Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.

Autor:	Richardson PG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;, Riches ML; 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;, Kernan NA; Pediatric Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY;, Brochstein JA; Department of Pediatrics, Stem Cell Transplant Program, Cohen Children's Medical Center, New Hyde Park, NY;, Mineishi S; Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL;, Termuhlen AM; Division of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, CA;, Arai S; Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, CA;, Grupp SA; Pediatric Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA;, Guinan EC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Hematology/Oncology, Children's Hospital, Boston, MA;, Martin PL; Division of Pediatric Blood and Marrow Transplant, Duke University Medical Center, Durham, NC;, Steinbach G; Gastroenterology Division, University of Washington School of Medicine and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;, Krishnan A; Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA;, Nemecek ER; Pediatric Bone Marrow Transplant Program, Oregon Health and Science University, Portland, OR;, Giralt S; Adult Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY;, Rodriguez T; Hematology/Oncology, Loyola University Medical Center, Chicago, IL;, Duerst R; Stem Cell Transplant Program, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL;, Doyle J; Pediatric Hematology/Oncology, CancerCare Manitoba and the University of Manitoba, Winnipeg, Manitoba, Canada;, Antin JH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;, Smith A; Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN;, Lehmann L; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Hematology/Oncology, Children's Hospital, Boston, MA;, Champlin R; Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, The University of Texas, Houston, TX;, Gillio A; Department of Pediatrics, Hackensack University Medical Center, Hackensack, NJ;, Bajwa R; Department of Hematology/Oncology/BMT, The Ohio State University/Nationwide Children's Hospital, Columbus, OH;, D'Agostino RB Sr; Department of Mathematics and Statistics, Boston University, Boston, MA;, Massaro J; Department of Mathematics and Statistics, Boston University, Boston, MA;, Warren D; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;, Miloslavsky M; Biostatistics, Jazz Pharmaceuticals, Palo Alto, CA;, Hume RL; Regulatory Affairs, Jazz Pharmaceuticals, Palo Alto, CA;, Iacobelli M; Life Sciences, Techitra Srl, Milano, Italy;, Nejadnik B; Research and Clinical Development, Galena Biopharma, San Ramon, CA; and., Hannah AL; Clinical Operations, Jazz Pharmaceuticals, Palo Alto, CA., Soiffer RJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2016 Mar 31; Vol. 127 (13), pp. 1656-65. Date of Electronic Publication: 2016 Jan 29.
DOI:	10.1182/blood-2015-10-676924
Abstrakt:	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 #. (© 2016 by The American Society of Hematology.)
Databáze:	MEDLINE
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