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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 737-744
RAPID COMMUNICATION
Treatment of Severe Veno-Occlusive Disease With Defibrotide:
Compassionate Use Results in Response Without Significant Toxicity in a
High-Risk Population
Paul G. Richardson,
Anthony D. Elias,
Amrita Krishnan,
Catherine Wheeler,
Raj Nath,
Debra Hoppensteadt,
Nancy M. Kinchla,
Donna Neuberg,
Edmund K. Waller,
Joseph H. Antin,
Robert Soiffer,
James Vredenburgh,
Michael Lill,
Ann E. Woolfrey,
Scott I. Bearman,
Massimo Iacobelli,
Jawed Fareed, and
Eva C. Guinan
From the Departments of Adult and Pediatric Oncology, Dana-Farber
Cancer Institute, Brigham and Women's Hospital and Children's
Hospital, the Division of Hematology/Oncology, Beth Israel Hospital,
Boston, MA; Loyola University Medical Center, Chicago, IL; Emory
University Medical Center, Atlanta, GA; Western Pennsylvania Cancer
Institute, Pittsburgh; Duke University Medical Center, Durham, NC;
University of Colorado Health Center, Denver; the Division of
Hematology/Oncology, UCLA Medical Center, Los Angeles, CA; Fred
Hutchinson Cancer Research Center, Seattle, WA; and Crinos SpA, Como,
Italy.
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.
© 1998 by The American Society of Hematology.
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