title: 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.
authors.affiliation: Department of Adult Oncology, Harvard Medical School, Boston, MA, USA. paul_richardson@dfci.harvard.edu
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Hajime
authors.initials: H
authors.lastname: Uno
authors.forename: Zhezhen
authors.initials: Z
authors.lastname: Jin
authors.forename: Joanne
authors.initials: J
authors.lastname: Kurtzberg
authors.forename: Paul L
authors.initials: PL
authors.lastname: Martin
authors.forename: Gideon
authors.initials: G
authors.lastname: Steinbach
authors.forename: Karen F
authors.initials: KF
authors.lastname: Murray
authors.forename: Georgia B
authors.initials: GB
authors.lastname: Vogelsang
authors.forename: Allen R
authors.initials: AR
authors.lastname: Chen
authors.forename: Amrita
authors.initials: A
authors.lastname: Krishnan
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Kernan
authors.forename: David E
authors.initials: DE
authors.lastname: Avigan
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Spitzer
authors.forename: Howard M
authors.initials: HM
authors.lastname: Shulman
authors.forename: Donald N
authors.initials: DN
authors.lastname: Di Salvo
authors.forename: Carolyn
authors.initials: C
authors.lastname: Revta
authors.forename: Diane
authors.initials: D
authors.lastname: Warren
authors.forename: Parisa
authors.initials: P
authors.lastname: Momtaz
authors.forename: Gary
authors.initials: G
authors.lastname: Bradwin
authors.forename: L J
authors.initials: LJ
authors.lastname: Wei
authors.forename: Massimo
authors.initials: M
authors.lastname: Iacobelli
authors.forename: George B
authors.initials: GB
authors.lastname: McDonald
authors.forename: Eva C
authors.initials: EC
authors.lastname: Guinan
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006504:Hepatic Veno-Occlusive Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide