Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: A multicenter, randomized, dose-finding trial Journal Article


Authors: Richardson, P. G.; Soiffer, R. J.; Antin, J. H.; Uno, H.; Jin, Z.; Kurtzberg, J.; Martin, P. L.; Steinbach, G.; Murray, K. F.; Vogelsang, G. B.; Chen, A. R.; Krishnan, A.; Kernan, N. A.; Avigan, D. E.; Spitzer, T. R.; Shulman, H. M.; Di Salvo, D. N.; Revta, C.; Warren, D.; Momtaz, P.; Bradwin, G.; Wei, L. J.; Iacobelli, M.; McDonald, G. B.; Guinan, E. C.
Article 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 ≥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. © 2010 American Society for Blood and Marrow Transplantation.
Keywords: adolescent; adult; child; controlled study; human tissue; treatment outcome; child, preschool; middle aged; survival rate; young adult; major clinical study; clinical trial; diarrhea; drug dose comparison; drug efficacy; drug safety; gastrointestinal hemorrhage; side effect; drug megadose; low drug dose; controlled clinical trial; phase 2 clinical trial; bleeding; lung disease; nausea; randomized controlled trial; vomiting; kidney failure; hematopoietic stem cell transplantation; dose-response relationship, drug; dizziness; drug dose escalation; drug fever; flushing; hypoxia; drug induced headache; hypotension; prothrombin time; disease severity; infant; infant, newborn; multicenter study; glomerulus filtration rate; phase 3 clinical trial; drug blood level; phase 1 clinical trial; drug dose increase; tacrolimus; liver biopsy; abdominal cramp; rapamycin; oxygen saturation; allergic reaction; oxygenation; drug exposure; fibrinolytic agents; creatinine clearance; multiple organ failure; vasomotor disorder; gemtuzumab ozogamicin; hematocrit; lung hemorrhage; liver venoocclusive disease; hepatic veno-occlusive disease; defibrotide; dose-finding study; multi-organ failure; severe veno-occlusive disease; polydeoxyribonucleotides
Journal Title: Biology of Blood and Marrow Transplantation
Volume: 16
Issue: 7
ISSN: 1083-8791
Publisher: Elsevier Inc.  
Date Published: 2010-07-01
Start Page: 1005
End Page: 1017
Language: English
DOI: 10.1016/j.bbmt.2010.02.009
PUBMED: 20167278
PROVIDER: scopus
PMCID: PMC2956581
DOI/URL:
Notes: --- - "Cited By (since 1996): 4" - "Export Date: 20 April 2011" - "CODEN: BBMTF" - "Source: Scopus"
Altmetric
Citation Impact
MSK Authors
  1. Nancy Kernan
    493 Kernan