title: Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study.
abstract: Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Electronic address: paul.richardson@dfci.harvard.edu.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: University of Minnesota, Minneapolis, Minnesota.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Smith
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Triplett
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Kernan
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Leslie
authors.initials: L
authors.lastname: Lehmann
authors.affiliation: Weill Cornell Medical College, New York, New York.
authors.forename: Tsiporah
authors.initials: T
authors.lastname: Shore
authors.affiliation: Formerly Gentium, Villa Guardia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Iacobelli
authors.affiliation: Jazz Pharmaceuticals, Palo Alto, California.
authors.forename: Maja
authors.initials: M
authors.lastname: Miloslavsky
authors.affiliation: Jazz Pharmaceuticals, Palo Alto, California.
authors.forename: Robin
authors.initials: R
authors.lastname: Hume
authors.affiliation: Formerly Jazz Pharmaceuticals, Palo Alto, California.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.affiliation: Formerly Jazz Pharmaceuticals, Palo Alto, California.
authors.forename: Bijan
authors.initials: B
authors.lastname: Nejadnik
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000401:mortality*; D006504:Hepatic Veno-Occlusive Disease / Q000150:complications / Q000188:drug therapy* / Q000401:mortality* / Q000628:therapy; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000209:etiology; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000401:mortality; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage* / Q000633:toxicity; D015996:Survival Rate; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods / Q000401:mortality; D055815:Young Adult
chemical_list: D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide
keywords: Defibrotide; Hematopoietic stem cell transplantation; Multiorgan dysfunction; Sinusoidal obstruction syndrome; Veno-occlusive disease