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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-04-1216.
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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4337-4343
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Multi-institutional use of defibrotide in 88 patients after stem
cell transplantation with severe veno-occlusive disease and multisystem
organ failure: response without significant toxicity in a high-risk
population and factors predictive of outcome
Paul G. Richardson,
Carol Murakami,
Zhezhen Jin,
Diane Warren,
Parisa Momtaz,
Deborah Hoppensteadt,
Anthony D. Elias,
Joseph H. Antin,
Robert Soiffer,
Thomas Spitzer,
David Avigan,
Scott I. Bearman,
Paul L. Martin,
Joanne Kurtzberg,
James Vredenburgh,
Allen R. Chen,
Sally Arai,
Georgia Vogelsang,
George B. McDonald, and
Eva C. Guinan
From the Departments of Adult and Pediatric Oncology,
Dana-Farber Cancer Institute and Brigham and Woman's Hospital, and
Children's Hospital, The Division of Hematology/Oncology,
Massachusetts General Hospital, Beth Israel Hospital, Harvard Medical
School, Boston, MA; Columbia University, New York, NY; Loyola
University Medical Center, Chicago, IL; University of Colorado Health
Center, Denver; Duke University Medical Center, Durham, NC; Johns
Hopkins Oncology Center, Baltimore, MD; and the Fred Hutchinson Cancer
Research Center, Seattle, WA.
Veno-occlusive disease (VOD) is the most common regimen-related
toxicity accompanying stem cell transplantation (SCT). Severe VOD complicated by multisystem organ failure (MOF) remains almost uniformly fatal. Preliminary experience with defibrotide (DF), a
single-stranded polydeoxyribonucleotide with fibrinolytic,
antithrombotic, and anti-ischemic properties, in the treatment for
severe VOD has suggested safety and activity. Eighty-eight patients who
developed severe VOD after SCT were treated with DF under a defined
treatment plan. At diagnosis, median bilirubin was 76.95 µM
(4.5 mg/dL), median weight gain was 7%, ascites was present in 84%,
and abnormal hepatic portal venous flow was present in 35%. At
DF initiation, median bilirubin had increased to 215.46 µM (12.6 mg/dL), and MOF was present in 97%. DF was administered intravenously
in doses ranging from 5 to 60 mg/kg per day for a median of 15 days. No severe hemorrhage or other serious toxicity related to DF was reported.
Complete resolution of VOD was seen in 36%, with 35% survival at day
+100. Predictors of survival included younger age, autologous SCT, and
abnormal portal flow, whereas busulfan-based conditioning and
encephalopathy predicted worse outcome. Decreases in mean creatinine
and plasminogen activator inhibitor 1(PAI-1) levels during DF therapy
predicted better survival. The complete response rate, survival to day
+100, and absence of significant DF-associated toxicity in this largest
patient cohort reported to date confirm the results of earlier studies.
Certain features associated with successful outcome may correlate with
DF-related treatment effects, and prospective evaluation of DF therapy
for severe VOD should allow better definition of predictors of response or failure.
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