title: Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: Final Results From the International Compassionate-Use Program.
abstract: Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable and potentially fatal complication of hematopoietic cell transplantation (HCT) or nontransplantation-associated chemotherapy/radiotherapy. In cases of severe hepatic VOD/SOS, typically defined by associated multiorgan failure (MOF, also known as multiorgan dysfunction), mortality exceeds 80%. Preclinical and early clinical data have provided a rationale for defibrotide treatment in hepatic VOD/SOS. Based on this evidence and in recognition of the dismal prognosis for these patients, defibrotide was made available through an international multicenter compassionate-use program conducted from December 1998 to March 2009. Physicians participating in the program voluntarily provided demographic and outcome data for patients given defibrotide. Efficacy and safety analyses were performed using the data received for 710 treated patients. Defibrotide was given at 10, 25, 40, 60, or 80 mg/kg/day for a median of 15 days (range, 1 to 119 days). By Kaplan-Meier analysis, the estimated overall day +100 survival was 54% (58% in the 25 mg/kg/day dose group). Adverse events (AEs) were reported in 53% of patients. The most common AEs were MOF, progression of hepatic VOD/SOS, sepsis, and graft-versus-host disease, which were consistent with the AEs expected for this patient population. No clinically meaningful trends in AEs were identified by gender, age, or dose group. Safety and efficacy resultswere consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25 mg/kg/day dose.
authors.affiliation: Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Hospital Regensburg, Regensburg, Germany. Electronic address: selim.corbacioglu@ukr.de.
authors.forename: Selim
authors.initials: S
authors.lastname: Corbacioglu
authors.affiliation: Spanish Bone Marrow Donor Program, Josep Carreras Foundation, and Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Carreras
authors.affiliation: Department of Hematology, Hopital Saint-Antoine, Paris, France; University Pierre & Marie Curie, Paris, France; INSERM UMRs 938, Paris, France.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Mohty
authors.affiliation: Department of Hematology, King's College Hospital, London, United Kingdom.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pagliuca
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, The Netherlands; UMC Utrecht, Laboratory of Translational Immunology, The Netherlands.
authors.forename: Jaap Jan
authors.initials: JJ
authors.lastname: Boelens
authors.affiliation: Department of Hematology, University Hospital Center of Caen, School of Medicine, France.
authors.forename: Gandhi
authors.initials: G
authors.lastname: Damaj
authors.affiliation: Gentium, Villa Guardia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Iacobelli
authors.affiliation: Department of Hematology and Medical Oncology, University of Leipzig, Germany.
authors.forename: Dietger
authors.initials: D
authors.lastname: Niederwieser
authors.affiliation: Blood and Marrow Transplantation Unit, Hammersmith Hospital, London, United Kingdom.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Olavarría
authors.affiliation: Department of Hematology, Necker-Enfants Malades University Hospital, Paris, France.
authors.forename: Felipe
authors.initials: F
authors.lastname: Suarez
authors.affiliation: Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Tapani
authors.initials: T
authors.lastname: Ruutu
authors.affiliation: Isala Clinics, Zwolle, The Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: Verdonck
authors.affiliation: Jazz Pharmaceuticals, Palo Alto, California.
authors.forename: Robin
authors.initials: R
authors.lastname: Hume
authors.affiliation: Jazz Pharmaceuticals, Palo Alto, California.
authors.forename: Bijan
authors.initials: B
authors.lastname: Nejadnik
authors.affiliation: Jazz Pharmaceuticals, Palo Alto, California.
authors.forename: Chinglin
authors.initials: C
authors.lastname: Lai
authors.affiliation: Jazz Pharmaceuticals, Villa Guardia, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Finetto
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D057176:Compassionate Use Trials; D018450:Disease Progression; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006504:Hepatic Veno-Occlusive Disease / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000209:etiology; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D018805:Sepsis / Q000209:etiology; D055815:Young Adult
chemical_list: D011089:Polydeoxyribonucleotides; C036901:defibrotide
keywords: Compassionate-use program; Defibrotide; Hepatic veno-occlusive disease; Sinusoidal obstruction syndrome; Stem cell transplantation