|
|
 Previous Article | Table of Contents | Next Article 
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
By
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.
 |
ABSTRACT |
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.
| |
INTRODUCTION |
REGIMEN-RELATED TOXICITY (RRT)
constitutes a barrier to successful allogeneic (allo) and autologous
(auto) hematopoietic stem cell transplantation (SCT).1
Perhaps the most common life-threatening RRT is hepatic veno-occlusive
disease (VOD), a clinical syndrome characterized by painful
hepatomegaly, jaundice, ascites, and fluid retention manifested by
otherwise unexplained weight gain.2-6 VOD develops in 10%
to 60% of patients after SCT, and ranges in severity from mild,
reversible disease to a severe syndrome associated with multiorgan
failure and death.2-4,7,8 Established severe VOD has been
estimated as having a mortality rate approaching 100% by day +100
post-SCT.2,3,6,8 VOD is thought to be caused by injury
first to the area surrounding the central veins where damage is seen in
sinusoidal endothelial cells and hepatocytes in zone 3 of the liver
acinus.2,9-11 Early pathologic changes include deposition
of fibrinogen and factor VIII within venular walls and liver
sinusoids.9 Progressive venular occlusion contributes to
the structural damage in zone 3 of the acinus and ultimately widespread
zonal liver disruption becomes manifest as VOD.2,11 Later
pathologic changes include deposition of collagen in the sinusoids,
sclerosis of venular walls, and fibrosis of venular lumens.9 Throughout, a procoagulant state is present with
low plasma levels of antithrombin III (AT III) and protein C,
consumption of factor VII, and increased levels of plasminogen
activator inhibitor 1 (PAI-1).4,12-15 In addition,
increased levels of vWF multimers and refractoriness to platelet
transfusions are seen in VOD, suggesting further activation of the
coagulation cascade with ongoing endothelial cell injury.12
Hepatocellular necrosis and vascular occlusion lead to hepatorenal
physiology, liver failure, multiorgan dysfunction (MOD), and death.
Although the pathophysiology is complex and remains incompletely
understood, antithrombotic and thrombolytic agents, including prostaglandin E1 and t-PA with or without concurrent heparin, have been
evaluated for the treatment of VOD.4,16,17 However, these
approaches have been limited by significant toxicity, including fatal
hemorrhage.4,16,18 In addition, efficacy itself has been
difficult to establish and as a result no therapies for VOD have been
evaluated in a prospective, randomized fashion. A search for an agent
having demonstrable antithrombotic properties but with little evidence
of increased bleeding associated with its use was therefore undertaken.
Defibrotide (DF), a large, single-stranded polydeoxyribonucleotide, has
such a profile.19 It is derived from mammalian tissue
(porcine mucosa) by controlled depolymerization and has been found to
have antithrombotic, anti-ischemic, anti-inflammatory, and thrombolytic
properties without significant systemic anti-coagulant effects.19 DF has a complex mechanism of
action.19,20 It is an adenosine receptor agonist with
affinity for receptors A1 and A2, apparently via aptameric activity
which results in thrombin antagonism in vitro.21,22 DF also
increases levels of endogenous prostaglandins (PGI2 and E2), reduces
levels of leukotriene B4, inhibits monocyte superoxide anion
generation, stimulates expression of thrombomodulin in human vascular
endothelial cells, modulates platelet activity, and stimulates
fibrinolysis by increasing endogenous t-PA function while decreasing
activity of PAI-1.23-27 DF is avidly bound to vascular
endothelium, has a relatively short circulating half-life ranging from
10 to 30 minutes with intravenous (IV) administration, and can be given
orally or parenterally.19 It has been studied in a number
of vascular disorders, including peripheral vascular disease,
microvascular thrombotic states, and chemotherapy-related hemolytic
uremic syndrome (HUS).28-30 An active dose range from 400 mg/d to 5.6 g/d has been described in various clinical
settings.31 DF appears to be well tolerated; adverse events
are mild, range in incidence from 1% to 9%, and include flushing,
transient mild systolic hypotension, nausea, and abdominal
discomfort.19
This relative lack of systemic anticoagulant activity coupled with its
potential for ameliorating diverse manifestations of vascular injury
suggested that DF might have a therapeutic advantage over other
available treatments in SCT patients at high risk of hemorrhage. This
hypothesis led to the investigation of the feasibility of using DF in
the treatment of severe VOD.
| |
MATERIALS AND METHODS |
Patient selection.
From March 1995 through August 1997, 23 patients with severe VOD were
treated with DF (Crinos SpA, Como, Italy) on a compassionate-use basis
and assigned sequential unique patient numbers (UPN). On retrospective
review, 19 patients were treated and observed in a comparable fashion
and are reported here. Insufficiently detailed data were available from
the treating centers of 3 patients, rendering them inevaluable. These 3 patients (UPN 10, 13, 20) were treated for 4, 12, and 21 days,
respectively, and no attributable toxicity was noted. One patient
appeared to respond while 2 patients appeared to have progressive
disease. A fourth patient (UPN 11) received concurrent low-dose heparin
during the first 6 days of DF, making that patient also inevaluable.
Although treatment with two agents makes attribution of both efficacy
and toxicity unclear, the patient was neither responsive nor had
apparent toxicity attributable to either treatment.
Patients were eligible for consideration if they were undergoing SCT
and the referrring physicians had made a clinical diagnosis of VOD
based on jaundice (bilirubin > 2.0 mg/dL) and two of the following:
hepatomegaly and/or right upper quadrant pain, ascites, or
greater than 5% weight gain above admission weight. Patients who did
not meet the above criteria but had a liver biopsy confirming the
diagnosis were also eligible. In addition, patients within the 16-day
window defined by the Bearman model were required to have a predicted
risk of 40% or more of severe VOD.8 Patients not formally
addressed by the Bearman model (ie, onset of VOD beyond day + 16) were
considered eligible for treatment if VOD constituted their major
clinical problem. Patients with concurrent, confounding causes of liver
dysfunction such as graft-versus-host disease or inconsistent findings
evident on ultrasound imaging required biopsy-proven VOD to be
considered eligible. Patients must have failed prior treatment with
t-PA and heparin (n = 7) based on progressive rise in bilirubin
and/or MOD, or they had to be considered inappropriate for such
treatment on the basis of risk for excessive bleeding (n = 12).
Patients with significant uncontrolled bleeding or hemodynamic
instability were excluded. Patients who had received t-PA had a minimum
3-day interval before DF was initiated. Heparin was discontinued at
least 6 hours before DF initiation. Concurrent therapy with warfarin or
nonsteroidal anti-inflammatory drugs was prohibited. Patients or their
parents/guardians or designated proxy gave voluntary informed consent
and in each case Institutional Review Board approval was
obtained per the guidelines of each participating institution. The US
Food and Drug Administration approved the use of DF in each case per
its compassionate-use guidelines.
Laboratory and clinical evaluation.
In addition to history and physical examination, each patient was
followed with abdominal ultrasound scans and serial laboratory studies
including bilirubin, serum chemistries, complete blood count, and
differential, platelet count, prothrombin time (PT), partial
thromboplastin time (PTT), and fibrinogen. Time of onset of VOD was defined as the first day that retrospective chart review could confirm that the patient fulfilled the diagnostic criteria detailed above. Retrospective chart review was also used to determine if there was evidence of MOD at the time of treatment initiation. Patients were said to have MOD if there was documentation of
dysfunction of one other system in addition to the
liver.3,32 Renal dysfunction was defined as a doubling of
the admission creatinine or dialysis dependence; pulmonary dysfunction
was defined by the need for supplemental oxygen and/or
documentation of hypoxemia by arterial blood gas determination or
oxygen saturation by oximetry, or the need for mechanical ventilation,
and central nervous system dysfunction was defined by the attending
physician's documentation of confusion, lethargy, delirium,
and/or coma.
Treatment design.
DF was administered IV in normal saline (NS) in four divided doses each
infused over 2 hours, starting at an initial daily dose of 10 mg/kg.
Where possible, doses were rounded to the nearest 10 or 100 mg in
children and adults, respectively, to facilitate efficient drug
administration. Drug was mixed with a minimum of 100 mL of
NS to a maximum concentration of 400 mg/dL. DF was increased incrementally by 10 mg/kg every 24 to 48 hours to a maximum potential daily dose of 60 mg/kg depending on tolerance and response. In one
patient (UPN 07), DF was administered as a 200-mg bolus in NS followed
by continuous infusion at the same daily doses. For purposes of
continuation and dose escalation, tolerance was defined as the ability
to administer drug without adverse events attributable to DF, while
response was defined as clinical improvement with fluid mobilization,
decrease in bilirubin, reduction in hepatomegaly and/or right
upper quadrant (RUQ) pain, improvement in coagulopathy, and/or reduction in other end-organ dysfunction. DF was
discontinued or dose reduced if significant toxicity potentially
attributable to the drug was encountered. The planned treatment course
was for a minimum of 14 days. Treatment was discontinued before 14 days
only for death (7 patients) or patient request (1 patient). In 4 patients DF administration was interrupted for the performance of
diagnostic or therapeutic surgical procedures. One patient discontinued
DF at the end of the initial 14-day course while 10 patients continued
treatment. During therapy, wherever possible, platelets were kept
 20,000/µL, hematocrit (HCT) greater than 30% with
transfusion, PT less than 15 seconds, and fibrinogen greater than 150 mg/dL with factor replacement including fresh-frozen plasma and
cryoprecipitate. One patient (UPN 05) also received antithrombin III
(ATIII) concentrates for documented low ATIII levels
( 25%) during the last 7 days of her 15-day DF course. Treating physicians and care providers were made aware of known adverse
effects of DF, and patients were followed prospectively per
institutional practice for evidence of both potential adverse events
and response. Toxicities were graded according to the National Cancer
Institute common toxicity criteria. For purposes of evaluating efficacy
in this series, response was defined as evidence of improvement in
VOD-related symptoms and a concomitant or subsequent decrease in
bilirubin to less than 2 mg/dL.
Statistical analysis.
Association of patient characteristics with response to therapy was
assessed using the exact Wilcoxon signed rank test for continuous
variables and the Fisher exact test for categorical variables. Exact
binomial confidence intervals are provided for binary variables.
| |
RESULTS |
Retrospective review of the medical charts and laboratory values of 19 patients who received DF for treatment of VOD occurring after SCT was
undertaken. This review confirmed that all patients met the diagnostic
criteria for VOD and had evidence of severe disease as defined by the
model of Bearman et al8 for patients diagnosed before day
16 or by clinical course for those falling outside the bounds of this
model. The presence or absence of MOD, and designation of response or
nonresponse were determined according to the definitions in Materials
and Methods.
Patient characteristics.
Of the 19 patients, only 1 had a nonmalignant disorder, thalassemia
(Table 1). Thirteen had
underlying hematologic malignancies and 5 had solid tumors. Eleven
patients underwent autoSCT and 8 received allografts. All but 1 patient
received cyclophosphamide (CY) in the preparative regimen. In addition
to CY, 4 of the alloSCT group received total body irradiation (TBI)
while the other four, including two patients who had previously
undergone autoSCT, received busulfan (BU). None received additional
agents. Conditioning regimens were more diverse for the autoSCT
recipients. Most (9 of 11) received three agents in combination. In 6 patients the regimen included carmustine (BCNU). In the
remainder, the regimen included BU (n = 2), TBI (n = 2), and melphalan
(n = 1). All except the patient with thalassemia had received prior
chemotherapy. Fourteen patients had normal aspartate aminotransferase
(AST) on admission to the hospital.
Characterization of VOD.
The median day to onset of VOD was 12 days (range, 5 to 32)
(Table 2). Although the median time to
onset was equivalent in autoSCT and alloSCT recipients, all patients
with allogeneic donors had VOD diagnosed within the first 3 weeks while
3 of 11 autograft recipients had later onset (P = .23). The
most consistent clinical features were RUQ pain and ascites, which were
present in 17 and 18 patients, respectively. In 9 patients, ultrasound
reports before DF initiation commented on hepatomegaly and abnormal
portal flow by Doppler was noted in five. On the day that the patients
first fulfilled the clinical criteria for diagnosis of VOD, bilirubin ranged from 2.3 to 28.1 mg/dL (median, 8.3 mg/dL). Weight gain, on that
same day, ranged from  2.9% to 24.5% (median, 6.8%) of the
admission baseline weight. Histologic confirmation of the diagnosis was
made in 7 patients (UPNs 07, 15, 16, 17, 21, 22, 23) by needle biopsy
(1 percutaneous, 6 transjugular).
Patient status at the time of DF initiation.
Seven of the 19 patients had received a therapeutic trial of t-PA and
heparin (Table 3). None of these patients
had evidence of clinical response nor did they respond by the 50%
reduction in bilirubin criterion used in published trials of t-PA and
heparin.16,18 Patients began treatment with DF at a median
of 25 days after BMT (range, 10 to 58 days) and a median of 6 days
after the diagnosis of VOD was established (range, 0 to 47 days). At
the time that DF was initiated, the patients had a median bilirubin of
22.3 mg/dL (range, 11.7 to 54.4 mg/dL). Autograft recipients had a slightly higher median bilirubin at 24.3 mg/dL (range, 11.7 to 54.4 mg/dL) while allograft recipients had a median bilirubin of 18.5 mg/dL
(range, 14.4 to 39 mg/dL), although the difference was not
statistically significant. In all cases except one where treatment with
DF was initiated on the day VOD was diagnosed, there had been a
significant increase in bilirubin (median, 3.7-fold; range, 1.1 to 17)
since initial diagnosis. The weight of patients at DF initiation was
influenced by their interim fluid management, including dialysis,
aggressive attempts at diuresis, fluid restriction, and volume
expansion. In half the patients, the weight was greater than that at
the time at which VOD was diagnosed while the remaining half weighed
less. At the time that DF was initiated, all patients had MOD. Renal
insufficiency was observed in 12 patients, of whom 5 were dialysis
dependent. Requirement for supplemental oxygen was documented in 14 patients, including 2 who required mechanical ventilation. Central
nervous system dysfunction was documented in 8 patients.
Toxicity.
Mild or moderate (grade 1 or 2) toxicities documented during the course
of DF administration included nausea (n = 6), transient mild systolic
hypotension (n = 5), fever (n = 5), abdominal cramping (n = 3), and
vasomotor symptoms [eg, hot flashes] (n = 1). All patients were
thrombocytopenic, platelet transfusion and plasma product dependent,
and uremic at the time of DF initiation. Seventeen had evidence of mild
to moderate bleeding consisting principally of mucosal hemorrhage
before initiation of DF. With the initiation and administration of DF,
there was no worsening of clinical bleeding as measured by hemodynamic
instability, acute transfusion requirement, or end-organ compromise.
Most patients thus had evidence of persistent or intermittent grade 1 or 2 bleeding while on treatment (n = 17). Grade 3-4 adverse events
during therapy consisted of sepsis, n = 7; pulmonary edema, n = 5;
cytomegalovirus (CMV) infection, n = 2; hypotension, n = 2; respiratory
failure, n = 2; and single observations of diarrhea, bronchospasm,
alveolar hemorrhage, renal failure, gastrointestinal (GI) bleeding from
an open rectal ulcer, supraventricular arrhythmia, and encephalopathy.
The episode of alveolar hemorrhage was observed in a patient with
established CMV pneumonitis. This patient (UPN 16) also had the
bleeding rectal ulcer. Other than these events, no significant
hemorrhage in any other patient was seen. Because of their complex
medical status as described above, the etiology of their adverse events
was inherently difficult to characterize. In the 8 patients in whom DF
was withheld per DF treatment guidelines and subsequently restarted at
the equivalent or decreased dose, a causative temporal relationship to
any grade 3 or 4 toxicity with DF could not be shown.
Response.
Complete responses (CR) were observed in 8 patients (42%, 90%
confidence interval of 23% to 63%; Table
4). Neither the pretreatment variables of patient sex,
source of stem cells, conditioning regimen, and abnormal liver function
tests (LFTs) on admission nor the immediate VOD-related
characteristics of prior therapy with t-PA/heparin, time of onset,
presence of RUQ pain, ascites, hepatomegaly, bilirubin at onset, weight
gain, and abnormal portal flow were associated with response to
treatment at the 0.05 significance level. A higher proportion of
younger patients (age < 20 years) responded (4 of 6 v 4 of
13), but this also did not reach statistical significance (P = .32). Neither patient undergoing second SCT
(UPNs 06 and 17) responded.
Of the 8 responders, 6 not only had a decrease in bilirubin to less
than 2 mg/dL but also had complete resolution of any other significant
end-organ dysfunction. The remaining 2 responders resolved their VOD
but had persistence or occurrence of other end-organ toxicity during or
after treatment. In 1 (UPN 18) renal failure and uremic coagulopathy
persisted and contributed to death on day +68. In the other (UPN 14) a
Candida krusei and CMV pneumonia supervened, resulting in
intubation during DF administration and death on day +47. Because
escalating doses of DF were used on a compassionate basis and the cases
analyzed retrospectively, it is difficult to be definitive on the
timing and dose dependence of response. Response was noted in the first
4 days in 7 patients who went on to CR, with 1 where
response was noted more definitively at day 7. Evidence of
responsiveness was seen at doses less than 25 mg/kg/d in all 8 patients. The dose was subsequently escalated in 3 patients to 40 to 60 mg/kg/d, but a dose-response relationship was not obvious. Moreover, 3 of the 8 responders were dialysis dependent at the initiation of DF.
The requirement for dialysis resolved in 2 patients during treatment.
Eleven patients failed to meet the definition of response. One of these
patients (UPN 17) had apparent improvement after 11 days of DF but
subsequently elected to discontinue therapy. She subsequently died of
progressive VOD and MOD. The remaining patients were treated until they
had clear progression despite 14 days of therapy, had overwhelming
infectious complications, or died of progressive VOD with MOD. The
median survival of the nonresponding patients was 19 days (range, 4 to
59) from the diagnosis of VOD with deaths occurring a median of 36 days
(range, 15 to 89) after SCT. In contrast, only 3 responders have died
(Table 4) while 5 are alive, in remission, and remain well without any
known hepatic dysfunction at a median of 324 days (range, 217 to
1,046).
Pathology reports of pretreatment biopsy samples or autopsy materials
were available in 12 patients. Biopsy speciments obtained on 7 patients
before treatment were believed to be confirmatory of the diagnosis of
VOD by the pathologists of the treating institutions. Two of these 7 went on to have CR with DF therapy. The remaining 5, including UPN 17 who voluntarily discontinued DF, did not respond after receiving DF for
7 to 35 days (median, 11). Causes of death in this group of
nonresponders are listed in Table 4 and occurred on DF in 1 patient and
3 to 22 days after DF discontinuation in the remainder. Autopsies were
obtained in 6 patients, including UPN 18 who died of complications
related to her renal failure after demonstrating a clinical CR of her
VOD. She died 43 days after discontinuation of DF and no evidence of
established or active VOD was reported on autopsy. Postmortem pathology
on the 5 remaining patients, none of whom had clinical response to DF, was reported to show active, ongoing VOD in 3 (UPNs 05, 06, 07) while
no definitive evidence of VOD was noted in the other 2 (UPNs 03 and
12). UPN 03, who died of fungal sepsis, was reported to show evidence
of bile-duct epithelial damage and surrounding lymphocytes, interpreted
as possibly representing GVHD. A reticulin stain showed mild fibrosis
around central veins with mild septal fibrosis. In UPN 12, examination
of the liver disclosed hepatomegaly with centrilobular congestion and
sinusoidal damage, although the reported interpretation was that
pathognomonic findings of VOD were not present.
| |
DISCUSSION |
In this report we describe the outcome of administering DF to 19 patients with the clinical diagnosis of severe hepatic VOD occurring
after SCT. DF was obtained for compassionate use and administered in
escalating doses via IV infusion in doses ranging from 5 to 60 mg/kg/d.
Previously described toxicities of DF such as transient hypotension
during infusion were observed in some patients but were mild and did
not require interruption or discontinuation of treatment. The severe
adverse events experienced by patients receiving DF appeared to be
those commonly observed in patients in this clinical context and were
not directly attributable to DF administration. No life-threatening
hemorrhage during treatment was observed in this very high-risk
population. Eight (42%) patients had clinical resolution of their
severe VOD and improvement of other organ dysfunction. Six (32%)
survived past day +100, with five currently remaining alive and well
217 to 1,046 days post-SCT.
While up to half of patients undergoing SCT meet one of the current
definitions of VOD, there is a broad spectrum of clinical illness.2,3,6,7 This has made the interpretation of
prophylactic and therapeutic studies problematic. However, analyses of
symptom onset, symptom severity, and outcome have begun to define
populations that are likely to do particularly poorly.3,8
In addition, time to VOD diagnosis with concomitant degree of
hyperbilirubinemia and weight gain have been used to generate a model
that predicts probable severity and the likelihood of fatal
outcome.8 Overall, patients with mild or moderate disease
most often do well without any particular treatment and have a
predicted survival of 91% (mild VOD) and 77% (moderate VOD) at day
+100.3 In contrast, those with severe disease have an
expected survival of only 2% at day +100.3 All of the
patients in this case series meet the definition of severe VOD used to
generate this survival data. In addition, there has been considerable
interest in the area of MOD and survival after SCT.32,33
Patients with evidence of dysfunction in more than one organ have been
reported to have a much higher mortality rate than
others.1,3,32,33 Again, all of the patients receiving DF
had evidence of failure in at least one other system than the liver at
the time of DF initiation. Dialysis dependence alone, seen at DF
initiation in 5 of our patients (including 3 responders), has been
reported to be associated with an 84% mortality rate, whereas doubling
of the serum creatinine, seen in an additional 7 patients including 2 responders, has been associated with a 37% mortality
rate.34
The selection of DF as a novel approach was based on its unique
pharmacologic characteristics. DF represents one of a new class of
agents derived from nucleic acids with polyelectrolyte effects through
the presence of multiple phosphate groups and adenosine receptor
agonist properties from the stearic arrangement of its base
sequences.21 This polyfunctional pharmacology makes the
evaluation of measurable parameters of the drug's activity complex.
For example, as well as increasing the release of PGI2,35 PGE2,36 and decreasing levels of leukotriene B4 in whole
blood,37 it also appears to reduce the the production of
superoxide anions by neutrophils and monocytes through the inhibition
of calcium ion movement,25,38 it prevents
neutrophil-induced platelet activation via an effect on cathepsin
G,23 and corollary studies in solid organ transplantation
have shown improved graft survival with DF and synergy with
cyclosporine.39 Although DF does not produce systemic
anticoagulation or significant in vitro anticoagulant effects on blood,
both preclinical and clinical studies show profibrinolytic action,
decreased levels of endothelin and tissue factor with blunted vascular
smooth muscle contractile response, and increased levels of tissue
factor pathway inhibitor.20,24,40 Primate studies confirm
t-PA antigen increase and PAI-1 decrease in DF-treated animals.41 Although the pathogenesis of VOD remains
incompletely understood, in vitro, clinical and pathologic data support
the concept that damage to sinusoidal endothelium is at least a major contributor to the development of VOD.4,9,42 DF as a
modulator of endothelial cell injury may interrupt the progression of
the endothelial-based processes which contribute to the syndrome and therefore impact favorably on the course of the disease.
Current therapeutic approaches to established VOD occurring after SCT
are limited both in number and efficacy, and fraught with toxicity.
Patients are typically severely ill with confounding causes of their
MOD, making diagnosis, evaluation, and attribution of drug effects
problematic. Nonetheless, despite both advanced supportive care and a
variety of interventions, outcomes have uniformly resulted in high
death rates by day +100, usually from MOD and, frequently,
hemorrhage.18 Recognizing that the same difficulties in
attributing both response and toxicity exist in the series reported
here, the observed survival to beyond day +100 of a significant
fraction of patients with severe VOD and MOD is encouraging. In this
small, retrospectively analyzed experience of extremely sick patients,
it is not possible to be definitive about the attribution of
toxicities. However, the absence of significant hemorrhagic or
unexpected toxicity is compelling. The patient subgroups in this report
are too small to analyze for factors predicting response to DF, but it
is noteworthy that approximately equivalent rates of response were
observed in alloSCT and autoSCT recipients and in those conditioned for
SCT with either TBI, BU, or BCNU. We are conducting a larger,
prospective evaluation of DF in severe VOD. This study will better
define toxicity, efficacy, and patient characteristics predictive of
response or failure. Although this report does not address any
potential role of DF in prophylaxis, this area may also merit
investigation.
| |
FOOTNOTES |
Submitted February 11, 1998;
accepted May 7, 1998.
Supported in part by the National Cancer Institute, National Institutes
of Health, United States Public Health Service Grant Nos. 5PO1-CA
39542, P50 HL54785, PO1-AI 35225, and 5PO1-CA 38493; and the American
Cancer Society Grant No. ACS CDA 9674.
Address reprint requests to Paul G. Richardson, MD, Dana-Farber Cancer
Institute, 44 Binney St, Boston, MA 02115.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank Diurka Rodriguez, Jane Amendolare Foley, and Haven Fyfe for
their assistance in data management; our research pharmacists Caroline
Harvey, Margaret Stephan, Keith Belken, and Kathleen Benfell; and the
medical and nursing staff who cared for these patients and facilitated
their treatment. Finally, we express our appreciation to the patients
and families themselves.
| |
REFERENCES |
1.
Bearman SI,
Appelbaum FR,
Buckner CD,
Petersen FB,
Fisher LD,
Clift RA,
Thomas ED:
Regimen-related toxicity in patients undergoing bone marrow transplantation.
J Clin Oncol
6:1562,
1988[Abstract/Free Full Text]
2.
McDonald GB,
Sharma P,
Matthews DE,
Shulman HM,
Thomas ED:
Venocclusive disease of the liver after bone marrow transplantation: Diagnosis, incidence, and predisposing factors.
Hepatology
4:116,
1984[Medline]
[Order article via Infotrieve]
3.
McDonald GB,
Hinds MS,
Fisher LD,
Schoch HG,
Wolford JL,
Banaji M,
Hardin BJ,
Shulman HM,
Clift RA:
Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: A cohort study of 355 patients.
Ann Intern Med
118:255,
1993[Abstract/Free Full Text]
4.
Bearman SI:
The syndrome of hepatic veno-occlusive disease after marrow transplantation.
Blood
85:3005,
1995[Abstract/Free Full Text]
5.
Ayash LJ,
Hunt M,
Antman K,
Nadler L,
Wheeler C,
Takvorian T,
Elias A,
Antin JH,
Greenough T,
Eder JP:
Hepatic venocclusive disease in autologous bone marrow transplantation of solid tumors and lymphomas.
J Clin Oncol
8:1699,
1990[Abstract]
6.
Jones RJ,
Lee KSK,
Beschorner WE,
Vogel VG,
Grochow LB,
Braine HG,
Vogelsang GB,
Sensenbrenner LL,
Santos GW,
Saral R:
Venoocclusive disease of the liver following bone marrow transplantation.
Transplantation
44:778,
1987[Medline]
[Order article via Infotrieve]
7.
Blostein MD,
Paltiel OB,
Thibault A,
Rbka WB:
A comparison of clinical criteria for the diagnosis of veno-occlusive disease of the liver after bone marrow transplantation.
Bone Marrow Transplant
10:439,
1992[Medline]
[Order article via Infotrieve]
8.
Bearman SI,
Anderson GL,
Mori M,
Hinds MS,
Shulman HM,
McDonald GB:
Venoocclusive disease of the liver: Development of a model for predicting fatal outcome after marrow transplantation.
J Clin Oncol
11:1729,
1993[Abstract/Free Full Text]
9.
Shulman HM,
Gown AM,
Nugent DJ:
Hepatic veno-occlusive disease after bone marrow transplantation. Immunohistochemical identification of the material within occluded central venules.
Am J Pathol
127:549,
1987[Abstract]
10.
Rollins BJ:
Hepatic veno-occlusive disease.
Am J Med
81:297,
1986[Medline]
[Order article via Infotrieve]
11.
Shulman HM,
Fisher LB,
Schoch HG,
Kenne KW,
McDonald GB:
Venoocclusive disease of the liver after marrow transplantation: Histological correlates of clinical signs and symptoms.
Hepatology
19:1171,
1994[Medline]
[Order article via Infotrieve]
12.
Scrobohaci ML,
Drouet L,
Monem-Mansi A,
Devergie A,
Baudin B,
D'Agay MF,
Gluckman E:
Liver veno-occlusive disease after bone marrow transplantation changes in coagulation parameters and endothelial markers.
Thromb Res
63:509,
1991[Medline]
[Order article via Infotrieve]
13.
Salat C,
Holler E,
Reinhardt B,
Kolb HJ,
Seeber B,
Ledderose G,
Mittermueller J,
Duell T,
Wilmanns W,
Hiller E:
Parameters of the fibrinolytic system in patients undergoing BMT: Elevation of PAI-1 in veno-occlusive disease.
Bone Marrow Transplant
14:747,
1994[Medline]
[Order article via Infotrieve]
14.
Salat C,
Holler E,
Hans-Jochem K,
Brigitte R,
Pihusch R,
Wolfgang W,
Hiller E:
Plasminogen activator inhibitor-1 confirms the diagnosis of hepatic veno-occlusive disease in patients with hyperbilirubinemia after bone marrow transplant.
Blood
89:2184,
1997[Abstract/Free Full Text]
15.
Faioni EM,
Krachmalnicoff A,
Bearman SI,
Federici AB,
Decarli A,
Gianni AM,
McDonald GB,
Mannucci PM:
Naturally occuring anticoagulants and bone marrow transplantation: Plasma protein C predicts the development of venocclusive disease of the liver.
Blood
81:3458,
1993[Abstract/Free Full Text]
16.
Bearman SI,
Shuhart MC,
Hinds MS,
McDonald GB:
Recombinant human tissue plasminogen activator for the treatment of established severe venocclusive disease of the liver after bone marrow transplantation.
Blood
80:2458,
1992[Abstract/Free Full Text]
17. (suppl)
Ibrahim A,
Pico JL,
Maraninchi D,
Zambon E,
Attal M,
Brault P,
Tilly H,
Blaise D,
Hayat M:
Hepatic veno-occlusive disease following bone marrow transplantation treated by prostaglandin E1.
Bone Marrow Transplant
7:53,
1991
18.
Bearman SI,
Lee JL,
Baron AE,
McDonald GB:
Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients.
Blood
89:1501,
1997[Abstract/Free Full Text]
19.
Palmer KJ,
Goa KL:
Defibrotide: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders.
Drugs
45:259,
1993[Medline]
[Order article via Infotrieve]
20.
Pescador R,
Porta R,
Ferro L:
An integrated view of the activities of defibrotide.
Semin Thromb Hemost
22:71,
1996
21.
Bianchi G,
Barone D,
Lanzarotti E,
Tettamanti R,
Porta R,
Moltrasio D,
Cedro A,
Salvetti L,
Mantovani M,
Prino G:
Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist.
Eur J Pharmacol
238:327,
1993[Medline]
[Order article via Infotrieve]
22.
Bracht F,
Schror K:
Isolation and identification of aptamers from defibrotide that act as thrombin antagonists in vitro.
Biochem Biophys Res Commun
200:933,
1994[Medline]
[Order article via Infotrieve]
23.
Evangelista V,
Piccardoni P,
de Gaetano G,
Cerletti C:
Defibrotide inhibits platelets activation by cathepsin G relased from stimulated polymorphonuclear leukocytes.
Thromb Haemost
67:660,
1992[Medline]
[Order article via Infotrieve]
24.
Berti F,
Rossoni G,
Biasi G,
Buschi A,
Mandelli V:
Defibrotide by enhancing prostacyclin generation prevents endothelin-I induced contraction in human saphenous veins.
Prostaglandins
40:337,
1990[Medline]
[Order article via Infotrieve]
25.
Cirillo F,
Margaglione M,
Vecchione G,
Ames PRJ,
Coppola A,
Grandone E,
Cerbone AM,
Marelli C,
Di Minno G:
In vitro inhibition by defibrotide of monocyte superoxide anion generation. A possible mechansim for the antithrombotic effect of a polydeoxribonucleotide-derived drug.
Haemostasis
21:98,
1991[Medline]
[Order article via Infotrieve]
26.
Bacher P,
Kindel G,
Walenga JM,
Fareed J:
Modulation of endothelial and platelet function by a polydeoxyribonucleotide derived drug "defibrotide". A dual mechanism in the control of vascular pathology.
Thromb Res
70:343,
1993[Medline]
[Order article via Infotrieve]
27.
Zhou Q,
Chu X,
Ruan C:
Defibrotide stimulates expression of thrombomodulin in human endothelial cells.
Thromb Haemost
71:507,
1994[Medline]
[Order article via Infotrieve]
28. (letter)
Bonomini V,
Vangelista A,
Frasca GM:
A new antithrombotic agent in the treatment of acute renal failure due to hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura.
Nephron
37:144,
1984[Medline]
[Order article via Infotrieve]
29.
Bonomini V,
Frasca GM,
Raimondi C,
D'arcangelo GL,
Vangelista A:
Effect of a new antithrombotic agent (Defibrotide) in acute renal failure due to thrombotic microangiopathy.
Nephron
40:195,
1985[Medline]
[Order article via Infotrieve]
30.
Ulutin ON:
Antithrombotic effect and clinical potential of defibrotide.
Semin Thromb Hemost
19:186,
1993
31.
Coccheri S,
Biagi G:
Defibrotide.
Cardiovasc Drug Rev
9:172,
1991
32.
Haire WD,
Ruby EI,
Gordon BG,
Patil KD,
Stephens LC,
Kotulak GD,
Reed EC,
Vose JM,
Bierman PJ,
Kessinger A,
Armitage JO:
Multiple organ dysfunction syndrome in bone marrow transplantation.
JAMA
274:1289,
1995[Abstract/Free Full Text]
33.
Rubenfeld GD,
Crawford SW:
Withdrawing life support from mechanically ventilated recipients of bone marrow transplants: A case for evidence-based guidelines.
Ann Intern Med
125:625,
1996[Abstract/Free Full Text]
34.
Zager RA,
O'Quigley J,
Zager BK,
Alpers CE,
Shulman HM,
Gamelin LM,
Stewart P,
Thomas ED:
Acute renal failure following bone marrow transplantation: A retrospective study of 272 patients.
Am J Kid Dis
13:210,
1989[Medline]
[Order article via Infotrieve]
35.
Lobel P,
Schror K:
Selective stimulation of coronary vascular PGI2 but not of platelet thromboxane formation by defibrotide in the platelet perfused heart.
Arch Pharmacol
331:125,
1985
36.
Coccheri S,
Biagi G,
Legnani C,
Bianchini B,
Grauso F:
Acute effects of defibrotide, an experimental antithrombotic agent, on fibrinolysis and blood prostanoids in man.
Eur J Clin Pharmacol
35:151,
1988[Medline]
[Order article via Infotrieve]
37. Biagi G, Legnani C, Rodorigo G, Coccheri S: Modulation of
arachidonate metabolite generation in human blood by oral defibrotide.
Arzneimittelforschung/Drug Res 41:511, 1991
38. Di Perri T, Laghi-Pasini F, Ceccatelli L, Pasqui AL: Defibrotide
inhibits Ca2+ dependent neutrophil activiation: Implications for its
pharmacological activity in vascular disorders. Angiology-J Vasc Dis:
971, 1991
39.
Ferraresso M,
Rigotti P,
Stepkowski SM,
Chou T-C,
Kahan BD:
Immunosuppressive effects of defibrotide.
Transplantation
56:928,
1993[Medline]
[Order article via Infotrieve]
40.
Fareed J,
Callas DD,
Hoppensteadt D,
Jeske W,
Walenga JM:
Recent development in antithrombotic agents.
Exp Opin Invest Drugs
4:389,
1995
41.
Fareed J:
Modulation of endothelium by heparin and related polyelectrolytes
, in Nicolaides A,
Novo S
(eds):
Advances in Vascular Pathology 1997.
Amsterdam, The Netherlands, Elsevier Science BV
, 1997
42.
DeLeve LD:
Cellular target of cyclophosphamide toxicity in the murine liver: Role of glutathione and site of metabolic activation.
Hepatology
24:830,
1996[Medline]
[Order article via Infotrieve]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. S. Mitsiades, C. Rouleau, C. Echart, K. Menon, B. Teicher, M. Distaso, A. Palumbo, M. Boccadoro, K. C. Anderson, M. Iacobelli, et al.
Preclinical Studies in Support of Defibrotide for the Treatment of Multiple Myeloma and Other Neoplasias
Clin. Cancer Res.,
February 15, 2009;
15(4):
1210 - 1221.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Benimetskaya, S. Wu, A. M. Voskresenskiy, C. Echart, J.-F. Zhou, J. Shin, M. Iacobelli, P. Richardson, K. Ayyanar, and C. A. Stein
Angiogenesis alteration by defibrotide: implications for its mechanism of action in severe hepatic veno-occlusive disease
Blood,
November 15, 2008;
112(10):
4343 - 4352.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.C. MacQuillan and D. Mutimer
Fulminant liver failure due to severe veno-occlusive disease after haematopoietic cell transplantation: a depressing experience
QJM,
September 1, 2004;
97(9):
581 - 589.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J. Hogan, M. Maris, B. Storer, B. M. Sandmaier, D. G. Maloney, H. G. Schoch, A. E. Woolfrey, H. M. Shulman, R. Storb, and G. B. McDonald
Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients
Blood,
January 1, 2004;
103(1):
78 - 84.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Wadleigh, P. G. Richardson, D. Zahrieh, S. J. Lee, C. Cutler, V. Ho, E. P. Alyea, J. H. Antin, R. M. Stone, R. J. Soiffer, et al.
Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation
Blood,
September 1, 2003;
102(5):
1578 - 1582.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kumar, L. D. DeLeve, P. S. Kamath, and A. Tefferi
Hepatic Veno-occlusive Disease (Sinusoidal Obstruction Syndrome) After Hematopoietic Stem Cell Transplantation
Mayo Clin. Proc.,
May 1, 2003;
78(5):
589 - 598.
[Abstract]
[PDF]
|
|
|
|
|
|
|
P. G. Richardson, C. Murakami, Z. Jin, D. Warren, P. Momtaz, D. Hoppensteadt, A. D. Elias, J. H. Antin, R. Soiffer, T. Spitzer, et al.
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
Blood,
December 15, 2002;
100(13):
4337 - 4343.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ruutu, B. Eriksson, K. Remes, E. Juvonen, L. Volin, M. Remberger, T. Parkkali, H. Hagglund, and O. Ringden
Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation
Blood,
August 28, 2002;
100(6):
1977 - 1983.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. A. Tabbara, K. Zimmerman, C. Morgan, and Z. Nahleh
Allogeneic Hematopoietic Stem Cell Transplantation: Complications and Results
Arch Intern Med,
July 22, 2002;
162(14):
1558 - 1566.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Cella, A. Sbarai, G. Mazzaro, G. Motta, P. Carraro, G. M. Andreozzi, D. A. Hoppensteadt, and J. Fareed
Tissue Factor Pathway Inhibitor Release Induced by Defibrotide and Heparins
Clinical and Applied Thrombosis/Hemostasis,
July 1, 2001;
7(3):
225 - 228.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. MANDEL, E. J. MARK, and C. A. HALES
Pulmonary Veno-occlusive Disease
Am. J. Respir. Crit. Care Med.,
November 1, 2000;
162(5):
1964 - 1973.
[Full Text]
|
|
|
|
|
|
|
S. A. Grupp, J. W. Stern, N. Bunin, C. Nancarrow, A. A. Ross, M. Mogul, R. Adams, H. E. Grier, J. B. Gorlin, R. Shamberger, et al.
Tandem High-Dose Therapy in Rapid Sequence for Children With High-Risk Neuroblastoma
J. Clin. Oncol.,
July 1, 2000;
18(13):
2567 - 2575.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract