Dataset Information

Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research.

ABSTRACT: Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD.

SUBMITTER: Strouse C

PROVIDER: S-EPMC4914048 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research.

Strouse Christopher C Richardson Paul P Prentice Grant G Korman Sandra S Hume Robin R Nejadnik Bijan B Horowitz Mary M MM Saber Wael W

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20160419 7

Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identif ...[more]

PMID: 27108694

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Project description:Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) that is traditionally diagnosed using Baltimore or modified Seattle criteria. Whereas the Baltimore criteria require the presence of hyperbilirubinemia (bilirubin ≥2 mg/dL) for a diagnosis of VOD/SOS, the modified Seattle criteria do not. Before approval by the US Food and Drug Administration, defibrotide was available in the United States through an expanded-access study (T-IND). The T-IND protocol initially required post-HCT diagnosis of VOD/SOS by the Baltimore criteria or biopsy but was later amended to include patients diagnosed using the modified Seattle criteria. This post hoc analysis examined the incidence of VOD/SOS with a bilirubin level <2 mg/dL before and after Day 21 post-HCT in T-IND patients enrolled following the amendment allowing for diagnosis by the modified Seattle criteria. Survival of adult and pediatric patients with or without hyperbilirubinemia and with or without multiorgan dysfunction (MOD) was also evaluated. Of 803 post-HCT patients with VOD/SOS enrolled following the protocol amendment, 181 (23%) had a bilirubin level <2 mg/dL and would not have been diagnosed if hyperbilirubinemia was required. The bilirubin level at diagnosis was <2 mg/dL in 165 of 331 patients (50%) diagnosed by the modified Seattle criteria and in 16 of 23 patients (70%) diagnosed by biopsy. VOD/SOS with a bilirubin level <2 mg/dL was more common in pediatric patients (29%), although it also occurred in adult patients (15%). Patients with hyperbilirubinemia had lower Day 100 survival (54% versus 87% in patients with bilirubin <2 mg/dL) and a higher incidence of MOD (41% versus 26% in patients with bilirubin <2 mg/dL). The incidence of treatment-emergent adverse events and serious adverse events was lower in patients with a bilirubin level <2 mg/dL. These results indicate that anicteric VOD/SOS occurs in both adult and pediatric patients post-HCT and can be diagnosed before and after Day 21 in both groups. The worse survival in patients with bilirubin ≥2 mg/dL suggests that requiring hyperbilirubinemia may result in a progressed disease stage associated with worse outcomes. Taken together, these results highlight the importance of awareness and the possibility of VOD/SOS in the absence of elevated bilirubin level.

Project description:Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.

Dataset Information

Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research.

Publications

Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research.

Similar Datasets

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