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.
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 microM (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 microM (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.
Richardson
Paul G
PG
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. paul_richardson@dfci.harvard.edu
Murakami
Carol
C
Jin
Zhezhen
Z
Warren
Diane
D
Momtaz
Parisa
P
Hoppensteadt
Deborah
D
Elias
Anthony D
AD
Antin
Joseph H
JH
Soiffer
Robert
R
Spitzer
Thomas
T
Avigan
David
D
Bearman
Scott I
SI
Martin
Paul L
PL
Kurtzberg
Joanne
J
Vredenburgh
James
J
Chen
Allen R
AR
Arai
Sally
S
Vogelsang
Georgia
G
McDonald
George B
GB
Guinan
Eva C
EC
D000293:Adolescent; D000328:Adult; D001201:Ascites / Q000209:etiology / Q000401:mortality; D001663:Bilirubin / Q000097:blood; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000150:complications; D006504:Hepatic Veno-Occlusive Disease / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000209:etiology; D009369:Neoplasms / Q000150:complications / Q000628:therapy; D036102:Peripheral Blood Stem Cell Transplantation / Q000009:adverse effects*; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D019172:Transplantation Conditioning / Q000009:adverse effects; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D001663:Bilirubin