statistically improved outcome in CR (30% vs 9%, p=0.0006) and D+100 survival (46% vs 25%; p=0.006). Of 200 pts with sVOD, CR was 28% and D+100 survival was 44%. In the 18 chemo only pts, CR was 39% and D+100 survival was 50%. CR rate and D+100 survival for the 69 pts with non-severe VOD were 42% and 62%, respectively. Delay of >2 d (vs Conclusions: In 269 pts with mainly sVOD/MOF, DF therapy achieved significantly improved outcome compared to an untreated historical control. Importantly, CR and survival were improved in pts who were treated within 2d of VOD diagnosis (vs. later) and in pts who had not yet progressed to sVOD. As with prior studies, there was a low incidence of DF-associated toxicities. Interestingly, the incidence of GvHD in allo-SCT pts was low, consistent with the reduction of GvHD seen in the large randomized EBMT pediatric prevention study. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after SCT, as well as its use in pts who have not progressed to advanced MOF. The use of DF for VOD following intensive chemotherapy without SCT also appears promising, but more research in this patient population is needed. Enrollment to the T-IND study continues. Disclosures: Richardson:Gentium: Membership on an entity9s Board of Directors or advisory committees. Arai:Gentium: Research Funding. Symons:Otsuka Pharmaceuticals: Research Funding. Martin:Gentium: Research Funding. Massaro:Gentium: Consultancy. D9Agostino:Gentium: Membership on an entity9s Board of Directors or advisory committees. Hannah:Gentium: Consultancy. Tudone:Gentium: Employment. Hume:Gentium: Employment. Iacobelli:Gentium SpA: Employment. Soiffer:Gentium: Honoraria.

Therapeutic Nucleic Acids: A Potential Source of Resistance to Cancer, Antiviral and Immunosuppressive Therapy.

According to their unique structural and chemical properties nucleic acids were recognized to provide inherent therapeutic potential beyond sole information storage. In the meantime an increasing number of nucleic acid based drugs achieved FDA approval and entered clinical trails (e.g. “antisense” or “immunosustimulatory CpG” oligodeoxynucletides (ODNs), aptamers, ribozymes, RNA interference or defibrotide). But so far, no or less information is available whether these compounds mightcompete with chemically and structurally related drugs, e.g. nucleoside analogues (NA) widely used in cancer or antiviral therapy, orinterfere with the intracellular nucleic acid metabolism.In the present report we provide evidence, that nucleic-acid based drugs antagonize fludarabine, acyclovir or mycophenolate mofetil (MMF). In presence of defibrotide (DF), a polydisperse mixture of single-stranded oligodeoxyribonucleotides (15 to 30 kD) e.g. used for treatment of hepatic veno-occlusive disease and other endothelial disorders, fludarabine treated lymphocytes or myeloid blasts where rescued from apoptosis. According to nucleic acid degradation the resulting metabolite deoxycytidine turned out to be the key substrate competing with fludarabine for phosphorylation by deoxycitidine kinase (dCK) and suggested interference with nucleic acid metabolism rather than direct competition with the drug for cellular uptake. Moreover, in standard drug resistance assays using acyclovir sensitive herpes simplex virus (HSV) strains (V0631508), 4 mM of DF restored viral replication in presence of 50 mM acyclovir. This was confirmed by quantitative PCR of viral DNA. Here, deoxythymidine turned out to be the main competitor for intracellular phosphorylation mediated by virus thymidine kinase. To further extent our findings, that an increase of the extracellular concentration of nucleic acids directly interfere with the intracellular nucleic acid metabolism, mixed lymphocyte reactions (MLRs) were performed, to test whether the immunosuppressive effects of mycophenolate mofetil (MMF) could be reversed. As control cyclosporine A (CsA) was used. Here, addition of singular ribonucleotides almost completely antagonized the T cell inhibitory effects of mycophenolic acid (MPA), respectively its prodrug MMF, but not of CsA. As MPA is known to be a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, a key enzyme for the de novo pathway of guanosine nucleotide synthesis, addition of guanosine to the MLRs was found to be effective and sufficient to reverse the immunosuppressive effects of MPA. We conclude that treatment with nucleic-acid-based drugs interfere with the intracellular nucleic acid metabolism, thus decreasing the efficacy of NAs used for cancer and antiviral therapy or the immunosuppressive therapy using MMF. Prospective clinical trials are required to confirm these in vitro findings.