Hepatic Veno-Occlusive Disease After Hematopoietic Stem Cell Transplantation: Update on Deﬁbrotide and Other Current Investigational Therapies

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REVIEW Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on deﬁbrotide and other current investigational therapies

VT Ho, C Revta and PG Richardson

Department of Adult Oncology, Center for Hematologic Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Hepatic veno-occlusive disease (VOD), also known as Prognosis depends on the extent of hepatic injury, sinusoidal obstruction syndrome (SOS), remains one of liver dysfunction and presence of multiorgan failure the most serious and common complications after (MOF).2,3,6,7 Severe VOD is associated with an all-cause myeloablative hematopoietic stem cell transplantation mortality of over 90% by D þ 100 post-SCT.2,3,7 Standard (HSCT). Clinical diagnosis of hepatic VOD is based therapy for VOD in North America is supportive. Clinical on the clinical triad of (1)painful hepatomegaly, (2) trials using systemic anticoagulants or thrombolytics have hyperbilirubinemia and (3)unexplained fluid retention. been associated with excessive bleeding complications, and While milder cases usually resolve spontaneously, severe have not improved survival. Defibrotide (DF), a poly- VOD is associated with a grim prognosis. Defibrotide disperse oligonucleotide mixture that has protective effects (DF), a polydisperse mixture of single-stranded oligonu- on vascular endothelium, has demonstrated encouraging cleotide with antithrombotic and fibrinolytic effects on responses with little toxicity in multicenter phase I/II microvascular endothelium, has emerged as an effective trials.8–11 Recent studies have also demonstrated that DF is and safe therapy for patients with severe VOD. Multiple an effective agent for VOD prophylaxis after transplant- studies, including a recent large international multicenter ation in patients at high risk for this complication.12–14 phase II clinical trial, have demonstrated 30–60% complete remission rates with DF, even among patients with severe VOD and multiorgan failure. This article will review our current understanding of hepatic VOD, and Pathogenesis update the clinical trial experience with DF and other potential therapies for this feared transplant complication. Injury to sinusoidal endothelial cells and hepatocytes by Bone Marrow Transplantation (2008) 229–237; high-dose alkylating chemotherapy agents appear to be the 41, 15–18 doi:10.1038/sj.bmt.1705899; published online 12 November 2007 primary event in the pathogenesis of VOD. A number of Keywords: veno-occlusive disease; sinusoidal obstruction markers of endothelial injury and adhesion molecules are syndrome; defibrotide; SCT upregulated in patients with VOD. These include plasma thrombomodulin (TM), P- and E-selectins, tissue factor pathway inhibitor (TFPI), soluble tissue factor (sTF) and plasminogen activator inhibitor (PAI-1).19–23 Increased serum levels of PAI-1is both a diagnostic and prognostic Introduction marker for VOD.21–26 In vitro studies show that endothelial PAI-1production is triggered by transforming growth factor Hepatic veno-occlusive disease (VOD) is among a spectrum beta (TGF-b) released from activated platelets,27 and of organ injury syndromes that occurs after the high-dose elevated plasma TGF-b levels in patients pretransplant have chemotherapy employed with hematopoietic stem cell been associated with the development of hepatic VOD.28 transplantation.1 VOD incidence varies but generally Murine models have also demonstrated that decreased nitric occurs in about 10% of patients after allogeneic stem cell oxide (NO) production contributes to the development of transplantation employing myeloablative conditioning regi- VOD.29 It is noteworthy that NO is pivotal in the prevention mens.2–4 The incidence of VOD is lower after autologous of ischemic/reperfusion injury in the liver, and is a potent SCT and reduced intensity conditioning transplantation.3,5 suppressor of PAI-1production. 30 Tiplaxtinin, an active PAI-1inhibitor, has been shown to prevent hepatic venous injury in murine models, and PAI-1null ( À/À) knockout Correspondence: Dr VT Ho, Medical Oncology, Dana-Farber Cancer mice are protected against hepatic vein thrombosis mediated Institute, 44 Binney Street, D1B06, Boston, MA 02115, USA. 31 E-mail: [email protected] by chronic NO synthase inhibition. Received 20 September 2007; accepted 20 September 2007; published Based on recent studies suggesting that sinusoidal online 12 November 2007 endothelial cells are key initial sites of injury, especially in VOD after HSCT VT Ho et al 230 gemtuzumab ozogamicin (Mylotarg, Wyeth Pharmaceuti- VOD has been reported in patients receiving T cell-depleted cals, Philadelphia, PA, USA) associated VOD, the term grafts compared to calcineurin inhibitor plus methotrexate ‘sinusoidal obstruction syndrome’ (SOS) is sometimes used based regimens.49–51 The fact that the GVHD prophylaxis as an alternative to the established terminology of VOD.32 combination of sirolimus and tacrolimus is associated with Further clinico-pathologic validation of this concept is an increased incidence of thrombotic microangiopathy warranted because sinusoidal obstruction is not a promi- after transplant has raised some speculation as to whether nent early feature in all cases of human VOD. In the it would predispose to VOD as well.52,53 interim, a preferred terminology that has been coined is VOD/SOS.33

Defibrotide Risk factors for VOD DF, a polydisperse mixture of single-stranded oligonucleo- The incidence and severity of VOD can be influenced by tide with local antithrombotic, anti-ischemic and anti- differences in pretransplant patient characteristics, trans- inflammatory activity, has shown great promise as therapy plant conditioning regimens, GVHD prophylaxis regimens in severe VOD in clinical trials. DF appears to modulate and source of graft (allogeneic vs autologous).3,34–36 endothelial cell injury without enhancing systemic bleeding Recognized pretransplant risk factors for the development and protects sinusoidal endothelium without compromising of VOD include older transplant recipient age, poor the antitumor effects of cytotoxic therapy.54 DF binds to performance status, female gender, donor-recipient HLA vascular endothelium via adenosine receptors A1and A2, disparity, advanced malignancy, prior abdominal radia- which are part of the growing family of nucleotide tion, second myeloablative transplant, reduced pulmonary receptors involved in endothelial cell regulation and diffusion capacity (DLCO) and prior liver disease including response to injury.55,56 DF modulates platelet activity by elevated AST prior to conditioning or preexisting cirrho- increasing levels of endogenous prostaglandins (PGI-2 and sis.3,34,37,38 In the pediatric literature, younger age at E-2) and TM and promotes fibrinolysis via upregulation of transplant (o6.5 years) also appears to be a risk factor TFPI and tissue plasminogen activator (tPA).57–60 DF also for the development of hepatic VOD.39 decreases thrombin generation and reduces circulating The type and intensity of the transplant conditioning levels of PAI-1.57,61,62 Preclinical studies demonstrate that regimen is probably the greatest determining factor of risk DF has profibrinolytic activity and prevents fibrin deposi- for developing severe VOD. VOD risk increases with TBI tion with selective activity in small vessels. Studies using dose, radiation dose rate and dose of BU.3,6 A randomized human-derived endotoxin-damaged endothelium have study and a large IBMTR analysis have both shown a shown selective protective effects of DF for microvascular, higher incidence of VOD in patients receiving BU/CY but not macrovascular, endothelium.63,64 compared to cyclophosphamide and TBI (CY/TBI).35,40 High plasma levels of BU or the metabolites of cyclophosphamide are associated with an increased risk of Defibrotide as treatment of hepatic VOD VOD.18,41,42 VOD occurs less frequently when targeted A summary of reported studies using DF in the treatment BU dosing or intravenous BU (Busulfex, PDL BioPharma, of patients with VOD after SCT is presented in Table 1. Fremont, CA, USA) administration is employed.43,44 The first trial using DF in patients with VOD post-SCT was Metabolites of CY have also been implicated in the conducted in the United States from 1995 to 1997. In this development of VOD after SCT.18,42 However, a recent compassionate use study, DF was administered to 19 analysis in patients receiving targeted Bu/CY conditioning consecutive SCT patients with clinically established severe demonstrated striking interpatient variability in levels of VOD defined by 430% risk on the Bearman model and/or cyclophosphamide and its metabolites, and no correlation the presence of MOF.65 Patient age ranged from 4 to 58 between exposure of cyclophosphamide and its metabolites years (median 35), with 4 patients aged less than 18 years. to development of VOD.45 At the initiation of treatment, the median bilirubin was Prior exposure to gemtuzumab ozogamicin (Mylotarg) is 22.3 mg/dl. All had evidence of MOF, with encephalopathy increasingly recognized as a significant pretransplant risk in 8 patients, renal insufficiency in 12 (with 5 dialysis- factor for the development of severe VOD after SCT. In a dependent) and oxygen requirement, including ventilator retrospective analysis of 62 patients who received gemtu- dependence, in 14 patients. Ascites was present in all but zumab ozogamicin and subsequently underwent allogeneic one patient. Treatment with DF was initiated at a median myeloablative SCT, the incidence of VOD was 64%, and of 6 days after the diagnosis of VOD. DF was administered the risk of VOD was greatest among those patients who intravenously in doses ranging from 5 to 60 mg/kg per day had received gemtuzumab ozogamicin within 3.5 months of for a planned minimum course of 14 days. Response to DF SCT.46 Increased incidence of VOD in association with therapy was demonstrated by resolution of VOD (bilirubin gemtuzumab ozogamicin pre-SCT have also been reported o2 mg/dl with improvement in other VOD-related symp- in the pediatric literature,47 and in a recently published toms and signs) in 8/19 patients (42%) and 6/19 (32%) report from the Research on Adverse Drug Events and survived past D þ 100. Most importantly, this favorable Reports (RADAR) project.48 response and survival was seen in the absence of toxicity or GVHD prophylaxis regimens for allogeneic transplant- severe hemorrhage. In light of the historical data at the time ation also affect the risk of VOD. A low incidence of showing predicted 100-day survival of comparable patients

Bone Marrow Transplantation VOD after HSCT VT Ho et al 231 Table 1 Deﬁbrotide (DF) for the treatment of hepatic VOD

Author N DFdose (mg/kg/d) CR rate % D+100 survival (%) Patient characteristics

Richardson et al.65 19 5–60 42 32 High risk patients only: all had MOF Chopra et al.9 40 10–40 55 (overall) 36 (high risk) 43 28/40 patients considered high risk Richardson et al.66 88 10–60 36 35 All high risk by Bearman model or MOF Corbacioglu et al.11 45 10–110 76 (overall) 50 (high risk) 64 (overall) 36 (high risk) Pediatric. 22/45 patients considered high risk Bulley et al.67 14 11–40 64a 79 Pediatric only. Risk group not given Richardson et al.68 150 25 (Arm A) 40 (Arm B) 46 41 All high risk. 99% had MOF. No CR or OS difference b/w 2 doses

Abbreviations: CR ¼ complete remission, DF ¼ defibrotide, MOF ¼ multiorgan failure, OS ¼ overall survival, VOD ¼ veno-occlusive disease. aCR rate not reported, 9/14 (64%) discontinued DF due to clinical improvement. to be less than 10%, the observed response rate of 42 and evaluable for response: 65 patients achieved CR (46%) and 32% survival rate at D þ 100 were compelling. 62 survived to D þ 100 (41%), including patients with prior These favorable results were confirmed in a subsequent dialysis or ventilator dependence. No significant difference European compassionate use trial by Chopra et al.9 In this in CR and D þ 100 survival was found between the two study of 40 patients with established VOD treated with DF doses, although in pediatric patients receiving 25 mg/kg per in 19 European transplant centers, 22 (55%) achieved a day, CR and D þ 100 survival was superior at 67% complete response and 17 (43%) survived to D þ 100. (P ¼ 0.06). Toxicity was limited, but there was a statistically Among the 28 patients in this series who were considered to nonsignificant increase in attributable Grade 3/4 events, have severe VOD, characterized by the presence of MOF, including bleeding and hypotension, in patients getting the complete response rate after DF therapy was 36%. 40 mg/kg per day. Endothelial cell stress marker studies As an extension of the American compassionate use have shown a reduction in median levels of PAI-1and nitric study, eight US transplantation centers formed a working oxide, and an increase in Protein C in patients achieving group and enrolled 69 more patients following the original CR (Po0.05). In contrast, median serum TM, TFPI and eligibility criteria and treatment protocol. In this combined sTF levels increased in patients without response (Po0.05). cohort of 88 patients, 36% (32/88) of patients achieved CR Because no difference in efficacy was observed between the (95% confidence interval: 26 and 47%) and 35% (31/88) two dose levels, and there was a trend toward more toxicity survived beyond D þ 100 (95% CI: 25 and 46%).10 This with the higher dose, the lower dose of 25 mg/kg per day result is better than expected given the extremely compro- has been selected for future studies. A pivotal phase III trial mised condition of these patients, almost all of whom had using this dose DF as therapy for severe VOD is currently MOF. Importantly, in responding patients, no chronic liver underway at 36 transplant centers across North America dysfunction or recurrent VOD was reported during long- and Israel, using a historical control methodology. term follow-up. Continuous variables associated with Encouraging responses to DF have also been reported in better outcome in this study included mean decrease in the treatment of children with severe VOD. In a retro- creatinine and PAI-1levels during DF therapy. The spective analysis of 45 VOD patients aged 0.2–20 years observation that decreases in both actual and mean serum treated with DF, 34 (76%) achieved a complete response, creatinine predicted better outcome is interesting and may defined as resolution of VOD and MOF-related symptoms reflect the favorable renovascular effects associated with together with normalization of bilirubin to less than 2 mg/ DF treatment in other disease states.69 dl.11 The CR rate was 50% in the subset of 22 patients with To determine the effective dose of DF for use in future severe VOD. Interestingly, the authors reported that the studies of patients with severe VOD, a large multicenter, average DF dose in the CR patients were significantly prospective phase II randomized study has been recently higher than in the nonresponders: 45 vs 27 mg/kg per day, completed testing both 25 mg/kg per day (arm A) and and there was no apparent dose-related increase in toxicity. 40 mg/kg per day (arm B), and the final results were These results suggest that in children and adolescents, recently reported at the meeting of the American Society of higher doses of DF may be beneficial. In a more recent Hematology in 2006.68 The clinical diagnosis of VOD was Canadian single-center report of 14 children treated with defined by Baltimore criteria and severity was determined DF for VOD after SCT, 9 (60%) had resolution of VOD, by X30% risk on the Bearman model70 and/or the presence and the D þ 100 survival was 79%.67 of MOF. Treatment was planned for at least 14 days and patients receiving o3 days of therapy were inevaluable for response but were evaluable for toxicity and survival. A Defibrotide as prophylaxis for hepatic VOD total of 150 patients were treated, 75 on each arm and 99% Encouraging results with DF as treatment have also had evidence of MOF. Median duration of DF therapy was spawned interest into its use in the prophylaxis setting. 19 days (range 1–82). Of 150 patients treated, 141 were To date, the published literature on DF as VOD

Bone Marrow Transplantation VOD after HSCT VT Ho et al 232 Table 2 Deﬁbrotide (DF) as prophylaxis for Hepatic VOD

Author N DFDose/duration VOD incidence Historical control VOD Comment incidence

Chalandon et al.12 52 10–25 mg/kg/d(d0–20) 0/52 (0%) Baltimore criteria 10/52 (19%) Low-dose heparin 5–10 K IU per day IVCI concurrently with DF Dignan et al.14 58 10 mg/kg/d(d1–21) 0/58 (0%) Baltimore criteria N/A Majority 37/58 (64%) received reduced intensity regimen. 42/58 received Alemtuzumab in vivo as GVHD prophylaxis Corbacioglu et al.13 9 40 mg/kg/d(median) 1/9 (11%) Seattle criteria, 7/11 (63.6%) 3 severe, 4 All children receiving SCT for conditioning until D+30 moderate severity mild/moderate infantile osteopetrosis Versluys et al.71 5 10–20 mg/kg/d conditioning 0/5 (0%) N/A All pts received gentuzumab until D+30 ozogamicin within 2 months of SCT

Abbreviations: DF ¼ Deﬁbrotide; GVHD ¼ graft-versus-host disease; IU ¼ international unit; IVCI ¼ intravenous continous infusion; SCT ¼ stem cell transplantation; VOD ¼ veno-occlusive disease.

prophylaxis is restricted to smaller retrospectively con- a 50% reduction in pre-treatment bilirubin. However, trolled studies, as summarized in Table 2. In one series of overall survival was poor and no patients with MOF 52 allogeneic myeloablative PBSC/BMT patients given responded. Furthermore, 10 patients (24%) developed DF þ low-dose heparin as VOD prophylaxis, none (0%) severe bleeding attributable to tPA and a significant developed VOD (defined by Baltimore criteria) compared number proved fatal.73 Based on these results, the to 10 cases in historical control cohort of 52 patients who investigators concluded that tPA with or without heparin received heparin alone.12 Furthermore, the maximum level should not be administered as treatment in VOD patients of total bilirubin up to D þ 100 and the percentage of with MOF, and should only be considered as part of a patients with a total bilirubin 450 mmol/l were significantly clinical trial. lower in the DF-treated group. In a different series of 58 patients who received DF alone as VOD prophylaxis after Antithrombin III and prostaglandin E1 allogeneic SCT, no cases of VOD meeting the Baltimore Based on findings that antithrombin III (ATIII) confers a criteria were reported.14 However, approximately half of protective effect on vascular endothelium and ATIII levels the patients in this series actually received reduced intensity are decreased in patients with VOD, a number of trials and conditioning, and their risk for developing VOD was likely case studies have tested whether ATIII has activity in VOD to be lower at baseline, although, like the prior study, without causing bleeding diatheses.86–88 However, concor- comparison to historical control data in similar patient dant with prior studies in adults, a recent large pediatric cohorts was shown to be highly favorable. Encouraging transplant trial in which 91children received preemptive results with DF as VOD prophylaxis have also been ATIII replacement (ATIII given when plasma ATIII reported in a case series of high VOD risk transplant activity 70%) demonstrated that ATIII administration recipients previously exposed to gemtuzumab ozogami- p did not reduce the incidence of VOD compared to the cin,71 and in children transplanted for infantile osteo- control group of 71children who received no VOD petrosis.13 While the results of these various studies are prophylaxis.89 exciting, they must be interpreted with caution given their Prostaglandin E1(PGE1)is a vasodilator with a retrospective nature and limited sample size. Definitive cytoprotective effect on endothelium as well as being an conclusions regarding the efficacy of DF in the prophylaxis inhibitor of platelet aggregation with prothrombolytic setting should await the results of the prospective activity.90 Successful treatment of VOD using PGE1 randomized trials. combined with low-dose heparin was reported in one small pediatric series.91 Unfortunately, a larger prophylactic trial using PGE1was complicated by excessive toxicity and no Other therapeutic agents in VOD benefit.92 Until the results of larger prospective studies are Tissue plasminogen activator performed, use of either PGE1or ATIII in the prophylaxis Because micro-thromboses and fibrin deposition in hepatic or treatment setting for VOD cannot be endorsed outside central venules are hallmark features in VOD, many of the clinical trial setting. investigational efforts have focused around the use of systemic anticoagulants and more potent thrombolytics. There have been numerous reports in the literature of Low-dose heparin and low molecular weight heparins patients treated with tPA, with or without heparin, but only Anticoagulation with low-dose heparin by continuous a few series have included more than 10 patients (Table 3). infusion, alone or in combination with other agents, has In the largest of these studies involving 42 patients with been evaluated as VOD prophylaxis in a number of clinical established VOD treated with tPA and unfractionated trials. While a single randomized study reported a benefit heparin, 12 (29%) had a clinical improvement with at least for low-dose continuous heparin prophylaxis,93 other

Bone Marrow Transplantation VOD after HSCT VT Ho et al 233 Table 3 tPA for the treatment of hepatic VOD

Author (ref no.) N Dose (mg/d) Duration (days) Heparin (yes/no) Number of

Responses Life threatening hemorrhage

Baglin et al.72 150 4 No 1 0 Bearman et al.73 42 5.4–30 2–4 Yes 12 10 LaPorte et al.74 150 4 No 1 0 Rosti et al.75 150 4 No 1 0 Ringden et al.76 150 4 No 0 1 Leahey and Bunin77 9 5–10 2–4 Yes 5 0 Feldman et al.78 315 4 No3 0 Goldberg et al.79 120 4 Yes 1 0 Higashigawa et al.80 12–5 4 Yes a 10 Hagglund et al.81 10 3–50 3–8 Yesb 44 Lee et al.82 3 10–20 7–14 Yes 3 0 Yu et al.83 8 0.25–0.5c 4No40 Schriber et al.84 37 30–40 1–21 Yes 10d 13 Kulkarni et al.85 17 10 1–12 Yes 6 0

Abbreviations: tPA ¼ tissue plasminogen activator; VOD ¼ veno-occlusive disease. aPoint also received PGE1. b3 points received heparin, 7 points did not. cDose reported as mg kgÀ1. dIn points who met established criteria for VOD. uncontrolled studies have shown that low-dose heparin was the circulation has been reported to be successful in two ineffective and/or dangerous, primarily due to an increased patients,108 but larger studies evaluating this approach are risk of hemorrhage.3,94,95 Low-molecular-weight heparins needed. seem to be relatively safe and may have some effect in the prevention of VOD,82,96–100 but well-designed, multicenter randomized studies are needed to confirm these preliminary Future directions results. Despite the promise of emerging therapies such as DF, VOD remains a much feared transplant complication Ursodeoxycholic acid associated with dismal prognosis. Risk stratification of Ursodeoxycholic acid (UDCA), a hydrophilic nonhepato- patients before SCT will continue to be key for minimizing toxic bile acid, has been studied in a number of randomized severe VOD and improving transplant outcome. For placebo-controlled prospective trials as a prophylaxis for example, improved understanding of the risk factors for VOD. While two randomized trials, including a multicenter VOD will enable transplant physicians to offer patients at study from Japan, demonstrated a statistically benefit for high risk a reduced intensity conditioning regimen, or T-cell UDCA in patients at high risk of VOD,101–103 a larger depletion to minimize their risk for transplant mortality. randomized study by the Nordic Bone Marrow Transplan- For patients undergoing myeloablative SCT who are at tation group failed to show a significant reduction in VOD increased risk for VOD, use of UDCA may be reasonable incidence.104 However, the UDCA patients in this trial did since it is associated with reduced hepatic complications experience significantly fewer hepatic complications, espe- (specifically hepatic GVHD) and better survival after cially liver GVHD, and enjoyed improved overall survival SCT in a randomized trial,104 although its efficacy as a compared to the control arm. Taken together, these studies prophylaxis agent against VOD remains debatable. Tar- suggest a possible role for UDCA in the prevention of geted dosing of BU and pharmacokinetic monitoring of CY VOD and other hepatic complications after myeloablative and its metabolites could also be an effective method for allogeneic transplantation. reducing the risk of VOD. However, the feasibility of such a monitoring approach could be an issue among smaller Nonpharmacologic interventions in VOD transplant centers. Liver transplantation has led to clinical improvement of As PAI-1is now recognized to be associated with the some patients with VOD, but this approach is limited by pathogenesis of VOD, laboratory measurement of plasma the availability of organs, perioperative complications of PAI-1is coming into clinical practice. Serial monitoring of MOF, and liver graft rejection.105 Transjugular intrahepa- blood PAI-1levels peritransplant should offer a new tic porto-systemic shunts (TIPS) have also been tested as a diagnostic, and potential prognostic tool for this disease. therapeutic strategy to relieve portal hypertension in VOD Patients with rising PAI-1levels could potentially benefit patients after SCT. Available data suggest that while portal from earlier clinical intervention with agents such as hypertension and ascites improve after TIPS, long-term DF that could in turn curtail the development of severe efficacy and overall survival in VOD patients undergoing VOD/MOF. this procedure remain poor.106,107 Charcoal hemofiltration For patients who develop significant VOD, DF has intended to adsorb bilirubin and protein bound toxins from emerged as an effective and safe treatment option, whereas

Bone Marrow Transplantation VOD after HSCT VT Ho et al 234 previous clinical trials using systemic anticoagulants conditioning followed by allogeneic hematopoietic cell and thrombolytics, including heparin and tPA, have transplantation: a study of 193 patients. Blood 2004; 103: been fraught with bleeding complications and limited 78–84. efficacy. Multiple phase II studies in North America and 6 Bearman SI. The syndrome of hepatic veno-occlusive disease Europe have demonstrated consistent response rates and after marrow transplantation. Blood 1995; 85: 3005–3020. improved survival with DF, even among patients with 7 Pihusch R, Salat C, Schmidt E, Gohring P, Pihusch M, Hiller E et al. Hemostatic complications in bone marrow severe disease and advanced MOF. Results of the current transplantation: a retrospective analysis of 447 patients. North American/Israeli multicenter phase III trial will Transplantation 2002; 74: 1303–1309. hopefully confirm this drug’s efficacy in established VOD. 8 Richardson P, Bearman SI. Prevention and treatment of Future efforts to improve transplant outcomes should then hepatic venocclusive disease after high-dose cytoreductive focus on using DF prophylactically in the peritransplant therapy. Leuk Lymphoma 1998; 31: 267–277. period, especially for patients at high risk. Prophylactic 9 Chopra R, Eaton JD, Grassi A, Potter M, Shaw B, Salat C trials of DF in SCT patients at risk for VOD are already et al. Defibrotide for the treatment of hepatic veno-occlusive underway in Europe and are now planned for North disease: results of the European compassionate-use study. America. Br J Haematol 2000; 111: 1122–1129. Despite the encouraging responses observed with DF in 10 Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D et al. Multi-institutional use of defibrotide in clinical trials to date, there remains room for improvement 88 patients after stem cell transplantation with severe veno- both in terms of response rate and D þ 100 survival, occlusive disease and multisystem organ failure: response especially in severe disease. Efforts to enhance effective without significant toxicity in a high-risk population and therapy for VOD in the future are needed. As we better factors predictive of outcome. Blood 2002; 100: 4337–4343. understand the pathogenesis of VOD, newer therapies 11 Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, targeting different endothelial injury response and platelet Dilloo D et al. Defibrotide in the treatment of children with aggregation pathways can be used rationally in combina- veno-occlusive disease (VOD): a retrospective multicentre tion with DF to improve VOD outcome. For example, study demonstrates therapeutic efficacy upon early inter- agents such as tiplaxtinin that inhibit PAI-1, or phospho- vention. Bone Marrow Transplant 2004; 33: 189–195. diesterase-5 inhibitors which potentiate nitric oxide effects 12 Chalandon Y, Roosnek E, Mermillod B, Newton A, Ozsahin H, Wacker P et al. Prevention of veno-occlusive disease with on the vascular endothelium and reduce platelet aggrega- defibrotide after allogeneic stem cell transplantation. Biol tion may justify study in the clinical setting as part of a Blood Marrow Transplant 2004; 10: 347–354. combination approach. Other treatment strategies with 13 Corbacioglu S, Honig M, Lahr G, Stohr S, Berry G, Friedrich established safety profiles such as antithrombin III and N- W et al. Stem cell transplantation in children with infantile acetylcysteine may also be worthy of further investigation, osteopetrosis is associated with a high incidence of VOD, again likely best as part of combinations with DF. A which could be prevented with defibrotide. Bone Marrow similar approach in prophylaxis is warranted, including Transplant 2006; 38: 547–553. agents such as UDCA and perhaps low molecular weight 14 Dignan F, Gujral D, Ethell M, Evans S, Treleaven J, Morgan heparin, although for the latter, care regarding bleeding G et al. Prophylactic defibrotide in allogeneic stem cell risk remains a priority. transplantation: minimal morbidity and zero mortality from veno-occlusive disease. Bone Marrow Transplant 2007; 40: 79–82. 15 DeLeve LD, Kaplowitz N. Selective susceptibility of hepatic References endothelial cells to dacarbazine toxicity, a model for hepatic venoocclusive disease. Hepatology 1991; 14: 161A. 1Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, 16 DeLeve LD. Cellular target of cyclophosphamide toxicity in Fisher LD, Clift RA et al. Regimen-related toxicity in the murine liver: role of glutathione and site of metabolic patients undergoing bone marrow transplantation. J Clin activation. Hepatology 1996; 24: 830–837. Oncol 1988; 6: 1562–1568. 17 Hassan M, Ljungman P, Ringden O, Hassan Z, Oberg G, 2 McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford Nilsson C et al. The effect of busulphan on the pharmaco- JL, Banaji M et al. Veno-occlusive disease of the liver and kinetics of cyclophosphamide and its 4-hydroxy metabolite: multiorgan failure after bone marrow transplantation: a time interval influence on therapeutic efficacy and therapy- cohort study of 355 patients. Ann Intern Med 1993; 118: related toxicity. Bone Marrow Transplant 2000; 25: 915–924. 255–267. 18 de Jonge ME, Huitema AD, Beijnen JH, Rodenhuis S. High 3 Carreras E, Bertz H, Arcese W, Vernant JP, Tomas JF, exposures to bioactivated cyclophosphamide are related to Hagglund H et al. Incidence and outcome of hepatic veno- the occurrence of veno-occlusive disease of the liver following occlusive disease after blood or marrow transplantation: a high-dose chemotherapy. Br J Cancer 2006; 94: 1226–1230. prospective cohort study of the European Group for Blood 19 Salat C, Holler E, Reinhardt B, Kolb HJ, Seeber B, and Marrow Transplantation. European Group for Blood Ledderose G et al. Parameters of the fibrinolytic system in and Marrow Transplantation Chronic Leukemia Working patients undergoing BMT: elevation of PAI-1in veno- Party. Blood 1998; 92: 3599–3604. occlusive disease. Bone Marrow Transplant 1994; 14: 747–750. 4 Lee JL, Gooley T, Bensinger W, Schiffman K, McDonald 20 Richardson P, Krishnan A, Wheeler C, Hoppensteadt D, GB. Veno-occlusive disease of the liver after busulfan, Tuchin J, Fyfe H et al. Elevation of PAI-1levels in BMT- melphalan, and thiotepa conditioning therapy: incidence, risk associated VOD and changes seen with the use of defibrotide. factors, and outcome. Biol Blood Marrow Transplant 1999; 5: Blood 1996; 88: 458a. 306–315. 21Richardson P, Hoppensteadt D, Elias A, Frei III E, Iacobelli 5 Hogan WJ, Maris M, Storer B, Sandmaier BM, Maloney M, Guinan E et al. Elevation of tissue factor pathway DG, Schoch HG et al. Hepatic injury after nonmyeloablative inhibitor [TFPI], thrombomodulin [TM] and plasminogen

Bone Marrow Transplantation VOD after HSCT VT Ho et al 235 activator inhibitor-1[PAI-1]levels in stem cell transplant the liver after HLA-identical sibling allogeneic peripheral [SCT]-associated veno-occlusive disease [VOD] and changes blood stem cell transplantation. Exp Hematol 2003; 31: seen with the use of defibrotide [DF]. Blood 1997; 90: 219a. 545–550. 22 Richardson PG, Hoppensteadt D, Elias AD, Kinchla N, 37 Nevill TJ, Barnett MJ, Klingemann HG, Reece DE, Shepherd Warren D, Iacobelli M et al. Elevation of endothelial stress JD, Phillips GL. Regimen-related toxicity of a busulfan- products and trends seen in patients with severe veno- cyclophosphamide conditioning regimen in 70 patients occlusive disease treated with defibrotide. Thromb Hemost undergoing allogeneic bone marrow transplantation. J Clin 1999; 3185 (Suppl): 628. Oncol 1991; 9: 1224–1232. 23 Nurnberger W, Michelmann I, Burdach S, Gobel U. 38 Matute-Bello G, McDonald GD, Hinds MS, Schoch HG, Endothelial dysfunction after bone marrow transplantation: Crawford SW. Association of pulmonary function testing increase of soluble thrombomodulin and PAI-1in patients abnormalities and severe veno-occlusive disease of the liver with multiple transplant-related complications. Ann Hematol after marrow transplantation. Bone Marrow Transplant 1998; 1998; 76: 61–65. 21: 1125–1130. 24 Salat C, Holler E, Kolbe HJ, Brigitte R, Pihusch R, Wolfgang 39 Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello W et al. Plasminogen activator inhibitor-1confirms the G et al. A prospective survey on incidence, risk factors and diagnosis of hepatic veno-occlusive disease in patients with therapy of hepatic veno-occlusive disease in children after hyperbilirubinemia after bone marrow transplant. Blood hematopoietic stem cell transplantation. Haematologica 2005; 1997; 89: 2184–2188. 90: 1396–1404. 25 Lee JH, Lee KH, Kim S, Seol M, Park CJ, Chi HS et al. 40 Ringden O, Ruutu T, Remberger M, Nikoskelainer L, Volin Plasminogen activator inhibitor-1is an independent L, Vindelov T et al. A randomized trial comparing busulfan diagnostic marker as well as severity predictor of hepatic with total body irradiation as conditioning in allogeneic veno-occlusive disease after allogeneic bone marrow trans- marrow transplant recipients with leukemia: a report from the plantation in adults conditioned with busulphan and cyclo- Nordic Bone Marrow Transplantation Group. Blood 1994; phosphamide. Br J Haematol 2002; 118: 1087–1094. 83: 2723–2730. 26 Richardson P, Krishnan A, Wheeler C, Fyfe H, Hoppen- 41Copelan EA, Bechtel TP, Avalos BR, Elder PJ, Ezzone SA, steadt D, Fareed J et al. The use of defibrotide (DF) in BMT- Scholl MD et al. Busulfan levels are influenced by prior associated veno-occlusive disease (VOD) (Meeting abstract). treatment and are associated with hepatic veno-occlusive Proc Annu Meet Am Soc Clin Oncol 1996; 15: A13 1996. disease and early mortality but not with delayed complica- 27 Pihusch V, Pihusch M, Penovici M, Kolb HJ, Hiller E, tions following marrow transplantation. Bone Marrow Pihusch R. Transforming growth factor beta-1released from Transplant 2001; 27: 1121–1124. platelets contributes to hypercoagulability in veno-occlusive 42 McDonald GB, Slattery JT, Bouvier ME, Ren S, Batchelder disease following hematopoietic stem cell transplantation. AL, Kalhorn TF et al. Cyclophosphamide metabolism, liver Thromb Res 2005; 116: 233–240. toxicity, and mortality following hematopoietic stem cell 28 Anscher MS, Peters WP, Reisenbichler H, Petros WP, Jirtle transplantation. Blood 2003; 101: 2043–2048. RL. Transforming growth factor beta as a predictor of liver 43 Lee JH, Choi SJ, Kim SE, Park CJ, Chi HS, Lee MS et al. and lung fibrosis after autologous bone marrow transplant- Decreased incidence of hepatic veno-occlusive disease and ation for advanced breast cancer. N Engl J Med 1993; 328: fewer hemostatic derangements associated with intravenous 1592–1598. busulfan vs oral busulfan in adults conditioned with 29 DeLeve LD, Wang X, Kanel GC, Ito Y, Bethea NW, busulfan+cyclophosphamide for allogeneic bone marrow McCuskey MK et al. Decreased hepatic nitric oxide produc- transplantation. Ann Hematol 2005; 84: 321–330. tion contributes to the development of rat sinusoidal 44 Clopes A, Sureda A, Sierra J, Queralto JM, Broto A, Farre R obstruction syndrome. Hepatology 2003; 38: 900–908. et al. Absence of veno-occlusive disease in a cohort of 30 Kuroki I, Miyazaki T, Mizukami I, Matsumoto N, Matsu- multiple myeloma patients undergoing autologous stem moto I. Effect of sodium nitroprusside on ischemia-reperfu- cell transplantation with targeted busulfan dosage. Eur sion injuries of the rat liver. Hepatogastroenterology 2004; 51: J Haematol 2006; 77: 1–6. 1404–1407. 45 McCune JS, Batchelder A, Deeg HJ, Gooley T, Cole S, 31Smith LH, Dixon JD, Stringham JR, Eren M, Elokdah H, Phillips B et al. Cyclophosphamide following targeted oral Crandall DL et al. Pivotal role of PAI-1in a murine model of busulfan as conditioning for hematopoietic cell transplant- hepatic vein thrombosis. Blood 2006; 107: 132–134. ation: pharmacokinetics, liver toxicity, and mortality. Biol 32 DeLeve L, Shulman HM, McDonald GB. Toxic injury to Blood Marrow Transplant 2007; 13: 853–862. hepatic sinusoids: sinusoidal obstruction syndrome (veno- 46 Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, occlusive disease). Semin Liver Dis 2002; 22: 27–42. Ho V et al. Prior gemtuzumab ozogamicin exposure 33 Kumar S, DeLeve LD, Kamath PS, Tefferi A. Hepatic significantly increases the risk of veno-occlusive disease in veno-occlusive disease (sinusoidal obstruction syndrome) patients who undergo myeloablative allogeneic stem cell after hematopoietic stem cell transplantation. Mayo Clin transplantation. Blood 2003; 102: 1578–1582. Proc 2003; 78: 589–598. 47 Arceci RJ, Sande J, Lange B, Shannon K, Franklin J, 34 McDonald GB. Venocclusive disease of the liver following Hutchinson R et al. Safety and efficacy of gemtuzumab marrow transplantation. Marrow Transplant Rev 1993; 3: ozogamicin in pediatric patients with advanced CD33+ acute 49–56. myeloid leukemia. Blood 2005; 106: 1183–1188. 35 Rozman C, Carreras E, Qian C, Gale RP, Bortin MM, 48 McKoy JM, Angelotta C, Bennett CL, Tallman MS, Rowlings PA et al. Risk factors for hepatic veno-occlusive Wadleigh M, Evens AM et al. Gemtuzumab ozogamicin- disease following HLA-identical sibling bone marrow trans- associated sinusoidal obstructive syndrome (SOS): an over- plants for leukemia. Bone Marrow Transplant 1996; 17: view from the research on adverse drug events and reports 75–80. (RADAR) project. Leuk Res 2007; 31: 599–604. E-pub 7 36 Moscardo F, Urbano-Ispizua A, Sanz GF, Brunet S, September 2006. Caballero D, Vallejo C et al. Positive selection for CD34 49 Soiffer RJ, Dear K, Rabinowe SN, Anderson KC, Freedman reduces the incidence and severity of veno-occlusive disease of AS, Murray C et al. Hepatic dysfunction following T-cell-

Bone Marrow Transplantation VOD after HSCT VT Ho et al 236 depleted allogeneic bone marrow transplantation. Transplant- in 88 patients post stem cell transplant with severe veno- ation 1991; 52: 1014–1019. occlusive disease and multi-system organ failure; response 50 Moscardo F, Sanz GF, de La Rubia J, Jimenez C, Saavedra without significant toxicity in a high risk population and S, Regadera A et al. Marked reduction in the incidence of factors predictive of outcome. Blood 2002; 100: 4337–4343. hepatic veno-occlusive disease after allogeneic hematopoietic 67 Bulley SR, Strahm B, Doyle J, Dupuis LL. Defibrotide for the stem cell transplantation with CD34(+) positive selection. treatment of hepatic veno-occlusive disease in children. Bone Marrow Transplant 2001; 27: 983–988. Pediatr Blood Cancer 2007; 48: 700–704. 51Moscardo F, Urbano-Ispizua A, Sanz GF, Brunet S, 68 Richardson P, Soiffer R, Antin J, Jin Z, Kurtzberg J, Martin Caballero D, Vallejo C et al. Positive selection for CD34+ P et al. Defibrotide (DF) for the treatment of severe veno- reduces the incidence and severity of veno-occlusive disease of occlusive disease (sVOD) and multi-organ failure (MOF) post the liver after HLA-identical sibling allogeneic peripheral SCT: final results of a multi-center, randomized, dose-finding blood stem cell transplantation. Exp Hematol 2003; 31: trial. Blood 2006; 108: 178. 545–550. 69 Vangelista A, Frasca GM, Raimondi C, Liviano-D’Arcange- 52 Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB lo G, Bonomini V. Effects of defibrotide in acute renal failure et al. Sirolimus, tacrolimus, and low-dose methotrexate for due to thrombotic microangiopathy. Haemostasis 1986; 16 graft-versus-host disease prophylaxis in mismatched related (Suppl 1): 51–54. donor or unrelated donor transplantation. Blood 2003; 102: 70 Bearman SI, Anderson GL, Mori M, Hinds MS, Shulman 1601–1605. HM, McDonald GB. Venoocclusive disease of the liver: 53 Cutler C, Henry NL, Magee C, Li S, Kim HT, Alyea E et al. development of a model for predicting fatal outcome after Sirolimus and thrombotic microangiopathy after allogeneic marrow transplantation. J Clin Oncol 1993; 11: 1729–1736. hematopoietic stem cell transplantation. Biol Blood Marrow 71Versluys B, Bhattacharaya R, Steward C, Cornish J, Oakhill Transplant 2005; 11: 551–557. A, Goulden N. Prophylaxis with defibrotide prevents veno- 54 Eissner G, Multhoff G, Gerbitz A, Kirchner S, Bauer S, occlusive disease in stem cell transplantation after gemtuzu- Haffner S et al. Fludarabine induces apoptosis, activation, mab ozogamicin exposure. Blood 2004; 103: 1968; letter to and allogenicity in human endothelial and epithelial cells: editor. protective effect of defibrotide. Blood 2002; 100: 334–340. 72 Baglin TP, Harper P, Marcus RE. Veno-occlusive disease of 55 Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, the liver complicating ABMT successfully treated with Moltrasio D et al. Defibrotide, a single-stranded polydeox- recombinant tissue plasminogen activator (rt-PA). Bone yribonucleotide acting as an adenosine receptor agonist. Eur Marrow Transplant 1990; 5: 439–441. J Pharmacol 1993; 238: 327–334. 73 Bearman SI, Lee JL, Baron AE, McDonald GB. Treatment 56 Bracht F, Schror K. Isolation and identification of aptamers of hepatic venocclusive disease with recombinant human from defibrotide that act as thrombin antagonists in vitro. tissue plasminogen activator and heparin in 42 marrow Biochem Biophys Res Commun 1994; 200: 933–936. transplant patients. Blood 1997; 89: 1501–1506. 57 Coccheri S, Biagi G, Legnani C, Bianchini B, Grauso F. 74 Laporte JP, Lesage S, Tilleul P, Najman A, Gorin NC. Acute effects of defibrotide, an experimental antithrombotic Alteplase for hepatic veno-occlusive disease complicating agent, on fibrinolysis and blood prostanoids in man. Eur J bone-marrow transplantation [letter] [see comments]. Lancet Clin Pharmacol 1988; 35: 151–156. 1992; 339: 1057. 58 Berti F, Rossoni G, Biasi G, Buschi A, Mandelli V. 75 Rosti G, Bandini G, Belardinelli A, Calori E, Tura S, Defibrotide by enhancing prostacyclin generation prevents Gherlinzoni F et al. Alteplase for hepatic veno-occlusive endothelin-I induced contraction in human saphenous veins. disease after bone-marrow transplantation [letter; comment] Prostaglandins 1990; 40: 337–350. [see comments]. Lancet 1992; 339: 1481–1482. 59 Zhou Q, Chu X, Ruan C. Defibrotide stimulates expression of 76 Ringden O, Wennberg L, Ericzon BG, Kallman R, Astrom thrombomodulin in human endothelial cells. Thromb Hemost M, Duraj F et al. Alteplase for hepatic veno-occlusive disease 1994; 71: 507–510. after bone marrow transplantation [letter; comment]. Lancet 60 Fareed J. Modulation of endothelium by heparins and 1992; 340: 546–547. defibrotide. In: Nicolaides A, Novo S (eds). Advances in 77 Leahey AM, Bunin NJ. Recombinant human tissue plasmi- Vascular Pathology 1997. Elsevier Science B.V.: Amsterdam, nogen activator for the treatment of severe hepatic veno- 1997, pp 25–32. occlusive disease in pediatric bone marrow transplant 61Ulutin ON. Antithrombotic effect and clinical potential of patients. Bone Marrow Transplant 1996; 17: 1101–1104. defibrotide. Sem Thromb Hemost 1993; 19: 186–191. 78 Feldman L, Gabai E, Milovic V, Jaimovich G. Recombinant 62 Jamieson A, Alcock P, Tuffin DP. The action of polyanionic tissue plasminogen activator (rTPA) for hepatic veno- agents defibrotide and pentosan sulphate on fibrinolytic occlusive disease after allogeneic BMT in a pediatric patient. activity in the laboratory rat. Fibrinolysis 1996; 10: 27–35. 1995; 16: 727–731. 63 Falanga A, Marchetti M, Vignoli A, Barbui T. Defibrotide 79 Goldberg SL, Shubert J, Rao AK, Redei I, Klumpp TR, (DF) modulates tissue factor expression by microvascular Mangan KF. Treatment of hepatic veno-occlusive disease with endothelial cells. Blood 1999; 94: 146a. low-dose tissue plasminogen activator: impact on coagulation 64 Falanga A, Marchetti M, Vignoli A, Barbui T. Impact of profile. Bone Marrow Transplant 1996; 18: 633–636. defibrotide on the fibrinolytic and procoagulant properties of 80 Higashigawa M, Watanabe M, Nishihara H, Tabata N, endothelial cell macro- and micro-vessels. Blood 2000; 96: Azuma E, Ido M et al. Successful treatment of an infant with 53a. veno-occlusive disease developed after allogeneic bone 65 Richardson PG, Elias AD, Krishnan A, Wheeler C, Nath R, marrow transplantation by tissue plasminogen activator, Hoppensteadt D et al. Treatment of severe veno-occlusive heparin and prostaglandin E1. Leuk Res 1995; 19: 477–480. disease with defibrotide: compassionate use results in 81Hagglund H, Ringden O, Ljungman P. No beneficial effects, response without significant toxicity in a high-risk popula- but severe side effects caused by recombinant human tissue tion. Blood 1998; 92: 737–744. plasminogen activator for treatment of hepatic veno-occlusive 66 Richardson P, Murakami C, Jin Z, Warren D, Momtaz P, disease after allogeneic bone marrow transplantation. Trans- Hoppensteadt DA et al. Multi-institutional use of defibrotide plantation 1995; 27: 3535.

Bone Marrow Transplantation VOD after HSCT VT Ho et al 237 82 Lee JH, Lee KH, Choi JS, Zang DY, Kim SB, Kim SW et al. 96 Or R, Nagler A, Shpilberg O, Elad S, Naparstek E, Veno-occlusive disease (VOD) of the liver in Korean Kapelushnik J et al. Low molecular weight heparin for the patients following allogeneic bone marrow transplantation prevention of veno-occlusive disease of the liver in bone (BMT): efficacy of recombinant human tissue plasminogen marrow transplantation patients. Transplantation 1996; 61: activator (rt-PA) treatment. J Korean Med Sci 1996; 11: 1067–1071. 118–126. 97 Simon M, Hahn T, Ford LA, Anderson B, Swinnich D, 83 Yu LC, Malkani I, Regueira O, Ode DL, Warrier RP. Baer MR et al. Retrospective multivariate analysis of hepatic Recombinant tissue plasminogen activator (rt-PA) for veno-occlusive disease after blood or marrow transplantation: veno-occlusive liver disease in pediatric autologous bone possible beneficial use of low molecular weight heparin. Bone marrow transplant patients. Am J Hematol 1994; 46: 194–198. Marrow Transplant 2001; 27: 627–633. 84 Schriber J, Milk B, Shaw D, Christiansen N, Baer M, Slack J 98 Park SH, Lee MH, Lee H, Kim HS, Kim K, Kim WS et al. A et al. Tissue plasminogen activator (tPA) as therapy for randomized trial of heparin plus ursodiol vs heparin alone to hepatotoxicity following bone marrow transplantation. Bone prevent hepatic veno-occlusive disease after hematopoietic Marrow Transplant 1999; 24: 1311–1314. stem cell transplantation. Bone Marrow Transplant 2002; 29: 85 Kulkarni S, Rodriguez M, Lafuente A, Mateos P, Mehta J, 137–143. Singhal S et al. Recombinant tissue plasminogen activator 99 Forrest DL, Thompson K, Dorcas VG, Couban SH, Pierce (rtPA) for the treatment of hepatic veno-occlusive disease R. Low molecular weight heparin for the prevention of (VOD). Bone Marrow Transplant 1999; 23: 803–807. hepatic veno-occlusive disease (VOD) after hematopoietic 86 Morris JD, Harris RE, Hashmi R, Sambrano JE, Gruppo stem cell transplantation: a prospective phase II study. Bone RA, Becker AT et al. Antithrombin-III for the treatment of Marrow Transplant 2003; 31: 1143–1149. chemotherapy-induced organ dysfunction following bone 100 Forrest DL, Thompson K, Dorcas VG, Couban SH, Pierce marrow transplantation. Bone Marrow Transplant 1997; 20: R. Low molecular weight heparin for the prevention of veno- 871–878. occlusive disease (VOD) after hematopoietic stem cell 87 Mertens R, Brost H, Granzen B, Nowak-Gottl U. Anti- transplantation: a prospective phase II study. Bone Marrow thrombin treatment of severe hepatic veno-occlusive disease Transplant 2003; 31: 1143–1149. in children with cancer. Eur J Pediatr 1999; 158 (Suppl 3): 101 Ohashi K, Tanabe J, Watanabe R, Tanaka T, Sakamaki H, S154–S158. Maruta A et al. The Japanese multicenter open randomized 88 Ibrahim RB, Peres E, Dansey R, Abidi MH, Abella EM, trial of ursodeoxycholic acid prophylaxis for hepatic veno- Klein J. Anti-thrombin III in the management of hemato- occlusive disease after stem cell transplantation. Am J poietic stem-cell transplantation-associated toxicity. Ann Hematol 2000; 64: 32–38. Pharmacother 2004; 38: 1053–1059. 102 Essell JH, Thompson JM, Harman GS, Halvorson RD, 89 Haussmann U, Fischer J, Eber S, Scherer F, Seger R, Gungor Snyder MJ, Callander NS et al. Pilot trial of prophylactic T. Hepatic veno-occlusive disease in pediatric stem cell ursodiol to decrease the incidence of veno-occlusive disease of transplantation: impact of pre-emptive antithrombin III the liver in allogeneic bone marrow transplant patients. Bone replacement and combined antithrombin III/defibrotide Marrow Transplant 1992; 10: 367–372. therapy. Haematologica 2006; 91: 795–800. 103 Essell JH, Schroeder MT, Harman GS, Halvorson R, Lew V, 90 Vaughan DE, Plavin SR, Schafer AI, Loscalzo J. PGE1 Callander N et al. Ursodiol prophylaxis against hepatic accelerates thrombolysis by tissue plasminogen activator. complications of allogeneic bone marrow transplantation. A Blood 1989; 73: 1213–1217. randomized, double-blind, placebo-controlled trial. Ann 91Schlegel PG, Haber HP, Beck J, Krumpelmann S, Hand- Intern Med 1998; 128 (12 Part 1): 975–981. gretinger R, Bader P et al. Hepatic veno-occlusive disease in 104 Ruutu T, Eriksson B, Remes K, Juvonen E, Volin L, pediatric stem cell recipients: successful treatment with Remberger M et al. Ursodeoxycholic acid for the prevention continuous infusion of prostaglandin E1and low-dose of hepatic complications in allogeneic stem cell transplant- heparin. Ann Hematol 1998; 76: 37–41. ation. Blood 2002; 100: 1977–1983. 92 Bearman SI, Shen DD, Hinds MS, Hill HA, McDonald GB. 105 Schlitt HJ, Tischler HJ, Ringe B, Raddatz G, Maschek H, A phase I/II study of prostaglandin E1for the prevention of Dietrich H et al. Allogeneic liver transplantation for hepatic hepatic venocclusive disease after bone marrow transplant- veno-occlusive disease after bone marrow transplantation— ation. Br J Haematol 1993; 84: 724–730. clinical and immunological considerations. Bone Marrow 93 Attal M, Huguet F, Rubie H, Huynh A, Charlet JP, Payen JL Transplant 1995; 16: 473–478. et al. Prevention of hepatic veno-occlusive disease after 106 Smith FO, Johnson MS, Scherer LR et al. Transjugular bone marrow transplantation by continuous infusion of low- intrahepatic portosystemic shunting (TIPS) for the treatment dose heparin: a prospective, randomized trial. Blood 1992; 79: of severe hepatic veno-occlusive disease. Bone Marrow 2834–2840. Transplant 1996; 18: 643–646. 94 Bearman SI, Hinds MS, Wolford JL, Petersen FB, Nugent 107 Alvarez R, Banares R, Casariego J, Echenagusia A, Simo G, DL, Slichter SJ et al. A pilot study of continuous infusion Alvarez E et al. Percutaneous intrahepatic portosystemic heparin for the prevention of hepatic veno-occlusive disease shunting in the treatment of veno-occlusive disease of the liver after bone marrow transplantation. Bone Marrow Transplant after bone marrow transplantation. Gastroenterol Hepatol 1990; 5: 407–411. 2000; 23: 177–180. 95 Marsa-Vila L, Gorin NC, Laporte JP. Prophylactic heparin 108 Tefferi A, Kumar S, Wolf RC, Lacy MQ, Inwards DJ, Gloor does not prevent liver veno-occlusive disease following JM et al. Charcoal hemofiltration for hepatic veno-occlusive autologous bone marrow transplantation. Eur J Haematol disease after hematopoietic stem cell transplantation. Bone 1991; 47: 346–352. Marrow Transplant 2001; 28: 997–999.

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