Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population.
Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation.
Richardson
P G
PG
Departments of Adult and Pediatric Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Children's Hospital, Boston, MA, USA.
Elias
A D
AD
Krishnan
A
A
Wheeler
C
C
Nath
R
R
Hoppensteadt
D
D
Kinchla
N M
NM
Neuberg
D
D
Waller
E K
EK
Antin
J H
JH
Soiffer
R
R
Vredenburgh
J
J
Lill
M
M
Woolfrey
A E
AE
Bearman
S I
SI
Iacobelli
M
M
Fareed
J
J
Guinan
E C
EC
D000293:Adolescent; D000328:Adult; D001663:Bilirubin / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004341:Drug Evaluation; D005240:Feasibility Studies; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000627:therapeutic use; D006504:Hepatic Veno-Occlusive Disease / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure / Q000517:prevention & control; D009369:Neoplasms / Q000401:mortality / Q000628:therapy; D010166:Palliative Care; D011089:Polydeoxyribonucleotides / Q000009:adverse effects / Q000627:therapeutic use*; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D012189:Retrospective Studies; D012306:Risk; D013789:Thalassemia / Q000628:therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; D018047:Receptors, Purinergic P1; C036901:defibrotide; D006493:Heparin; D010959:Tissue Plasminogen Activator; D001663:Bilirubin