title: Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.
abstract: Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Division of Hematology/Oncology, University of North Carolina Hospitals, Bone Marrow and Stem Cell Transplant Clinic, University of North Carolina Cancer Hospital, Chapel Hill, NC;
authors.forename: Marcie L
authors.initials: ML
authors.lastname: Riches
authors.affiliation: Pediatric Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Kernan
authors.affiliation: Department of Pediatrics, Stem Cell Transplant Program, Cohen Children's Medical Center, New Hyde Park, NY;
authors.forename: Joel A
authors.initials: JA
authors.lastname: Brochstein
authors.affiliation: Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: Shin
authors.initials: S
authors.lastname: Mineishi
authors.affiliation: Division of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA;
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Termuhlen
authors.affiliation: Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA;
authors.forename: Sally
authors.initials: S
authors.lastname: Arai
authors.affiliation: Pediatric Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Hematology/Oncology, Children's Hospital, Boston, MA;
authors.forename: Eva C
authors.initials: EC
authors.lastname: Guinan
authors.affiliation: Division of Pediatric Blood and Marrow Transplant, Duke University Medical Center, Durham, NC;
authors.forename: Paul L
authors.initials: PL
authors.lastname: Martin
authors.affiliation: Gastroenterology Division, University of Washington School of Medicine and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Gideon
authors.initials: G
authors.lastname: Steinbach
authors.affiliation: Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA;
authors.forename: Amrita
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Pediatric Bone Marrow Transplant Program, Oregon Health and Science University, Portland, OR;
authors.forename: Eneida R
authors.initials: ER
authors.lastname: Nemecek
authors.affiliation: Adult Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Sergio
authors.initials: S
authors.lastname: Giralt
authors.affiliation: Hematology/Oncology, Loyola University Medical Center, Chicago, IL;
authors.forename: Tulio
authors.initials: T
authors.lastname: Rodriguez
authors.affiliation: Stem Cell Transplant Program, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL;
authors.forename: Reggie
authors.initials: R
authors.lastname: Duerst
authors.affiliation: Pediatric Hematology/Oncology, CancerCare Manitoba and the University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: John
authors.initials: J
authors.lastname: Doyle
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;
authors.forename: Angela
authors.initials: A
authors.lastname: Smith
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Hematology/Oncology, Children's Hospital, Boston, MA;
authors.forename: Leslie
authors.initials: L
authors.lastname: Lehmann
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, The University of Texas, Houston, TX;
authors.forename: Richard
authors.initials: R
authors.lastname: Champlin
authors.affiliation: Department of Pediatrics, Hackensack University Medical Center, Hackensack, NJ;
authors.forename: Alfred
authors.initials: A
authors.lastname: Gillio
authors.affiliation: Department of Hematology/Oncology/BMT, The Ohio State University/Nationwide Children's Hospital, Columbus, OH;
authors.forename: Rajinder
authors.initials: R
authors.lastname: Bajwa
authors.affiliation: Department of Mathematics and Statistics, Boston University, Boston, MA;
authors.forename: Ralph B
authors.initials: RB
authors.lastname: D'Agostino
authors.affiliation: Department of Mathematics and Statistics, Boston University, Boston, MA;
authors.forename: Joseph
authors.initials: J
authors.lastname: Massaro
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Diane
authors.initials: D
authors.lastname: Warren
authors.affiliation: Biostatistics, Jazz Pharmaceuticals, Palo Alto, CA;
authors.forename: Maja
authors.initials: M
authors.lastname: Miloslavsky
authors.affiliation: Regulatory Affairs, Jazz Pharmaceuticals, Palo Alto, CA;
authors.forename: Robin L
authors.initials: RL
authors.lastname: Hume
authors.affiliation: Life Sciences, Techitra Srl, Milano, Italy;
authors.forename: Massimo
authors.initials: M
authors.lastname: Iacobelli
authors.affiliation: Research and Clinical Development, Galena Biopharma, San Ramon, CA; and.
authors.forename: Bijan
authors.initials: B
authors.lastname: Nejadnik
authors.affiliation: Clinical Operations, Jazz Pharmaceuticals, Palo Alto, CA.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006504:Hepatic Veno-Occlusive Disease / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology / Q000209:etiology; D011089:Polydeoxyribonucleotides / Q000627:therapeutic use*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide
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