PMID- 26825712
OWN - NLM
STAT- MEDLINE
DCOM- 20160815
LR  - 20240325
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 127
IP  - 13
DP  - 2016 Mar 31
TI  - Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease 
      and multi-organ failure.
PG  - 1656-65
LID - 10.1182/blood-2015-10-676924 [doi]
AB  - 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 #.
CI  - (c) 2016 by The American Society of Hematology.
FAU - Richardson, Paul G
AU  - Richardson PG
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
FAU - Riches, Marcie L
AU  - Riches ML
AD  - 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;
FAU - Kernan, Nancy A
AU  - Kernan NA
AD  - Pediatric Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, 
      New York, NY;
FAU - Brochstein, Joel A
AU  - Brochstein JA
AD  - Department of Pediatrics, Stem Cell Transplant Program, Cohen Children's Medical 
      Center, New Hyde Park, NY;
FAU - Mineishi, Shin
AU  - Mineishi S
AD  - Division of Hematology and Oncology, University of Alabama at Birmingham, 
      Birmingham, AL;
FAU - Termuhlen, Amanda M
AU  - Termuhlen AM
AD  - Division of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, 
      Children's Hospital Los Angeles, Los Angeles, CA;
FAU - Arai, Sally
AU  - Arai S
AD  - Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, 
      CA;
FAU - Grupp, Stephan A
AU  - Grupp SA
AD  - Pediatric Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA;
FAU - Guinan, Eva C
AU  - Guinan EC
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 
      Department of Hematology/Oncology, Children's Hospital, Boston, MA;
FAU - Martin, Paul L
AU  - Martin PL
AD  - Division of Pediatric Blood and Marrow Transplant, Duke University Medical 
      Center, Durham, NC;
FAU - Steinbach, Gideon
AU  - Steinbach G
AD  - Gastroenterology Division, University of Washington School of Medicine and 
      Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
FAU - Krishnan, Amrita
AU  - Krishnan A
AD  - Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, 
      Duarte, CA;
FAU - Nemecek, Eneida R
AU  - Nemecek ER
AD  - Pediatric Bone Marrow Transplant Program, Oregon Health and Science University, 
      Portland, OR;
FAU - Giralt, Sergio
AU  - Giralt S
AD  - Adult Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New 
      York, NY;
FAU - Rodriguez, Tulio
AU  - Rodriguez T
AD  - Hematology/Oncology, Loyola University Medical Center, Chicago, IL;
FAU - Duerst, Reggie
AU  - Duerst R
AD  - Stem Cell Transplant Program, Ann and Robert H. Lurie Children's Hospital of 
      Chicago, Chicago, IL;
FAU - Doyle, John
AU  - Doyle J
AD  - Pediatric Hematology/Oncology, CancerCare Manitoba and the University of 
      Manitoba, Winnipeg, Manitoba, Canada;
FAU - Antin, Joseph H
AU  - Antin JH
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
FAU - Smith, Angela
AU  - Smith A
AD  - Division of Blood and Marrow Transplantation, University of Minnesota, 
      Minneapolis, MN;
FAU - Lehmann, Leslie
AU  - Lehmann L
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 
      Department of Hematology/Oncology, Children's Hospital, Boston, MA;
FAU - Champlin, Richard
AU  - Champlin R
AD  - Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer 
      Center, The University of Texas, Houston, TX;
FAU - Gillio, Alfred
AU  - Gillio A
AD  - Department of Pediatrics, Hackensack University Medical Center, Hackensack, NJ;
FAU - Bajwa, Rajinder
AU  - Bajwa R
AD  - Department of Hematology/Oncology/BMT, The Ohio State University/Nationwide 
      Children's Hospital, Columbus, OH;
FAU - D'Agostino, Ralph B Sr
AU  - D'Agostino RB Sr
AD  - Department of Mathematics and Statistics, Boston University, Boston, MA;
FAU - Massaro, Joseph
AU  - Massaro J
AD  - Department of Mathematics and Statistics, Boston University, Boston, MA;
FAU - Warren, Diane
AU  - Warren D
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
FAU - Miloslavsky, Maja
AU  - Miloslavsky M
AD  - Biostatistics, Jazz Pharmaceuticals, Palo Alto, CA;
FAU - Hume, Robin L
AU  - Hume RL
AD  - Regulatory Affairs, Jazz Pharmaceuticals, Palo Alto, CA;
FAU - Iacobelli, Massimo
AU  - Iacobelli M
AD  - Life Sciences, Techitra Srl, Milano, Italy;
FAU - Nejadnik, Bijan
AU  - Nejadnik B
AD  - Research and Clinical Development, Galena Biopharma, San Ramon, CA; and.
FAU - Hannah, Alison L
AU  - Hannah AL
AD  - Clinical Operations, Jazz Pharmaceuticals, Palo Alto, CA.
FAU - Soiffer, Robert J
AU  - Soiffer RJ
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
LA  - eng
SI  - ClinicalTrials.gov/NCT00358501
GR  - P01 CA023766/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160129
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Polydeoxyribonucleotides)
RN  - 438HCF2X0M (defibrotide)
SB  - IM
CIN - Blood. 2016 Mar 31;127(13):1630-1. PMID: 27034420
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Child
MH  - Child, Preschool
MH  - Cohort Studies
MH  - Female
MH  - Fibrinolytic Agents/*therapeutic use
MH  - Hepatic Veno-Occlusive Disease/complications/diagnosis/*drug therapy/epidemiology
MH  - Humans
MH  - Infant
MH  - Infant, Newborn
MH  - Male
MH  - Middle Aged
MH  - Multiple Organ Failure/diagnosis/*drug therapy/epidemiology/etiology
MH  - Polydeoxyribonucleotides/*therapeutic use
MH  - Severity of Illness Index
MH  - Young Adult
PMC - PMC4817309
EDAT- 2016/01/31 06:00
MHDA- 2016/08/16 06:00
PMCR- 2016/03/31
CRDT- 2016/01/31 06:00
PHST- 2015/10/21 00:00 [received]
PHST- 2016/01/22 00:00 [accepted]
PHST- 2016/01/31 06:00 [entrez]
PHST- 2016/01/31 06:00 [pubmed]
PHST- 2016/08/16 06:00 [medline]
PHST- 2016/03/31 00:00 [pmc-release]
AID - S0006-4971(20)30298-6 [pii]
AID - 2015/676924 [pii]
AID - 10.1182/blood-2015-10-676924 [doi]
PST - ppublish
SO  - Blood. 2016 Mar 31;127(13):1656-65. doi: 10.1182/blood-2015-10-676924. Epub 2016 
      Jan 29.