Veno-occlusive Disease/sinusoidal Obstruction Syndrome Research Articles

A Multi-Center, Multinational, Prospective Observational Registry Study of Defibrotide in Patients Diagnosed with Severe Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT)

Severe hepatic VOD/SOS is a potentially life-threatening complication of HCT conditioning that may also develop after high-dose chemotherapy. The most severe form of VOD/SOS is often accompanied by multi-organ failure (MOF) and is associated with a mortality rate of >80% when managed with supportive care alone. As part of the marketing authorization in Europe, there was an obligation to set up a disease registry of patients with severe VOD/SOS post-HCT who were treated with defibrotide. The goal of this registry was to collect safety and outcome data and assess patterns of defibrotide utilization in the post-approval setting. This multicenter, multinational, prospective observational study (NCT03032016) was performed by the European Society for Blood and Marrow Transplantation (EBMT). The study included patients with severe VOD/SOS post-HCT who were treated with defibrotide and enrolled from April 2015 to July 2018. Participating centers were members of the EBMT. Physicians registered patients diagnosed with severe VOD/SOS, as assessed by the investigator using classical/standard criteria (including but not limited to hyperbilirubinemia, hepatomegaly, ascites, and weight gain >5%), who consented to participate in the study. In addition, patients who were prescribed defibrotide for purposes other than the approved indication (eg, VOD/SOS prophylaxis, treatment of non-severe VOD/SOS or thrombotic microangiopathy) and consented to participate were registered and information collected. There were no specific exclusion criteria; however, treating physicians were alerted to contraindications, special warnings, and precautions detailed in the defibrotide summary of product characteristics. After inclusion, patient information was collected from participating centers at 100 days, 6 months, and 12 months post-HCT. The primary objective was to assess the incidence of specific serious adverse events (SAEs) of interest, which were hemorrhage and site of bleeding, hypotension, coagulopathy, allergic or hypersensitivity reactions, injection-site reaction, infection and septicemia, and thromboembolic events. Secondary endpoints included Day 100 survival, and overall rate of VOD/SOS (and MOF, if present) resolution (based on standard criteria). Summary statistics were calculated for baseline data and safety variables; outcome analyses are descriptive. Here we report an analysis of data with a cutoff of June 18, 2019. Database lock is planned for October 2019, and the presentation will be updated to include the final data. A total of 61 patients with severe VOD/SOS were included; MOF was diagnosed at registration in 34 (56%) patients. The median age of patients with severe VOD/SOS was 14.4 (range: 0-68) years, 34 (56%) aged <18 years and 27 (44%) aged ≥18 years. A total of 54 (89%) patients received allogeneic HCT. Primary diseases included acute myeloid leukemia (26%), acute lymphoid leukemia (13%), solid tumor (12%), and myelodysplastic syndrome (8%). The median length of defibrotide exposure was 17 (IQR: 11-25) days. An SAE of interest occurred in 19 (31%; 95% confidence interval [CI]: 20%-43%) patients with severe VOD/SOS. The most common SAEs of interest by category were infection (n = 13 [21%; 95% CI: 11%-32%]) and bleeding events (n = 8 [13%; 95% CI: 5%-22%]). The most common individual SAEs of interest (≥5% of patients) were pneumonia (8%), gastrointestinal bleeding (8%), and sepsis (5%). Death occurred in 30 (49%) patients within 1 year, with VOD/SOS indicated as a cause of death in 13/30 (43%) patients. The Kaplan-Meier-estimated survival rate at Day 100 for patients diagnosed with severe VOD/SOS post-HCT who were treated with defibrotide was 74% (95% CI: 61%-83%). At latest follow-up, the survival rate was 51%, with median Kaplan-Meier-estimated survival post-HCT not yet reached. VOD/SOS resolved in 46 (75%) patients; the cumulative rate of VOD/SOS resolution at Day 100 was 87% (95% CI: 72%-94%). Resolution of MOF was achieved in 19/34 (56%) patients who had MOF at VOD/SOS diagnosis. In conclusion, among patients with severe VOD/SOS post-HCT (with/without MOF), the incidence of SAEs of interest was consistent with that observed in previous defibrotide clinical trials. Treatment with defibrotide resulted in high rates of Day 100 survival and VOD/SOS resolution. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Blaise:Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Pierre Fabre medicaments: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Hanvesakul:Jazz Pharmaceuticals: Employment, Equity Ownership. Ryan:Jazz Pharmaceuticals: Employment, Equity Ownership. Lawson:Jazz Pharmaceuticals: Consultancy, Honoraria.

A Meta-Analysis Evaluating the Risk of Bleeding-Related Adverse Events with Defibrotide Treatment

Introduction: Defibrotide is approved for adult and pediatric patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT) in the United States and Canada and for patients aged >1 month with severe hepatic VOD/SOS post-HCT in the European Union. The recommended dose is 6.25 mg/kg every 6 hours given as a 2-hour intravenous (IV) infusion. Defibrotide has been shown in vitro to reduce endothelial cell (EC) activation and promote EC-mediated fibrinolysis. Post-HCT patients with VOD/SOS are often at a high risk for bleeding events. In a phase 3 study of patients with VOD/SOS post-HCT, rates of bleeding-related adverse events (AEs) with defibrotide were generally similar to matched historic controls (Richardson PG, et al. Blood. 2016;127[13]:1656-1665). To broaden our understanding of the risk of bleeding events associated with defibrotide treatment, this meta-analysis assessed the incidence and risk of bleeding-related AEs with defibrotide treatment in studies outside of the VOD/SOS and HCT setting, using published literature. Methods: PubMed and Embase were searched from database inception through July 24, 2018 for studies using defibrotide (controlled trials with ≥1 arm assessing an intervention of interest, observational/retrospective studies, retrospective or post hoc analyses, and case series with ≥10 patients). Studies of patients with VOD/SOS or HCT, case reports with <10 patients, and reviews were excluded. Publications were evaluated for the presence of data on endpoints of interest, which included any bleeding-related event and overall safety or efficacy summaries; all studies with available data were included in the analysis. Overall bleeding rate was estimated for defibrotide and controls using the Freeman-Tukey double arcsine transformation and random-effects modeling (Stata Software). The risk ratio of bleeding was calculated using the Mantel-Haenszel method and random-effects modeling (RevMan 5.3 Software). Overall bleeding rate and risk ratio of bleeding were calculated from studies that used the IV defibrotide formulation; studies using oral or intramuscular formulations were excluded from these calculations. Results: A total of 1,857 records were identified in the search; 124 studies reported on defibrotide and 19 contained data related to bleeding and were included in the analysis. Of the 19 included studies, 2 had >1,000 patients. An IV defibrotide formulation was used in 12 studies; the other 7 used intramuscular or oral delivery or more than one method of defibrotide administration. The most common indications were prevention of deep vein thrombosis (11 of 19) and treatment of thrombosis (3 of 19). Most studies (14 of 19) had 2 treatment arms; among these studies, heparin was the most common comparator (11 of 14). For the other 5 of 19 studies, 4 studies were single-arm and 1 study had 3 arms. The majority of studies (16 of 19) were conducted in adults; the other 3 studies did not specify patients' age. The most commonly administered defibrotide dose was 800 mg daily (14 of 19 studies). Bleeding rate and risk ratio of bleeding were calculated based upon data from the 12 studies that used IV defibrotide. Rates of bleeding events reported in the 12 studies with IV defibrotide ranged from 0% to 10% in individual studies and the estimated overall bleeding rate was 1% (95% confidence interval [CI]: 0.00-0.03). In 10 studies with control treatments (9 calcium heparin, 1 urokinase), rates of bleeding events ranged from 1% to 37%, with 7 studies having rates ≥10%. Across the 10 control studies, the estimated overall bleeding rate for controls was 11% (95% CI: 0.05-0.20). Among the 8 studies with available data on IV defibrotide and controls (7 calcium heparin, 1 urokinase), the risk ratio for bleeding events with IV defibrotide versus controls was 0.36 (95% CI: 0.24-0.52; P <0.00001; Figure). Conclusions: This meta-analysis of defibrotide use outside of the VOD/SOS setting suggests that the bleeding risk with defibrotide is low, and there is comparable risk of bleeding with defibrotide treatment versus controls such as heparin or urokinase. Important limitations of this analysis include variations in AE reporting across studies and the use of a defibrotide dose that is lower than the currently approved recommendation in the majority of studies. Disclosures Tappe: Jazz Pharmaceuticals: Employment, Equity Ownership. Aggarwal:Jazz Pharmaceuticals: Consultancy. Topaloglu:Jazz Pharmaceuticals: Consultancy. Iacobelli:Massimo Iacobelli: Consultancy. OffLabel Disclosure: The abstract describes a meta-analysis of defibrotide (indicated for VOD/SOS) in the non-VOD/SOS setting. As this analysis drew data from existing literature, no patients were administered defibrotide for off-label indications in the course of this analysis.

Study Design of an Open-Label, Single-Arm, Multicenter, Phase 2 Study to Evaluate the Safety and Efficacy of Defibrotide in Adult Patients with Transplant-Associated Thrombotic Microangiopathy

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is an uncommon, but well-recognized, hematopoietic cell transplant (HCT) complication associated with high morbidity and mortality. TA-TMA may result from microvascular endothelial cell (EC) damage induced by HCT conditioning regimens, immunosuppressive drugs, and infections, and it may be mediated by complement activation in some cases. Although there is no consensus on optimal TA-TMA treatment, common interventions include withdrawal, replacement, or dose modification of calcineurin inhibitors (CI) and/or mammalian target of rapamycin (mTOR) inhibitors (ie, CI/mTORi changes). When increased complement activity is present, terminal complement cascade inhibition has been used. Defibrotide (DF) is approved for adult and pediatric patients (pts) with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction post-HCT in the US and Canada and for pts aged >1 month with severe hepatic VOD/SOS post-HCT in the EU. DF reduces EC activation, promotes fibrinolysis, and may be a novel therapy for TA-TMA. This prospective, open-label, single-arm, multicenter, phase 2 study (EUDRACT: 2018-001101-90) is designed to assess the efficacy and safety of DF for treating pts with high-risk TA-TMA (defined as definite TMA per Postalcioglu M, et al. Biol Blood Marrow Transplant. 2018;24(11):2344-2353) who have failed to respond to CR/mTORi changes. Study Design and Methods: Diagnostic criteria for "definite" TA-TMA include lactate dehydrogenase (LDH) >2 × the upper limit of normal, thrombocytopenia (platelet count <50 × 109/L or ≥50% decrease from peak platelets post-HCT), schistocytes ≥2 per high-power field in peripheral blood, serum creatinine increase >50% from baseline, and a negative Coombs test. Allogeneic HCT pts (aged ≥18 years) who have definite TA-TMA with persistent or progressive disease after 7 or 3 days, respectively, following CI/mTORi changes are eligible (Figure). Pts will be excluded if they relapse after HCT, have grade 4 acute graft-versus-host disease or VOD/SOS, or clinically significant bleeding within 24 hours of enrollment. Planned enrollment is 30 to 40 pts. Pts will receive a 2-hour intravenous infusion of DF 25 mg/kg/day (6.25 mg/kg every 6 hours) for a recommended duration of 21 days (up to 60 days). Pts will be followed for 180 days from DF start (Day 1). The study has 2 co-primary efficacy endpoints: hematologic response by Day 45 (relative to DF start) and renal response by Day 45. Hematologic response is defined as normalization of LDH and platelet count ≥50 × 109/L without platelet transfusion for 7 days (if baseline count was <50 × 109/L) or ≥50% increase in platelet count (if baseline count was ≥50 × 109/L). Renal response is defined as <25% increase or decrease in serum creatinine versus baseline at DF start (renal function stabilization) or ≥25% decrease in serum creatinine versus baseline at DF start or independence from dialysis (if pt was dialysis dependent at baseline or started dialysis after baseline) (renal function improvement). Secondary efficacy endpoints are overall survival, duration of hematologic or renal response, proportion of pts achieving hematologic or renal (measured by serum creatinine or estimated glomerular filtration rate) response by Days 60, 90, and 180, independence from dialysis at Days 60, 90, and 180 for pts with dialysis dependence, and neurologic improvement (defined as any increase in Mini-Mental Status Examination score versus baseline or resolution of TA-TMA seizure activity) at Days 7, 14, 21, and 45. Safety endpoints include incidence of treatment-emergent adverse events (AEs), treatment-emergent serious AEs, and AEs of interest (eg, hemorrhage and hypotension) occurring up to 30 days after the last DF dose. Analysis of the co-primary efficacy endpoints will be evaluated in pts who receive ≥1 DF dose. For each co-primary endpoint, a reference background rate, based upon data from literature and/or registries or research databases, will be established to represent the Day 45 hematologic and renal response rates in a similar pt population in the setting of currently available therapy without DF treatment. A clinically meaningful benefit from DF will be inferred if the lower bounds of the 95% confidence interval of the co-primary endpoints are greater than their respective reference background rates. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Keshelava:Jazz Pharmaceuticals: Employment, Equity Ownership. Swann:Jazz Pharmaceuticals: Employment, Equity Ownership. Tappe:Jazz Pharmaceuticals: Employment, Equity Ownership. OffLabel Disclosure: The abstract contains a description of off-label product use. Defibrotide is approved for treatment of hepatic VOD/SOS post-HCT (as described in the background) and this study is evaluating its use in patients with TA-TMA.

Incidence, Predictors, and Outcomes of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation.

fludarabine with intravenous busulfan at doses of 3.2 mg/kg (Flu/Bu1) or 6.4 mg/kg (Flu/Bu2). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced-intensity conditioning (RIC) HCT is low compared with myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007 and 2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range, 5 to 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval [CI], 1.1% to 2.4%). Day 100 nonrelapse mortality rate was 23% in the VOD/SOS cohort compared with 6.4% in patients without VOD/SOS (P=.006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2 ± ATG (fludarabine with two doses of busulfan, total dose 6.4 mg/kg, with or without anti-thymocyte globulin), compared with 0.15% after Flu/Bu1 ± ATG (fludarabine with single busulfan dose 3.2 mg/kg, with or without anti-thymocyte globulin) (P=.0002); the incidence rate was 2.1% after RIC HCT with sirolimus-containing graft-versus-host disease prophylaxis, compared with 0.8% for RIC without sirolimus (P=.06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio [HR], 5.1; 95% CI, 1.8 to 14.2; P=.002) and RIC regimen with Flu/Bu2 ± ATG (HR, 34; 95% CI, 4.5 to 252; P < .001) or other (HR, 32; 95% CI, 3.9 to 257; P=.001) compared with Flu/Bu1 ± ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared with a previously published cohort of 76 patients with VOD/SOS who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT.

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.

PF747 DEFIBROTIDE TREATMENT IN ADULTS WITH SEVERE OR VERY SEVERE VENO‐OCCLUSIVE DISEASE/SINUSOIDAL OBSTRUCTION SYNDROME AFTER HEMATOPOIETIC CELL TRANSPLANTATION: DEFIFRANCE STUDY INTERIM RESULTS

Background:Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication after hematopoietic cell transplantation (HCT) and may also develop after high‐dose chemotherapy alone. Severe VOD/SOS is often accompanied by multi‐organ failure (MOF) and is associated with a mortality rate of &gt;80% when managed with supportive care alone. Defibrotide is approved for the treatment of severe hepatic VOD/SOS post‐HCT in patients aged &gt;1 month in the European Union and for hepatic VOD/SOS with renal or pulmonary dysfunction post‐HCT in the United States and Canada. The DEFIFrance study is being performed to collect real‐world data on safety and efficacy of defibrotide in a broad patient population in France, including adult and pediatric patients.Aims:The goal of this interim analysis of the DEFIFrance study was to evaluate the safety and efficacy of defibrotide for the treatment of VOD/SOS in the subgroup of adult patients who received HCT, using the European Society for Blood and Marrow Transplantation (EBMT) diagnostic and severity criteria.Methods:DEFIFrance is an ongoing multicenter, post‐marketing study that is collecting safety and efficacy data on patients treated with defibrotide at HCT centers in France since July 2014. The data cut‐off for this analysis was 8 November 2018. VOD/SOS severity was categorized retrospectively and prospectively using the EBMT criteria (Mohty M, et al. Bone Marrow Transplantation. 2016;51[7]:906–912). Primary endpoints include the rates of Kaplan‐Meier–estimated Day 100 (post‐HCT) survival and Day 100 complete response (CR; total serum bilirubin &lt;2 mg/dL and resolution of MOF based on the investigators’ assessment).Results:A total of 324 patients treated with defibrotide at 36 active HCT centers in France were included in the DEFIFrance study as of 8 November 2018, including 120 patients diagnosed with VOD/SOS post‐HCT. Of these, 66 adults had severe/very severe VOD/SOS post‐HCT and were included in the current subgroup analysis. The median age was 54 (range, 18–73) years. Median time to onset of VOD/SOS post‐HCT, was 11 (range, −2–76) days. MOF was present in 32 (49%) patients. Fifteen of 26 (58%) patients with renal failure underwent dialysis, and 17/23 (74%) patients with respiratory failure required a ventilator. The Kaplan‐Meier–estimated survival rate at Day 100 post‐HCT was 47%, and the CR rate at Day 100 post‐HCT was 43% (Figure). The estimated Day 100 survival rates were 77% and 28% among adults with severe VOD/SOS (n = 26) and very severe VOD/SOS (n = 40), respectively; the Day 100 CR rates were 72% and 25%, respectively. Among adults with severe/very severe VOD/SOS post‐HCT, the overall survival rates were 39% and 31% at 6 months and 12 months post‐HCT, respectively. Mortality related to VOD/SOS was 15% at Day 100; all deaths after Day 100 were considered to be related to a cause other than VOD/SOS. Adverse events (AEs) of interest occurred in 55% of adult patients with severe/very severe VOD/SOS post‐HCT. The most frequently reported AEs of interest included infection (27%), bleeding (21%), and hypotension (6%).Summary/Conclusion:Among adults treated with defibrotide post‐HCT for severe/very severe VOD/SOS, per EBMT criteria, those with severe disease had better outcomes than those with progression to very severe disease, highlighting the potential importance of early VOD/SOS diagnosis and treatment initiation. The incidence of AEs of interest was consistent with that observed in previous defibrotide clinical trials.image

Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)

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.

A Pooled Analysis of Survival By Defibrotide (DF) Timing of Initiation in Adults with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) Following Hematopoietic Stem Cell Transplant (HSCT)

Introduction Hepatic VOD/SOS is a potentially life-threatening complication of HSCT or nontransplant chemotherapy. VOD/SOS with multi-organ dysfunction (MOD; eg, renal or pulmonary) may be associated with >80% mortality. DF is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the US and Canada, and severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the EU. Methods Data from the international compassionate use program (CUP) and expanded-access protocol (T-IND) were pooled (due to the nature of the protocols, both studies included patients with and without MOD) to investigate whether time to DF initiation after VOD/SOS diagnosis had an impact on Day +100 survival. In the CUP (N=710) and T-IND (N=1137), VOD/SOS was diagnosed by Baltimore or modified Seattle criteria or biopsy (CUP enrollment also included hemodynamic, ultrasound, or histologic evidence of VOD/SOS). Adults (>18 years) with VOD/SOS post-HSCT who received DF 25 mg/kg/day dosage and had time to dosing data were pooled. The analyses examined (1) initiation of DF before/after Days 1, 2, 3, 4, 7, and 14 after diagnosis (Fisher's exact test) and (2) starting DF on a particular day post-diagnosis: 0, 1, 2, 3, 4, 5, 6, 7, 8–14, and ≥15 (Cochran-Armitage test for trend). Results Of 534 pooled adults (aged ≥18) receiving 25 mg/kg/day with timing data, 300 (56%) had MOD. DF was initiated by Day 1 in 273 (51%) patients. In the analysis of DF initiation before or after Days 1, 2, 3, 4, 7, and 14, earlier initiation showed numerically higher survival rates for all cut points. Cochran-Armitage test for trend in the overall group suggested that Day +100 survival was higher with earlier initiation post diagnosis (Table). AEs in the CUP were consistently reported only for certain events. In all adults post-HSCT in the T-IND, treatment-related AEs in ≥2% were epistaxis and gastrointestinal hemorrhage (3.5% each), pulmonary hemorrhage (2.3%), and hematuria and hypotension (2.1% each). Conclusions DF administered at any given time point is of therapeutic value in patients with VOD/SOS. However, the results from the pooled post hoc analysis of post-HSCT adults suggest that earlier DF initiation after VOD/SOS diagnosis may improve Day +100 survival outcomes, although no specific day post-diagnosis provides a clinically meaningful cutoff for better outcome. Causes of treatment delay were not assessed. The safety profile for these patients was consistent with other DF studies in VOD/SOS. Support Jazz Pharmaceuticals.

Defibrotide Cost-Effectiveness in Canada for the Treatment of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) with Multi-Organ Dysfunction (MOD) after HSCT

Introduction Hepatic VOD/SOS is a progressive, potentially life-threatening complication of HSCT conditioning or of nontransplant chemotherapy. Without treatment, VOD/SOS with MOD (renal and/or pulmonary dysfunction) may be associated with >80% mortality. Defibrotide (DF) is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. The current analysis evaluates the cost-effectiveness of DF vs best supportive care (BSC) in Canada in patients with VOD/SOS with MOD post-HSCT. Methods A Markov cost-utility model, with an acute phase and a long-term phase, with a lifetime horizon, was adapted to reflect Canadian experience regarding epidemiology, management costs, and survival expectancy; only direct medical costs were included. In the acute phase, transition probabilities were based on endpoints of Day +100 survival and complete response (CR) from a phase 3 trial. The model included 4 health states: severe VOD/SOS, CR, survival, and death. Survival in the long-term phase was extrapolated using data from the literature. Hospital costs were calculated by taking the difference in time to CR in each arm in order to estimate the expected difference in hospital days between the BSC and DF arms. The severe VOD/SOS utility value was assumed to be the same as acute liver failure and end-stage liver disease scores (0.208), and the utility for CR was set to the age-matched general population. Costs and outcomes were discounted at 1.5% per year according to government guidance. Health effects were primarily expressed in terms of quality adjusted life years (QALYs). Results The difference in estimated costs between DF and BSC was $27,396 Canadian (Table). There was a 1.5 QALY increase for DF vs BSC. The incremental cost-effectiveness ratio (ICER; cost per QALY gained) was $17,724. In the probabilistic sensitivity analysis, for willingness to pay of $30,000 and $50,000 per QALY gained, the probabilities of DF being cost-effective were 85.6% and 100%, respectively, (Figure). Conclusions These results suggest that DF treatment for VOD/SOS with MOD is a cost-effective use of health resources in Canada, with an estimated ICER vs BSC below the accepted threshold for willingness to pay. Limitations include longer-term extrapolation of clinical trial data and assumptions about resource utilization patterns. Results were driven by estimates of more rapid recovery, reduced length of stay, and improved Day +100 survival in DF-treated patients. Results were supported by the sensitivity analysis. Support Jazz Pharmaceuticals.

Incidence of Anicteric Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) and Efficacy of Defibrotide (DF) in Patients Post-HSCT in an Expanded-Access Program

Introduction Hepatic VOD/SOS is a progressive, potentially life-threatening complication of HSCT or nontransplant chemotherapy. VOD/SOS diagnosis by Baltimore criteria requires bilirubin >2 mg/dL; hyperbilirubinemia is not required by modified Seattle criteria, and may be a late finding in the progression of VOD/SOS. DF is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the US and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients (pts) aged >1 month in the EU. This post hoc analysis examines incidence of VOD/SOS without elevated bilirubin, and survival in DF-treated, post-HSCT pts in the expanded-access T-IND program (2007–2016). Methods The T-IND enrolled pts with VOD/SOS diagnosed per Baltimore or modified Seattle criteria. Patients received DF 25 mg/kg/day, recommended for ≥21 days. Results Of 991 post-HSCT pts with recorded bilirubin at diagnosis, 190 (19%) had bilirubin 16 years (13% of the 427 post-HSCT adults). Across all 1000 post-HSCT pts in the T-IND (including 9 without baseline bilirubin data), Kaplan-Meier estimated Day +100 survival (Figure) was 58.9% (95% CI, 55.7%–61.9%). In the overall population of pts with bilirubin Conclusions In the T-IND, 19% of post-HSCT pts with VOD/SOS had bilirubin Support Jazz Pharmaceuticals.

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

IntroductionHepatic 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 <2 mg/dL before Day +21 is uncommon) but not for adults with late-onset (diagnosis >21 days post-HSCT) or pediatric patients (~30% of pediatric patients present with anicteric VOD/SOS [ie, bilirubin <2 mg/dL]). EBMT notes that hyperbilirubinemia may be a late finding in the progression of VOD/SOS. Defibrotide is approved to treat hepatic VOD/SOS with renal and/or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. 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).MethodsPrior 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.ResultsOf 991 patients in the T-IND with VOD/SOS post-HSCT and recorded bilirubin level at diagnosis, 190 (19%) had bilirubin <2 mg/dL (breakdown by subgroups in the Table), and 801 (81%) had bilirubin ≥2 mg/dL. Of those with bilirubin <2 mg/dL, 133 were pediatric patients aged ≤16 years (24% of all post-HSCT pediatric patients with recorded bilirubin [n=564]), and 57 were adult patients aged >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 <2 mg/dL (107/133 [80%] pediatric patients; 28/57 [49%] adults).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 <2 mg/dL at diagnosis and 52.3% (95% CI, 48.7%-55.7%) for the 801 patients with bilirubin ≥2 mg/dL (survival by age subgroups in the Figure). In the overall population of patients with bilirubin <2 mg/dL, 61.1% and 18.4% of patients had ≥1 treatment emergent adverse event (TEAE) and ≥1 treatment related adverse event (TRAE), respectively, and 21.1% had ≥1 hemorrhage event; for patients with bilirubin ≥2 mg/dL: 73.8% had ≥1 TEAE, 21.7% had ≥1 TRAEs, and 31.1% had ≥1 hemorrhage event.Conclusions:In the T-IND, 19% of post-HSCT patients with VOD/SOS had bilirubin <2 mg/dL at diagnosis, including 24% of children. Accordingly, 190 patients would not have been diagnosed if hyperbilirubinemia was a required criterion. Moreover, enrollment prior to 2012 required hyperbilirubinemia (or biopsy), so this percentage may understate the incidence of anicteric VOD/SOS. Of patients with bilirubin <2 mg/dL, 80% of pediatric patients and 49% of adults were diagnosed with VOD/SOS by Day +21 post-HSCT, suggesting that anicteric VOD/SOS may develop in this timeframe not only in pediatric patients but also in a sizeable number of adult patients. Defibrotide showed higher survival in patients with bilirubin <2 mg/dL compared to those with levels ≥2 mg/dL. These results compare favorably with the overall study findings, suggesting that treatment before the onset of hyperbilirubinemia may lead to better outcomes. The safety profile of the T-IND was similar to that of previous studies of defibrotide for the treatment of VOD/SOS.Support: Jazz Pharmaceuticals. [Display omitted] DisclosuresCorbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Kernan:National Cancer Institute: Research Funding. Pagliuca:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Tappe:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Pooled Analysis of Survival By Defibrotide Timing of Initiation in Adults with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) Following Hematopoietic Stem Cell Transplant (HSCT)

IntroductionHepatic VOD/SOS is a potentially life-threatening complication of HSCT or of nontransplant-associated high-dose chemotherapy. VOD/SOS associated with multi-organ dysfunction (MOD; eg, renal or pulmonary dysfunction) may be associated with >80% mortality. Defibrotide is approved to treat hepatic VOD/SOS with renal and/or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. Prior to US approval, defibrotide was available through an international compassionate-use program (CUP; 1998-2009) and an expanded-access protocol (T-IND; 2007-2016). Data for adults with VOD/SOS post-HSCT from the CUP and the T-IND were pooled to investigate whether the time to initiate defibrotide therapy after VOD/SOS diagnosis had an impact on Day +100 survival.MethodsIn both the CUP (N=710) and the T-IND (N=1137), defibrotide was used to treat hepatic VOD/SOS following HSCT or nontransplant-associated chemotherapy in pediatric and adult patients with or without MOD. Diagnosis of VOD/SOS was made using the Baltimore or modified Seattle criteria or was proven by biopsy (the CUP also allowed patients with hemodynamic, ultrasound, or histologic evidence of VOD/SOS to enroll). In the CUP cohort, the defibrotide median daily dose was 25 mg/kg/day administered for a median of 15 days; only patients who received 25 mg/kg/day were included in the analysis. In the T-IND, the defibrotide dose was 25 mg/kg/day for a recommended administration ≥21 days. In this analysis, adult patients (aged >18 years) from the CUP and the T-IND with VOD/SOS post-HSCT were pooled to examine Day +100 survival rates by time to start of defibrotide post-diagnosis. The first analysis examined patients who initiated defibrotide before/after Days 1, 2, 3, 4, 7, and 14 after VOD/SOS diagnosis, using Fisher's exact test, and the second examined starting defibrotide on a particular day: 0, 1, 2, 3, 4, 5, 6, 7, 8-14, and ≥15 (Cochran-Armitage test for trend across days).ResultsOf 534 pooled adult patients with VOD/SOS following HSCT who were treated with defibrotide 25 mg/kg/day and had reported time to dosing, 300 (56%) patients had MOD. Defibrotide treatment was initiated by Day 1 in 273 (51%) patients. In the analysis of treatment initiation before or after Days 1, 2, 3, 4, 7, and 14, earlier initiation of defibrotide showed numerically higher survival rates for all cut points (Day +100 survival before and after all cut points is provided in Table 1). Cochran-Armitage test for trend in the overall group suggested that Day +100 survival was higher with earlier initiation following diagnosis (nominal P=0.011; for patients with MOD, P=0.048; Table 2). Safety information for the CUP and T-IND were not pooled, as adverse events in the CUP were reported only if those events caused death in a consistent fashion. In all adult patients with post-HSCT VOD/SOS in the T-IND, treatment-related adverse events that occurred in ≥2% of adults were epistaxis and gastrointestinal hemorrhage (3.5% each), pulmonary hemorrhage (2.3%), and hematuria and hypotension (2.1% each).Conclusion: These results from the pooled post hoc analysis of adult patients with VOD/SOS post-HSCT from the CUP and T-IND studies suggest that earlier defibrotide initiation post-VOD/SOS diagnosis may improve Day +100 survival outcomes, although no specific day post-diagnosis provides a clinically meaningful cutoff for better outcome, suggesting that later intervention still retains value if therapy is not initiated sooner. Causes of treatment delay were not assessed. The safety profile for these patients was consistent with other defibrotide studies in VOD/SOS.Support: Jazz Pharmaceuticals. DisclosuresRichardson:Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Carreras:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pagliuca:Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Tappe:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Mohty:Molmed: Consultancy; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau.

Cost-Effectiveness of Defibrotide for the Treatment of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) with Multi-Organ Dysfunction (MOD) Post-Hematopoietic Stem Cell Transplantation (HSCT) in Canada

IntroductionHepatic VOD/SOS is a progressive, potentially life-threatening complication of conditioning for HSCT or of nontransplant-associated chemotherapy. Without treatment VOD/SOS with MOD (eg, renal and/or pulmonary dysfunction) may be associated with >80% mortality. Defibrotide (DF) is approved to treat hepatic VOD/SOS with renal and/or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. The current analysis evaluates the cost-effectiveness of DF vs best supportive care (BSC) in Canada in patients with VOD/SOS with MOD post-HSCT.MethodsA previously reported global Markov cost-utility model was adapted to reflect Canadian sources of care with regard to epidemiology, management costs, and survival expectancy; only direct medical costs were included. The model included an acute phase and a long-term phase, with a lifetime horizon. Transition probabilities in the acute phase were based on Phase 3 (Richardson et al, 2016) endpoints of Day +100 survival and complete response (CR). The model included 4 health states: severe VOD/SOS, CR, survival, and death. Survival in the long-term phase was extrapolated using Remberger et al (2011) and Ashton et al (2014).Hospital costs were calculated by taking the difference in time to CR in each arm in order to estimate the expected difference in hospital days between the BSC and DF arms. The severe VOD/SOS utility value was assumed to be the same as acute liver failure and end-stage liver disease scores (0.208), and the utility for CR was set to the age-matched general population. Costs and outcomes were discounted at 1.5% per year according to government guidance. Health effects were primarily expressed in terms of quality adjusted life years (QALYs).ResultsThe difference in estimated costs between DF and BSC was $27,396 (Canadian dollars; Table). DF showed an increase in 1.5 QALYs versus BSC. The incremental cost-effectiveness ratio (ICER; cost per QALY gained) was $17,724. In the probabilistic sensitivity analysis, for willingness to pay of $30,000 and $50,000 per QALY gained, the probabilities of DF being cost-effective were 85.6% and 100%, respectively (Figure).ConclusionThese results suggest that DF treatment for VOD/SOS with MOD represents cost-effective use of health resources in Canada, with an ICER estimate compared with BSC that was below the accepted willingness to pay threshold. Limitations of the analysis include longer-term extrapolation of clinical trial data and assumptions about resource utilization patterns. Results were driven by estimates of more rapid recovery, reduced length of stay, and improved Day +100 survival in DF-treated patients. Results were supported by the sensitivity analysis.Support: Jazz Pharmaceuticals. DisclosuresBelsey:Jazz Pharmaceuticals: Consultancy. Kemadjou:Jazz Pharmaceuticals: Consultancy. Isaila:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership, Other: Stock and stock options.

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.

482 - 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

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, (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 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 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 ~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 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 arm included hemorrhagic events and hypotension. Conclusion In this pooled analysis of studies of 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.

422 - Efficacy and Safety of Defibrotide in Pediatric Patients with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Stem Cell Transplantation (HSCT): Final Results From the Expanded-Access Program (T-IND)

422 - Efficacy and Safety of Defibrotide in Pediatric Patients with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Stem Cell Transplantation (HSCT): Final Results From the Expanded-Access Program (T-IND)

432 - Adults Receiving Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Stem Cell Transplantation (HSCT): Final Results From the Expanded-Access Program (T-IND)

432 - Adults Receiving Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Stem Cell Transplantation (HSCT): Final Results From the Expanded-Access Program (T-IND)

Defibrotide sodium for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome

ABSTRACTIntroduction: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is an unpredictable condition associated with endothelial-cell damage due to conditioning for hematopoietic stem-cell transplantation (HSCT) or chemotherapy without HSCT. Mortality in patients with VOD/SOS and multi-organ dysfunction (MOD) may be >80%.Areas covered: Defibrotide is the only approved drug for the treatment of severe hepatic VOD/SOS after HSCT in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction in the United States. Its efficacy in patients with VOD/SOS with MOD post-HSCT was demonstrated in a clinical-trial program that included a historically controlled treatment study, a phase 2 trial, and a large T-IND expanded-access program that also included patients without MOD and who received chemotherapy without HSCT.Expert commentary: Defibrotide appears to protect endothelial cells and restore the thrombolytic–fibrinolytic balance. It addresses a significant clinical need and has demonstrated favorable Day +100 survival and overall adverse-event rates that seem similar to control groups receiving supportive care alone. Currently, defibrotide is under investigation for the prevention of VOD/SOS in high-risk pediatric and adult patients.

Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation

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 only, and safety profiles are similar.Expert commentary: Defibrotide appears to act through multiple mechanisms to restore thrombo-fibrinolytic balance and protect endothelial cells, and there are promising data on the use of defibrotide for VOD/SOS prophylaxis in high-risk children undergoing HSCT. An ongoing randomized controlled trial in children and adults will better assess the clinical value of defibrotide as a preventive medication.

Efficacy and Safety of Defibrotide to Treat Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) After Primary Chemotherapy: A Post Hoc Analysis of Final Data From an Expanded-Access Protocol

Efficacy and Safety of Defibrotide to Treat Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) After Primary Chemotherapy: A Post Hoc Analysis of Final Data From an Expanded-Access Protocol