Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.
Abstract
Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and
outcomes are dismal, but early phase I/II studies have suggested promising activity
and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide.
This randomized phase II dose-finding trial determined the efficacy of defibrotide
in patients with severe VOD following hematopoietic stem cell transplantation (HSCT)
and identified an appropriate dose for future trials. Adult and pediatric patients
received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40
mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for
> or =14 days or until complete response, VOD progression, or any unacceptable toxicity
occurred. Overall complete response and day +100 post-HSCT survival rates were 46%
and 42%, respectively, with no significant difference between treatment arms. The
incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10%
in arm B); there was no significant difference in the overall rate of adverse events
between treatment arms. Early stabilization or decreased bilirubin was associated
with better response and day +100 survival, and decreased plasminogen activator inhibitor
type 1 (PAI-1) during treatment was associated with better outcome; changes were similar
in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating
severe VOD following HSCT. In the absence of any differences in activity, toxicity
or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase
III trials in VOD.
Type
Journal articleSubject
HumansHepatic Veno-Occlusive Disease
Multiple Organ Failure
Polydeoxyribonucleotides
Fibrinolytic Agents
Treatment Outcome
Hematopoietic Stem Cell Transplantation
Survival Rate
Dose-Response Relationship, Drug
Adolescent
Adult
Middle Aged
Child
Child, Preschool
Infant
Infant, Newborn
Female
Male
Young Adult
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https://hdl.handle.net/10161/24611Published Version (Please cite this version)
10.1016/j.bbmt.2010.02.009Publication Info
Richardson, Paul G; Soiffer, Robert J; Antin, Joseph H; Uno, Hajime; Jin, Zhezhen;
Kurtzberg, Joanne; ... Guinan, Eva C (2010). Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan
failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.
Biology of blood and marrow transplantation : journal of the American Society for
Blood and Marrow Transplantation, 16(7). pp. 1005-1017. 10.1016/j.bbmt.2010.02.009. Retrieved from https://hdl.handle.net/10161/24611.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Joanne Kurtzberg
Jerome S. Harris Distinguished Professor of Pediatrics
Dr. Kurtzberg is an internationally renowned expert in pediatric hematology/oncology,
pediatric blood and marrow transplantation, umbilical cord blood banking and transplantation,
and novel applications of cord blood and birthing tissues in the emerging fields of
cellular therapies and regenerative medicine. Dr. Kurtzberg serves as the Director
of the Marcus Center for Cellular Cures (MC3), Director of the Pediatric Transplant
and Cellular Therapy Program, Director of the Carolina
Paul Langlie Martin
Professor of Pediatrics
For most of my career in Pediatric Hematology/Oncology I have focused on the use of
stem cell transplant for the treatment of pediatric leukemias (ALL, AML, CML and JMML)
and other non-malignant blood disorders, such as sickle cell disease, hemaphagocytic
disorders, Wiskott-Aldrich, aplastic anemia, Diamond-Blackfan Anemia, as well as inherited
metabolic diseases. In addition to focusing on determining the best use of stem cell
transplants for these disorders, I have also been involved in clinic
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