Biology of Blood and Marrow Transplantation
Volume 16, Issue 2 , Pages 157-168, February 2010

Hepatic Veno-Occlusive Disease following Stem Cell Transplantation: Incidence, Clinical Course, and Outcome

  • Jason A. Coppell

      Affiliations

    • Department of Haematology, Royal Devon and Exeter Hospital, Exeter, UK
    • The first two authors contributed equally to this manuscript.
    • Corresponding Author InformationCorrespondence and reprint requests: Jason A. Coppell, MA, MRCP, FRCPath, Haematology Centre, Level 1 Area B, Royal Devon and Exeter Hospital, Barrack Road, Exeter, Devon, UK, EX2 5DW.
    • ,
  • Paul G. Richardson

      Affiliations

    • Dana-Farber Cancer Institute, Boston, Massachusetts
    • The first two authors contributed equally to this manuscript.
    • Corresponding Author InformationPaul G. Richardson, MD, FRCP, Division of Hematologic Malignancy, Dana-Farber Cancer Institute, Harvard Medical School, D1B30, 44 Binney Street, Boston, MA 02115.
    • ,
  • Robert Soiffer

      Affiliations

    • Dana-Farber Cancer Institute, Boston, Massachusetts
    • ,
  • Paul L. Martin

      Affiliations

    • Duke University Medical Center, Durham, North Carolina
    • ,
  • Nancy A. Kernan

      Affiliations

    • Memorial Sloan-Kettering Cancer Center, New York, New York
    • ,
  • Allen Chen

      Affiliations

    • Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
    • ,
  • Eva Guinan

      Affiliations

    • Dana-Farber Cancer Institute, Boston, Massachusetts
    • ,
  • Georgia Vogelsang

      Affiliations

    • Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
    • ,
  • Amrita Krishnan

      Affiliations

    • City of Hope Cancer Center, Duarte, California
    • ,
  • Sergio Giralt

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas
    • ,
  • Carolyn Revta

      Affiliations

    • Dana-Farber Cancer Institute, Boston, Massachusetts
    • ,
  • Nicole A. Carreau

      Affiliations

    • Dana-Farber Cancer Institute, Boston, Massachusetts
    • ,
  • Massimo Iacobelli

      Affiliations

    • Gentium SpA, Villa Guardia, Italy
    • ,
  • Enric Carreras

      Affiliations

    • Hospital Clinic, Barcelona, Spain
    • ,
  • Tapani Ruutu

      Affiliations

    • Helsinki University Central Hospital, Helsinki, Finland
    • ,
  • Tiziano Barbui

      Affiliations

    • Ospedali Riuniti, Bergamo, Italy
    • ,
  • Joseph H. Antin

      Affiliations

    • Dana-Farber Cancer Institute, Boston, Massachusetts
    • ,
  • Dietger Niederwieser

      Affiliations

    • University of Leipzig, Leipzig, Germany

Received 2 March 2009; accepted 21 August 2009. published online 09 October 2009.

Article Outline

The occurrence of hepatic veno-occlusive disease (VOD) has been reported in up to 60% of patients following stem cell transplantation (SCT), with incidence varying widely between studies depending on the type of transplant, conditioning regimen, and criteria used to make the diagnosis. Severe VOD is characterized by high mortality and progression to multiorgan failure (MOF); however, there is no consensus on how to evaluate severity. This review and analysis of published reports attempts to clarify these issues by calculating the overall mean incidence of VOD and mortality from severe VOD, examining the effect of changes in SCT practice on the incidence of VOD over time, and discussing the methods used to evaluate severity. Across 135 studies performed between 1979 and October 2007, the overall mean incidence of VOD was 13.7% (95% confidence interval [CI]=13.3%-14.1%). The mean incidence of VOD was significantly lower between 1979-1994 than between 1994-2007 (11.5% [95% CI, 10.9%-12.1%] vs 14.6% [95% CI, 14.0%-15.2%]; P <.05). The mortality rate from severe VOD was 84.3% (95% CI, 79.6%-88.9%); most of these patients had MOF, which also was the most frequent cause of death. Thus, VOD is less common than early reports suggested, but the current incidence appears to be relatively stable despite recent advances in SCT, including the advent of reduced-intensity conditioning. The evolution of MOF in the setting of VOD after SCT can be considered a reliable indication of severity and a predictor of poor outcome.

Key Words: Veno-occlusive disease, Stem cell transplantation, Incidence, Outcome, Severity, Multiorgan failure

 

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Introduction 

Hepatic veno-occlusive disease (VOD) is a syndrome characterized by clinical features of rapid weight gain, ascites, painful hepatomegaly, and jaundice [1]. It is more common after allogeneic stem cell transplantation (SCT) than after autologous SCT, with the most common precipitating event being the administration of conditioning therapy for hematopoietic SCT 1, 2, 3. Historically, VOD has been reported in up to 60% of patients after SCT, ranging in severity from a mild, reversible disease to a severe syndrome associated with multiorgan failure (MOF) and death 1, 4, 5, 6, 7.

VOD is thought to be caused by damage to sinusoidal endothelial cells and hepatocytes in zone 3 of the liver acinus, the area surrounding the central veins. Sinusoidal obstruction is prominent, leading to proposals for an alternate or complementary terminology of sinusoidal obstruction syndrome (SOS) 4, 8, 9. However this has not been universally adopted; thus the acronym “VOD (SOS)” is used to both reflect this debate and provide some consensus [10]. The pathogenesis is complex, involving cytokine release, endothelial injury, hemostatic activation, and hepatic drug detoxification through the glutathione pathway 3, 11, 12. Hepatocellular necrosis, fibrosis, and vascular occlusion ultimately lead to liver failure, hepatorenal syndrome, MOF, and death.

The first case reports describing VOD as a direct complication of SCT appeared in 1979 13, 14. Since then, numerous retrospective and prospective studies have been performed to determine the incidence of VOD, define risk factors, and assess the efficacy of prophylactic and treatment modalities. Two separate groups in the United States have proposed clinical criteria for the diagnosis of VOD in SCT recipients to preclude the need for histological confirmation of the disease (Table 1) 4, 6.

Table 1. Clinical Criteria for the Diagnosis of VOD
Original Seattle Criteria [4]Baltimore Criteria [6]
Presence before day 30 post-SCT of 2 or more of the following:
•Bilirubin≥2mg /dL (≈ 34μmol/L)

•Hepatomegaly, right upper quadrant pain

•Ascites with or without unexplained weight gain of >2% over baseline

Bilirubin≥2mg/dL before day 21 post-SCT and at least 2 of the following:
•Hepatomegaly (usually painful)

•Ascites

•Weight gain >5% over baseline

The modified Seattle criteria [5] require presentation of the clinical features of VOD before day 20 post-SCT.

In addition, prognostic classification (ie, mild, moderate, or severe) has been frequently quoted in the literature and in retrospective studies, primarily based on outcome [5]. As a tool for estimating prognosis, Cox regression analysis was used by Bearman et al. [7] to generate risk curves predictive of severe VOD derived from a large cohort of patients from the Seattle Transplant Registry. The investigators evaluated VOD occurring after the use of 1 of 3 specific chemotherapeutic regimens: cyclophosphamide and total body irradiation (TBI), busulphan and cyclophosphamide, or cyclophosphamide, BCNU, and VP-16. In this study severe VOD was associated with a case fatality rate of 98% by day +100 after SCT. Calculations based on total serum bilirubin and percentage weight gain at various time points subsequent to SCT, up to day +16 [7]. Similar models have not been proposed for other temporal or therapeutic settings, and models based on potential surrogates (eg, cytokines, endothelial stress products, markers of fibrosis) have yet to be fully defined [15]. Moreover, whereas there has been general agreement on the use of clinical criteria for diagnosing VOD, no definitive consensus has been reached on a suitable classification of severity of the disease, due to the limitations of existing methods 16, 17, 18.

This review analyzes data from the published literature, including a recent survey exploring the role of defibrotide in treating severe VOD/MOF as part of a randomized Phase II dose-finding trial 19, 20. The objectives were to (1) define the incidence of VOD after SCT and examine how this has changed over time with increased sophistication of SCT procedures; (2) explain the wide variation in VOD incidence reported in the literature; (3) identify the most commonly used classifications for “severe” VOD and discuss the limitations of these methods; (4) identify factors with predictive value for the evolution of severe disease, such as the development of MOF; and (5) determine expected outcomes for patients with severe VOD or with VOD with MOF when only supportive care is available.

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Methods 

Clinical literature was accessed through the PubMed database using the search terms “veno-occlusive disease” (and variations on this term), “incidence,” “stem cell transplantation” (and variations), “bone marrow transplantation (and variations), and “multiorgan failure” (and variations). Records from 1979 to October 2007 were included. A separate Medline search and bibliographies from articles obtained by both search methods also were examined for references not included in the database searches. A total of 387 citations were recovered; of these, 149 relevant articles (full tabular listing available from the corresponding author on request) were selected for detailed examination and analysis by 2 reviewers independently, using the inclusion and exclusion criteria outlined below. Where several articles reported on the same cohort of patients, the studies were considered as a single report to avoid duplication of data in the analysis (11 studies arranged into 4 groups). Of the final set of 142 studies, the incidence of VOD in the study group was reported in 135. The remaining 7 studies had missing or incomplete data for overall incidence of VOD but nonetheless were included in the review because they contained specific information on the incidence of and mortality from severe VOD.

Our analysis includes all retrospective data analyses, prospective cohort studies, and clinical trials addressing the incidence of VOD, as well as the degree of severity of VOD after SCT, published between 1979 and October 2007. For studies comparing parameters in subgroups of patients (eg, variations in conditioning regimens with standard conditioning), the overall incidence of VOD is presented. For studies investigating VOD prophylaxis, incidence and outcome data from historical or contemporary controls only (when available) were considered; however, administration of heparin or ursodiol prophylaxis for VOD during SCT may not have been clearly documented if it was not relevant to the theme of the article. Data are conflicting on the efficacy of heparin or ursodiol prophylaxis in VOD; although authors have reported a possible beneficial effect 21, 22, 23, 24, 25, most studies (including the large multicenter European Group for Blood and Marrow Transplantation [EBMT] study of more than 1600 SCT recipients) have found neither form of prophylaxis to be effective in reducing the incidence of VOD 2, 16, 26, 27, 28, 29, 30. Therefore, rather than exclude such studies from the analysis, the overall incidence of VOD was used, making it impossible to distinguish between patients receiving or not receiving prophylaxis with heparin or ursodiol.

Of the 347 citations recovered, 198 were excluded from the final analysis based on criteria applied in the following chronological sequence: in vitro or animal studies (n=1), studies in languages other than English (n=30; some of these were revised and published in English-language journals), review articles (n=41), and studies including <50 subjects (n=93). VOD is a rare disease with reported incidences as low as 0%; thus, studies including <50 SCT recipients were unlikely to yield statistically significant data on the incidence of and outcome from VOD. Studies in which prophylactic defibrotide was administered were excluded (n=8). The remaining exclusions (n=25) were a mixture of case reports, case-control studies, and other studies where the incidence of or outcome from VOD could not be determined from the text.

To validate this analysis of outcome from severe VOD reported in the literature, we also have presented historical control data from a recent survey conducted by our multicenter study group that explored the role of defibrotide for the treatment of severe VOD/MOF as part of a randomized Phase II dose-finding trial 19, 20. These data were not included in the main analysis, but serve to illustrate that severity criteria based on the evolution of MOF compare favorably with existing severity criteria and are predictive of VOD outcome. For this survey, retrospective data were collected at 3 of the participating centers (City of Hope National Medical Center, Memorial Sloan Kettering Cancer Center, and M.D. Anderson Cancer Center). Data were collected for 38 patients, all of whom had severe VOD as defined by the study criteria during the 5 years before Institutional Review Board approval of the study at each site. Eligible patients (adult and pediatric) met the Baltimore criteria (Table 1) by day +21 post-SCT and were diagnosed with encephalopathy and/or renal dysfunction and/or pulmonary dysfunction by day +28. Exclusion criteria included preexisting cirrhosis, viral hepatitis, and graft-versus-host disease involving the liver or gut, clinically significant bleeding, inability to maintain blood pressure except with multiple vasopressors, and treatment with defibrotide. Complete response was defined by complete resolution of the signs and symptoms of VOD after provision of the best available care. Outcome data for survival at day +100 post-SCT were collected and reviewed centrally at the Dana-Farber Cancer Institute.

Statistical Methods 

A comprehensive data analysis was performed using the following a priori techniques modeled on a meta-analytic approach. Elementary descriptive statistics for the overall incidence of VOD in the articles reviewed were expressed as frequency, percentage, mean (plus 95% confidence interval [CI]), minimum, maximum, and median values. The 95% CIs were calculated according to the method of Gardner and Altman [31]; for smaller samples, a more complex method for calculating 95% CIs described by Armitage and Berry [32], was used. These statistical parameters were calculated for the complete set of 135 articles reporting incidence data, as well on selected subsets of articles as defined by the selection criteria (eg, type of transplant, VOD criteria used for the diagnosis) (Table 2 and Figure 1). Where both the Baltimore and the Seattle criteria were applied to define the incidence of VOD in the same population of patients, only the incidence according to the more commonly used Seattle criteria was included in the statistical analysis. Survival data for the defibrotide study group were analyzed using χ2 and Kaplan-Meier tests.

Table 2. Descriptive Statistics for VOD Incidence from 135 Publications
GroupNumber of StudiesTotal Number of PatientsNumber of Patients with VODMean Incidence, %95% CIMin,
%		Max,
%		Median,
%
1. All patients13524,920342513.7%13.3-14.1062.313.3
2. Baltimore3352615039.6%8.8-10.4028.98.6
3. Seattle7814,798256517.3%16.7-17.9062.317.0
4. Auto-SCT1939673448.7%∗7.8-9.41.544.16.2
5. Allo-SCT6711,285145312.9%∗12.3-13.5062.312.0
6. Pre-19945010,943126011.5†10.9-12.1162.39.3
7. Post-19947412,234180514.6†14.0-15.2053.315.4

∗P < .001.

†P < .05.

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Results 

A total of 135 reports of VOD occurring in populations of >50 SCT patients were included in this analysis. (A full tabular listing is available in the supplement.) In these 135 studies, out of a total of 24,920 SCT recipients, 3425 developed VOD. The mean incidence of VOD was 13.7% (95% CI, 13.3%-14.1%), with absolute values ranging from 0 to 62.3% (Table 2 and Figure 1). However in the majority of studies (130/135), the variation in incidence was much smaller than this, ranging from 0 to 40%. Only 5 studies reported an incidence of VOD >40%; all of these studies included high-risk patient groups 5, 33, 34, 35, 36.

There were marked differences among studies depending on the criteria used for diagnosis and the type of transplant performed (Table 2 and Figure 1). Using the Seattle criteria, the mean incidence of VOD was 17.3% (95% CI, 16.7%-17.9%; range, 0-62.3%), whereas with the Baltimore criteria, the mean incidence was 9.6% (95% CI, 8.8%-10.4%; range, 0-28.9%), reflecting the increased stringency of the Baltimore criteria for diagnosing VOD. In 24 studies, the criteria used were not specified. The mean incidence of VOD was lower in studies that specifically reported data on autologous SCT recipients compared with those specifically reporting on allogeneic SCT (8.7% [95% CI, 7.8%-9.4%] vs 12.9% [95% CI, 12.3%-13.5%]; P < .001). The incidence range also was much narrower in studies reporting data on autologous SCT (0-12% in 13/18 studies vs 0-40% for allogeneic SCT in 53/57 studies). The 5 studies that reported an incidence exceeding 12% after autologous SCT were performed in high-risk patient groups 37, 38, 39, 40, 41.

A subanalysis of the data was undertaken to compare the mean incidence of VOD across studies reporting on patients undergoing transplantation before and after 1994, to assess the impact of high-resolution HLA matching and other technological advances since that time, such as the use of less hepatotoxic conditioning regimes 2, 42. Surprisingly, the incidence of VOD calculated across 50 out of 135 studies reporting on 10,943 patients who underwent SCT before 1994 was only 11.5% (95% CI, 10.9%-12.1%), compared with 14.6% (95% CI, 14.0%-15.2%) in 74 of 135 studies (12,324 patients) who underwent SCT after 1994 (P ≤.05). The timing of SCT was not clearly reported in the remaining 11/135 studies, and these were excluded from this calculation.

The incidence of severe VOD was specifically reported in 42 studies, in which it ranged from 0 to 77% of all cases of VOD. In 14 of these 42 studies, the method used to classify severity of VOD was not reported 24, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55. In studies that did specify which method was used, the most common classification (23/42 articles) was the retrospective system proposed by the Seattle group 2, 5, 16, 22, 34, 36, 39, 40, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70. In this classification system, patients with mild disease demonstrate no apparent adverse effects of liver disease, require no medications for diuresis of excessive fluid or for hepatic pain, and have completely reversible signs, symptoms, and laboratory abnormalities. Patients with moderate disease experience adverse effects from liver disease, require sodium restriction and diuretics to minimize signs of fluid excess (eg, edema) or medication to alleviate pain from hepatomegaly, and eventually demonstrate complete resolution of all signs of liver damage (ie, return of weight to baseline, decrease in liver size, and decrease in total serum bilirubin to <34.2μmol/L [2mg/dL]). In severe VOD, patients demonstrate adverse effects from liver disease; signs, symptoms, and laboratory values do not resolve before day +100; or death occurs [5]. Only 2 of the 42 studies used the Bearman model alone 35, 71, and another 2 studies used a combination of the Bearman model and retrospective Seattle classification 72, 73. Severe VOD also was classified based on the presence of MOF in combination with the Bearman criteria in studies by Wadleigh et al. [71] and Bajwa et al. [74], and based on MOF combined with the retrospective criteria in studies by Cesaro et al. [67], Sucak et al. [75], and Haussman et al. [76]. In these studies, MOF was defined as an oxygen requirement (oxygen saturation ≤90% in room air and/or ventilator dependence) and/or renal dysfunction (defined as a doubling of baseline creatinine and/or dialysis dependence) and/or encephalopathy, in addition to liver failure [77].

The mortality rate in patients with severe VOD was specifically documented in 19 studies 2, 5, 36, 40, 43, 45, 46, 50, 55, 56, 59, 62, 63, 70, 72, 76, 78, 79, 80. The overall mortality from severe VOD across all 19 of these studies was 84.3% (198/235 patients; 95% CI, 79.6%-88.9%). Fifteen of the 19 studies reported a mortality rate exceeding 75% when only supportive treatment was available 2, 5, 36, 40, 45, 50, 55, 59, 62, 63, 70, 72, 76, 78, 80. In 12 of the 19 studies, only limited information on the cause of death in patients with severe VOD was provided, but in the other 7, death from severe VOD was commonly associated with the development of MOF 5, 40, 45, 50, 56, 76, 78, 80. The correlation between severe VOD with MOF and high mortality was further validated by comparison with the defibrotide study group data 19, 20. This survey revealed a day +100 mortality of 79%, with 8 of 38 patients alive at this time point. Analysis by the χ2 test demonstrated a strong statistical association between complete response and day +100 survival (P <.0001), with a kappa coefficient of 0.885 (95% CI, 0.808-0.962), as also reflected by a 88% day +100 mortality in the nonresponders (Table 3 and Figure 2).

Table 3. Historical Patients with Severe VOD: CR and Mortality Correlation at Day +100 Post-SCT (n=38)
Number of PatientsSurvived to Day +100
Patients with CR4/38 (11%)4/4 (100%)
Nonresponders34/38 (89%)4/34 (12%)

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Discussion 

An early prospective study to determine the incidence of VOD associated with SCT reviewed 255 consecutive patients undergoing bone marrow transplantation for malignancy between 1978 and 1980 [4]. Fifty-three patients (21%) met the Seattle criteria for the diagnosis of VOD (Table 1). The accuracy of these criteria was demonstrated by comparing this data with histological findings in a cohort of 64 patents who underwent biopsy or autopsy.

Jones et al. [6] retrospectively evaluated 235 consecutive patients who underwent bone marrow transplantation between 1982 and 1985. Histological diagnosis performed in a subsection of patients was found to correlate well with the presence of a consistent clinical syndrome of liver dysfunction occurring within the first 3 weeks after marrow infusion. The incidence of VOD using the Baltimore or Jones criteria was 22% (52/235), which was comparable with the Seattle series [4] (Table 1).

The conclusion from both the original Seattle and Baltimore series was that VOD has a specific clinical presentation, which enables diagnosis without the need for liver biopsy. Both criteria are commonly used in clinical practice, but the Seattle criteria are quoted more frequently in the literature for defining the incidence of VOD among SCT recipients.

The largest multicenter prospective study to address incidence of VOD among SCT recipients was published in 1998 by the EBMT [2]. In that study, 1652 consecutive BMT patients were evaluated over a 6-month period in 73 participating EBMT centers for the occurrence of VOD according to Baltimore criteria. VOD was diagnosed in 87 patients overall (incidence, 5.3%; 95% CI, 4.2%-6.4%). There was a 3-fold difference in incidence between allograft and autograft recipients (8.9% and 3.1%; respectively; P < .0001), representing a significantly increased relative risk of VOD after allogeneic SCT compared with autologous SCT.

In some studies, both Baltimore and Seattle criteria were applied to the same cohort of patients, demonstrating significant differences in the incidence of VOD depending on the criteria used 30, 65, 72, 81, 82. This may account for some of the observed variation in VOD incidence in other studies. By definition, all patients meeting the Baltimore criteria also satisfy the Seattle criteria, but not vice versa. The Baltimore criteria result in a lower rate of VOD diagnosis and less variation in the incidence of VOD among studies (Table 1). The increased stringency of the Baltimore criteria comes from the requirement for hyperbilirubinemia of >34mmol/L, compared with >27mmol/L in the Seattle criteria, and the need for the presence of 2 or more additional clinical features of VOD, compared with only one additional feature in the Seattle criteria (Table 2) [81]. Blostein et al. [81] applied both sets of criteria to a cohort of 101 SCT recipients and noted that a larger proportion of patients with VOD diagnosed by the Baltimore criteria died from severe disease at an early stage compared with those diagnosed by the Seattle criteria. They concluded that the Baltimore criteria identify more patients at increased risk of poor outcome.

In addition to the diagnostic criteria used, other differences in study design, including endpoints and methods of data reporting, contribute to the between-study variation in VOD incidence. Many studies rely on retrospective data extraction, which is highly dependent on the accuracy and extent of documentation and, to a lesser extent, on the perceptions of the attending physician 83, 84. The development of jaundice after SCT often is attributable to multiple causes, including cholestasis, likely resulting in underdiagnosis or overdiagnosis of VOD in many cases 83, 84. Although clinical criteria appear to be adequate for a diagnosis of VOD in the majority of patients, recent interventional studies have sought to confirm the diagnosis by histological and other means in confounding cases 77, 85, 86.

In the second study published by the Seattle group in 1993 [5], VOD developed in 190 of 355 patients (incidence, 54%; 95% CI, 48%-59%). The clinical criteria used for that study were similar to those developed in the 1984 study [4], but with the stipulation that the clinical features of VOD appear within 20 days of transplantation (the modified Seattle criteria). Three additional studies from that group have reported similarly high occurrences of VOD 36, 58, 64. The increased incidence noted in the more recent reports compared with the incidence of 21% in the 1984 Seattle study was attributed to increased use of intensive high-dose conditioning regimens.

Similarly, the lower incidence of VOD reported in the 1998 EBMT study was thought to be related to the variable frequency of risk factors, patient selection, definitions of VOD used by different centers, and advances in HLA typing of allogeneic grafts since the 1993 Seattle report [47]. This is illustrated by the fact that the majority of the patients in the Seattle series received an allogeneic transplant and high-dose chemotherapy, compared with only 29% of those in the EBMT study. Indeed, when patients with several risk factors for VOD in the EBMT study were analyzed separately, the incidence was similar to that reported in the Seattle series. Other factors that likely contributed to the lower incidence of VOD reported in the EBMT and other studies include the widespread use of BEAM (BCNU, etoposide, cytarabine, and melphalan) conditioning (a regimen that lacks major sinusoidal liver toxins) for autologous SCT in Europe, and the historical administration of lower doses of TBI in European centers compared with their US counterparts [87].

In some of the smaller and more recent series reviewed here, no VOD was reported in the study population 88, 89, 90. This may be due to both small sample size and improved understanding of the biology of SCT, allowing modification of transplantation protocols to minimize toxicity. For example, lower incidences of VOD and other transplantation-related complications have been reported with the use of reduced-intensity conditioning (RIC) protocols 88, 91, i.v. or targeted busulfan (dose-adjusted according to individual patient pharmacokinetics) 72, 92, 93, 94, T cell depletion 62, 65, 88, 89, 92, 95, and fractionation of the TBI dose used for SCT conditioning 96, 97, 98, 99, 100. It is known that fewer SCT complications arise when HLA-matched siblings are used as donors 98, 101, 102, 103, and in the last decade, the advent of high-resolution HLA typing has led to a significantly reduced complication rate and improved outcome for SCT patients overall [104].

Despite these advances, our current analysis suggests that the overall incidence of VOD has actually increased over time. The reason for this is unclear, but in some studies specific strategies, such as i.v. dosing of busulfan in children, have been associated with more VOD rather than less, suggesting that such measures are not uniformly protective in all SCT populations [105]. Other contributing factors have included extension of the age limit for transplantation by more widespread use of RIC protocols, the use of multiple alkylating regimens in certain pediatric populations (eg, neuroblastoma), reservation of SCT for patients with relapsed or resistant disease due to advances in novel remission induction therapy, introduction of promising but potentially toxic new agents for graft-versus-host disease prophylaxis (eg, sirolimus, everolimus), second or third SCT in patients encountering secondary malignancies after cure of their first, and the increasing use of mismatched donors 37, 38, 104, 106, 107, 108, 109.

The variation in the reported incidence of VOD is multifactorial, reflecting differences among studies in the type of transplant, conditioning regimen, other drugs received, primary disease, coexisting medical conditions, risk factors for liver toxicity, study design, and the criteria used to make the diagnosis 15, 81, 110. Thus, a limitation of our analysis is that the data were not stratified according to such variables. Conversely, the strength of the study is the large number of patients included, which made it possible to obtain useful information about the overall incidence of VOD among SCT recipients.

Although the Seattle and Baltimore criteria have become widely accepted as standards for clinical diagnosis, there has been less agreement among researchers on a suitable classification for the severity of VOD 2, 16, 17. The classification based on the retrospective assessment of outcome for the cohort of 355 patients in the 1993 Seattle study identified 54 patients with severe VOD. Although death was not the only requirement for assignment to the severe VOD category in this study, 53/54 patients (98%) died by day +100.

This retrospective classification system was used in the 1998 EBMT study [2]. The incidence of severe VOD in those patients was 27.6% (24/87), which is comparable with the incidence in the Seattle cohort [5]. The mortality from all causes in this group of patients with severe VOD was 100%. Importantly, a similar incidence of severe VOD by this definition after allogeneic and autologous SCT has been reported in several smaller studies 16, 22, 39, 46, 58, 63, 65, but a much higher incidence of severe VOD (around 50%) has been reported in allograft recipients 36, 47, 49, 50, 57, 62, 111. The large EBMT study reported a 3-fold higher incidence of VOD in allogeneic SCT recipients (8.9% vs 3.1%; P < .0001), but did not include a separate analysis of the incidence of and mortality from “severe” disease (defined retrospectively) between autologous and allogeneic SCT patients. Given that allogeneic SCT is associated with greater immunologic and cytokine-mediated disturbances, the incidence of severe VOD and death would be expected to be higher in allogeneic SCT recipients, an observation also supported by more recent studies [77].

A prospective risk-benefit analysis is needed before any interventional trial using agents with potentially harmful side effects to treat VOD, such as recombinant tissue plasminogen activator (rtPA) 73, 112. For this purpose, data from the second Seattle cohort of 355 patients were used to develop a logistic regression model [7]. This model was found to have a specificity exceeding 90%, and its accuracy was tested on a cohort of similarly conditioned patients at the same center. However this model was specifically developed to justify a clinical trial of rtPA in VOD, which has the potential for serious hemorrhagic complications. It applies only to those patients receiving certain specific regimens of intensive cytoreductive therapy for hematologic malignancy [113] and accounts for only the first 16 days post-SCT, which is before VOD develops in a significant proportion of patients 40, 57, 114. Despite these limitations, investigators have found this model to be useful, particularly when the proposed treatment is associated with serious side effects [73].

Because of the limitations of existing criteria for evaluating the severity of VOD, the evolution of MOF in patients with VOD has been suggested as a more reliable indicator of both severity and outcome 17, 67, 71, 74, 75, 76, 77, 113, 115, 116. Importantly, the relationship between severe VOD and MOF was analyzed in the Seattle cohort study using time-dependent proportional hazards models. MOF was common in patients with severe VOD compared with patients with mild or moderate VOD (P <.001) [5]. Similarly, Jones et al. [6] reported that many patients with VOD died with MOF in the Baltimore cohort of 235 SCT patients. More recently, in a cohort study of 199 SCT patients, Haire and coworkers 117, 118, 119, 120 found that the occurrence of VOD was often predictive of the subsequent development of MOF and increased mortality. A series of other reports have demonstrated that the development of MOF in patients after SCT is associated with high mortality (60%-100%) regardless of the etiology 121, 122, 123, 124, 125, 126, 127. More specifically, hepatic dysfunction after SCT is often predictive of later MOF 117, 118, 119, 120, 128 and greatly reduces the likelihood of surviving MOF [129]. For instance, elevated bilirubin is a known risk factor for the development of acute renal failure (ARF) 130, 131, 132. ARF after SCT rarely occurs in isolation and usually occurs as part of MOF including the liver, often manifested as VOD 40, 50, 61, 128, 133. This association between severe VOD and ARF has been reported in numerous studies 5, 16, 39, 62, 114, 125, 133, 134, 135, 136, and the combination of VOD with ARF and/or mechanical ventilation as a result of pulmonary dysfunction is associated with especially high mortality, particularly in the pediatric population 125, 126, 131, 135, 137, 138, 139.

The Seattle study found that mortality from severe VOD commonly resulted from progressive MOF and rarely from liver failure per se 5, 140. Thus, the investigators concluded that all transplantation-related causes of death should be considered in the assessment of outcome in such patients. In support of this, 16/24 patients with severe VOD in the EBMT series died from VOD (corresponding to 1% of the whole series, 18.4% of VOD patients, and 66.7% of those with severe VOD) [2]. However, the remaining 8 patients with severe VOD in that report died before day +100 from a related cause, including sepsis. Thus, the all-cause mortality at day +100 was 100%. Jones et al. [6] also reported high mortality from MOF with VOD (47%; 24/52) in the Baltimore cohort. Several other studies also have reported MOF as the major cause of death in patients with severe VOD 21, 74, 141. Consequently, VOD with MOF has been used to prospectively define severe VOD in current clinical studies of therapy for VOD, such as rtPA and defibrotide 74, 75, 76, 77, 113, 115, 116, and the evolution of MOF in patients with VOD has become widely accepted as an indication of severity and a predictor of poor outcome 17, 67, 71, 74, 76, 77, 113, 115, 116.

It is noteworthy that the exploratory historical controls in the survey performed by the defibrotide study group demonstrate a mortality rate of 79% at day +100, which is similar to the 84.3% mortality estimated from the other studies reviewed here. Notable exceptions in the literature analysis included a multicenter study based in Philadelphia that reported a mortality of only 30% in patients with severe VOD 5, 56, and a study by Vassal et al. [46] in which the method for determining severity was not defined. These outliers highlight an additional problem with interpreting the retrospective severity criteria: what constitutes “resolution of the symptoms and signs of liver disease by day +100”? Minor elevations in bilirubin or serum transaminase concentration are common after SCT and are often due to the effects of drugs, such as cyclosporin. A recent publication reported a correlation between increasing serum bilirubin value in VOD patients with time and mortality, and noted that the increase in mortality for a given increase in bilirubin value is greater when the starting value was lower [142]. This suggests that patients with a high bilirubin level at presentation that remains stable are less likely to die than patients with a low bilirubin level that rises rapidly. Therefore, the retrospective evaluation of severity of VOD can be subjective, may result in erroneous classification, and has poor predictive value for outcome. We propose that classification of VOD severity should include concurrent organ dysfunction in at least one other system (eg, renal failure) to fulfill a requirement for MOF, and as such should be universally accepted by the transplantation community as the definitive replacement for previous classification systems.

In summary, despite recent advances, such as molecular HLA typing and the use of less-toxic SCT protocols, a small but significant increase in the mean incidence of VOD over time is reported in the published literature. The overall incidence of VOD is much lower than was indicated in early reports. However, the combination of clinical criteria with diagnostic tests, facilitated by advances in our understanding of the histopathology underlying VOD, should lead to increased diagnostic accuracy in confounding cases and thus reduce variation between future studies.

Severe VOD is associated with a mortality rate >80% on day +100 post-SCT based on our analysis, and is most frequently associated with hepatorenal syndrome and progression to MOF. The evolution of MOF in patients with VOD has become widely accepted as a reliable and clinically useful indicator of severity and outcome of VOD, and our analysis supports this view.

Future research directions will include large surveys of current SCT databases for incidence and outcome. Given that more innovative approaches to treatment of this disease are required, prospective studies of promising therapeutic and prophylactic interventions should be used as a platform to validate clinical features, prediction of outcome, and surrogate markers of severe VOD.

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Acknowledgments 

We thank Dr George McDonald for his review of the manuscript and helpful comments.

Financial disclosure: Jason A. Coppell serves on Gentium's Advisory Board; Paul G. Richardson serves on Gentium's Advisory Board; Robert Soiffer is a Consultant for Gentium; Nancy A. Kernan provides clinical research support for Gentium; Massimo Iacobelli is an employeee of Gentium; Tiziano Barbui serves on Gentium's Advisory Board; and Dietger Niederwieser serves on Gentium's Advisory Board and on the Speaker's Bureaus of Genzyme and Bristol Myers Squibb. The other authors have no potential conflicts of interest to disclose.

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References 

  1. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85:3005–3020
  2. Carreras E, Bertz H, Arcese W, et al. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. Blood. 1998;92:3599–3604
  3. Richardson P, Guinan E. The pathology, diagnosis, and treatment of hepatic veno-occlusive disease: current status and novel approaches. Br J Haematol. 1999;107:485–493
  4. McDonald GB, Sharma P, Matthews DE, et al. Veno-occlusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4:116–122
  5. McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255–267
  6. Jones RJ, Lee KS, Beschorner WE, et al. Veno-occlusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778–783
  7. Bearman SI, Anderson GL, Mori M, et al. Veno-occlusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol. 1993;11:1729–1736
  8. 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. 1987;127:549–558
  9. Shulman HM, Fisher LB, Schoch HG, et al. Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology. 1994;19:1171–1181
  10. Kumar S, DeLeve LD, Kamath PS, et al. Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc. 2003;78:589–598
  11. Bearman SI. Avoiding hepatic veno-occlusive disease: what do we know and where are we going?. Bone Marrow Transplant. 2001;27:1113–1120
  12. Coppell JA, Brown SA, Perry DJ. Veno-occlusive disease: cytokines, genetics, and haemostasis. Blood Rev. 2003;17:63–70
  13. Jacobs P, Miller JL, Uys CJ, et al. Fatal veno-occlusive disease of the liver after chemotherapy, whole-body irradiation and bone marrow transplantation for refractory acute leukaemia. S Afr Med J. 1979;55:5–10
  14. Berk PD, Popper H, Krueger GR, et al. Veno-occlusive disease of the liver after allogeneic bone marrow transplantation: possible association with graft-versus-host disease. Ann Intern Med. 1979;90:158–164
  15. Wadleigh M, Ho V, Momtaz P, et al. Hepatic veno-occlusive disease: pathogenesis, diagnosis and treatment. Curr Opin Hematol. 2003;10:451–462
  16. Reiss U, Cowan M, McMillan A, et al. Hepatic veno-occlusive disease in blood and bone marrow transplantation in children and young adults: incidence, risk factors, and outcome in a cohort of 241 patients. J Pediatr Hematol Oncol. 2002;24:746–750
  17. Vogelsang GB, Dalal J. Hepatic veno-occlusive disease in blood and bone marrow transplantation in children: incidence, risk factors, and outcome. J Pediatr Hematol Oncol. 2002;24:706–709
  18. Chalandon Y, Roosnek E, Mermillod B, et al. Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2004;10:347–354
  19. Richardson P, Kernan N, Tomblyn M, et al. A phase 3 randomized, historically controlled clinical trial investigating the use of defibrotide in the treatment of severe veno-occlusive disease post-SCT: a novel approach to the validation of a promising new drug for the treatment of a life-threatening disease. ASH Annual Meeting Abstracts. Blood. 2007;110:614
  20. Richardson P, Soiffer RJ, Antin JH, et al. Defibrotide (DF) for the treatment of severe veno-occlusive disease (sVOD) and multi-organ failure (MOF) post-SCT: final results of a multi-center, randomized, dose-finding trial. ASH Annual Meeting Abstracts. Blood. 2006;108:43
  21. Attal M, Huguet F, Rubie H, et al. Prevention of hepatic veno-occlusive disease after bone marrow transplantation by continuous infusion of low-dose heparin: a prospective, randomized trial. Blood. 1992;79:2834–2840
  22. Rosenthal J, Sender L, Secola R, et al. Phase II trial of heparin prophylaxis for veno-occlusive disease of the liver in children undergoing bone marrow transplantation. Bone Marrow Transplant. 1996;18:185–191
  23. Simon M, Hahn T, Ford LA, et al. Retrospective multivariate analysis of hepatic veno-occlusive disease after blood or marrow transplantation: possible beneficial use of low molecular weight heparin. Bone Marrow Transplant. 2001;27:627–633
  24. Ohashi K, Tanabe J, Watanabe R, et al. The Japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation. Am J Hematol. 2000;64:32–38
  25. Essell JH, Thompson JM, Harman GS, et al. Pilot trial of prophylactic ursodiol to decrease the incidence of veno-occlusive disease of the liver in allogeneic bone marrow transplant patients. Bone Marrow Transplant. 1992;10:367–372
  26. Marsa-Vila L, Gorin NC, Laporte JP, et al. Prophylactic heparin does not prevent liver veno-occlusive disease following autologous bone marrow transplantation. Eur J Haematol. 1991;47:346–354
  27. Hagglund H, Ringden O, Remberger M, et al. Risk factors for hepatic veno-occlusive disease in 500 allogeneic bone marrow transplant recipients. Bone Marrow Transplant. 1997;19(Suppl 1):S17
  28. Park YD, Yasui M, Yoshimoto T, et al. Changes in hemostatic parameters in hepatic veno-occlusive disease following bone marrow transplantation. Bone Marrow Transplant. 1997;19:915–920
  29. Hagglund H, Remberger M, Klaesson S, et al. Norethisterone treatment, a major risk-factor for veno-occlusive disease in the liver after allogeneic bone marrow transplantation. Blood. 1998;92:4568–4572
  30. Ruutu T, Eriksson B, Remes K, et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood. 2002;100:1977–1983
  31. Gardner M, Altman DG. Statistics With Confidence. Tavistock Square, London, UK: Wiley Blackwell; 1989;6–27
  32. Armitage P, Berry G. Statistical Methods in Medical Research. Oxford, UK: Oxford Blackwell; 1987;117–120
  33. Copelan EA, Penza SL, Theil KS, et al. The influence of early transplantation, age, GVHD prevention regimen, and other factors on outcome of allogeneic transplantation for CML following BuCy. Bone Marrow Transplant. 2000;26:1037–1043
  34. Lee JH, Lee KH, Kim S, et al. Plasminogen activator inhibitor-1 is an independent diagnostic marker as well as severity predictor of hepatic veno-occlusive disease after allogeneic bone marrow transplantation in adults conditioned with busulphan and cyclophosphamide. Br J Haematol. 2002;118:1087–1094
  35. Lee KH, Lee JH, Choi SJ, et al. Randomized comparison of two different schedules of granulocyte colony-stimulating factor administration after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1999;24:591–599
  36. Radich JP, Sanders JE, Buckner CD, et al. Second allogeneic marrow transplantation for patients with recurrent leukemia after initial transplant with total body irradiation–containing regimens. J Clin Oncol. 1993;11:304–313
  37. Lapierre V, Mahe C, Auperin A, et al. Platelet transfusion containing ABO-incompatible plasma and hepatic veno-occlusive disease after hematopoietic transplantation in young children. Transplantation. 2005;80:314–319
  38. Bouligand J, Le Maitre A, Valteau-Couanet D, et al. Elevated plasma ferritin and busulfan pharmacodynamics during high-dose chemotherapy regimens in children with malignant solid tumors. Clin Pharmacol Ther. 2007;82:402–409
  39. Horn B, Reiss U, Matthay K, et al. Veno-occlusive disease of the liver in children with solid tumors undergoing autologous hematopoietic progenitor cell transplantation: a high incidence in patients with neuroblastoma. Bone Marrow Transplant. 2002;29:409–415
  40. Lee JL, Gooley T, Bensinger W, et al. Veno-occlusive disease of the liver after busulfan, melphalan, and thiotepa conditioning therapy: incidence, risk factors, and outcome. Biol Blood Marrow Transplant. 1999;5:306–315
  41. Meresse V, Hartmann O, Vassal G, et al. Risk factors for hepatic veno-occlusive disease after high-dose busulfan–containing regimens followed by autologous bone marrow transplantation: a study in 136 children. Bone Marrow Transplant. 1992;10:135–141
  42. Baxter-Lowe LA. Molecular techniques for typing unrelated marrow donors: potential impact of molecular typing disparity on donor selection. Bone Marrow Transplant. 1994;14(Suppl 4):S42–S50
  43. Crilley P, Topolsky D, Styler MJ, et al. Extramedullary toxicity of a conditioning regimen containing busulphan, cyclophosphamide and etoposide in 84 patients undergoing autologous and allogenic bone marrow transplantation. Bone Marrow Transplant. 1995;15:361–365
  44. Nemunaitis J, Rosenfeld CS, Ash R, et al. Phase III randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1995;15:949–954
  45. Holland HK, Dix SP, Geller RB, et al. Minimal toxicity and mortality in high-risk breast cancer patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin plus autologous marrow/stem cell transplantation and comprehensive supportive care. J Clin Oncol. 1996;14:1156–1164
  46. Vassal G, Koscielny S, Challine D, et al. Busulfan disposition and hepatic veno-occlusive disease in children undergoing bone marrow transplantation. Cancer Chemother Pharmacol. 1996;37:247–253
  47. Carreras E, Viguria MC, Rovira M, et al. Veno-occlusive disease of the liver after allogeneic blood and marrow transplantation: a retrospective analysis of 376 consecutive BMT performed at a single centre. Bone Marrow Transplant. 1998;21(Suppl 1):S239
  48. Jillella AP, Doria R, Khan K, et al. Cyclophosphamide, cytosine arabinoside and TBI as a conditioning regimen for allogeneic bone marrow transplantation in patients with leukemia. Bone Marrow Transplant. 1999;23:1095–1100
  49. Rocha E, Viguria MC, Montes R, et al. Plasma levels of t-PA Ag and D-dimer predict development of veno-occlusive disease of the liver (VOD) in patients undergoing allogeneic stem cell transplant. Blood. 2001;98:3541
  50. Parikh CR, McSweeney PA, Korular D, et al. Renal dysfunction in allogeneic hematopoietic cell transplantation. Kidney Int. 2002;62:566–573
  51. Schetelig J, Kroger N, Held TK, et al. Allogeneic transplantation after reduced conditioning in high-risk patients is complicated by a high incidence of acute and chronic graft-versus-host disease. Haematologica. 2002;87:299–305
  52. Einsele H, Bamberg M, Budach W, et al. A new conditioning regimen involving total marrow irradiation, busulfan and cyclophosphamide followed by autologous PBSCT in patients with advanced multiple myeloma. Bone Marrow Transplant. 2003;32:593–599
  53. Hahn T, Rondeau C, Shaukat A, et al. Acute renal failure requiring dialysis after allogeneic blood and marrow transplantation identifies very poor prognosis patients. Bone Marrow Transplant. 2003;32:405–410
  54. de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104:857–864
  55. Srivastava A, Poonkuzhali B, Shaji RV, et al. Glutathione S-transferase M1 polymorphism: a risk factor for hepatic veno-occlusive disease in bone marrow transplantation. Blood. 2004;104:1574–1577
  56. Styler MJ, Crilley P, Biggs J, et al. Hepatic dysfunction following busulfan and cyclophosphamide myeloablation: a retrospective, multicenter analysis. Bone Marrow Transplant. 1996;18:171–176
  57. Hasegawa S, Horibe K, Kawabe T, et al. Veno-occlusive disease of the liver after allogeneic bone marrow transplantation in children with hematologic malignancies: incidence, onset time and risk factors. Bone Marrow Transplant. 1998;22:1191–1197
  58. Sullivan KM, Kansu E, Storer B, et al. Intravenous immunoglobulin and the risk of hepatic veno-occlusive disease after bone marrow transplantation. Biol Blood Marrow Transplant. 1998;4:20–26
  59. Locasciulli A, Testa M, Valsecchi MG, et al. The role of hepatitis C and B virus infections as risk factors for severe liver complications following allogeneic BMT: a prospective study by the Infectious Disease Working Party of the European Blood and Marrow Transplantation Group. Transplantation. 1999;68:1486–1491
  60. Copelan EA, Penza SL, Pohlman B, et al. Autotransplantation following busulfan, etoposide and cyclophosphamide in patients with non-Hodgkin's lymphoma. Bone Marrow Transplant. 2000;25:1243–1248
  61. Tomas JF, Sanz-Rodriguez C, de Soria VG, et al. Plasma endothelin-1 levels after stem cell transplantation. Bone Marrow Transplant. 2000;26:1199–1204
  62. Moscardo F, Sanz GF, de La Rubia J, et al. Marked reduction in the incidence of hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation with CD34(+) positive selection. Bone Marrow Transplant. 2001;27:983–988
  63. Park SH, Lee MH, Lee H, et al. A randomized trial of heparin plus ursodiol vs heparin alone to prevent hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;29:137–143
  64. McDonald GB, Slattery JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood. 2003;101:2043–2048
  65. Moscardo F, Urbano-Ispizua A, Sanz GF, et al. Positive selection for CD34+ reduces the incidence and severity of veno-occlusive disease of the liver after HLA-identical sibling allogeneic peripheral blood stem cell transplantation. Exp Hematol. 2003;31:545–550
  66. Kalayoglu-Besisik S, Yenerel MN, Caliskan Y, et al. Time-related changes in the incidence, severity, and clinical outcome of hepatic veno-occlusive disease in hematopoietic stem cell transplantation patients during the past 10 years. Transplant Proc. 2005;37:2285–2289
  67. Cesaro S, Pillon M, Talenti E, et al. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica. 2005;90:1396–1404
  68. Lee JH, Choi SJ, Kim SE, et al. Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol. 2005;84:321–330
  69. Sartori MT, Spiezia L, Cesaro S, et al. Role of fibrinolytic and clotting parameters in the diagnosis of liver veno-occlusive disease after hematopoietic stem cell transplantation in a pediatric population. Thromb Hemost. 2005;93:682–689
  70. Batsis I, Yannaki E, Kaloyannidis P, et al. Veno-occlusive disease prophylaxis with fresh-frozen plasma and heparin in bone marrow transplantation. Thromb Res. 2006;118:611–618
  71. Wadleigh M, Richardson PG, Zahrieh D, et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood. 2003;102:1578–1582
  72. Kashyap A, Wingard J, Cagnoni P, et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic veno-occlusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant. 2002;8:493–500
  73. Litzow MR, Repoussis PD, Schroeder G, et al. Veno-occlusive disease of the liver after blood and marrow transplantation: analysis of pre- and post-transplant risk factors associated with severity and results of therapy with tissue plasminogen activator. Leuk Lymphoma. 2002;43:2099–2107
  74. Bajwa RP, Cant AJ, Abinun M, et al. Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment. Bone Marrow Transplant. 2003;31:591–597
  75. Sucak GT, Aki ZS, Yagci M, et al. Treatment of sinusoidal obstruction syndrome with defibrotide: a single-center experience. Transplant Proc. 2007;39:1558–1563
  76. Haussmann U, Fischer J, Eber S, et al. Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy. Haematologica. 2006;91:795–800
  77. Richardson PG, Murakami C, Jin Z, 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. 2002;100:4337–4343
  78. Song JS, Seo JJ, Moon HN, et al. Prophylactic low-dose heparin or prostaglandin E1 may prevent severe veno-occlusive disease of the liver after allogeneic hematopoietic stem cell transplantation in Korean children. J Korean Med Sci. 2006;21:897–903
  79. Brice K, Valerie B, Claire G, et al. Risk-adjusted monitoring of veno-occlusive disease following Bayesian individualization of busulfan dosage for bone marrow transplantation in paediatrics. Pharmacoepidemiol Drug Saf. 2007;17:135–143
  80. Cheuk DK, Wang P, Lee TL, et al. Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant. 2007;40:935–944
  81. Blostein MD, Paltiel OB, Thibault A, et al. A comparison of clinical criteria for the diagnosis of veno-occlusive disease of the liver after bone marrow transplantation. Bone Marrow Transplant. 1992;10:439–443
  82. Andersson BS, Kashyap A, Gian V, et al. Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant. 2002;8:145–154
  83. Barker CC, Anderson RA, Sauve RS, et al. GI complications in pediatric patients post-BMT. Bone Marrow Transplant. 2005;36:51–58
  84. Barker CC, Butzner JD, Anderson RA, et al. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2003;32:79–87
  85. Richardson P, Soiffer R, Antin JH, et al. Defibrotide (DF) for the treatment of severe veno-occlusive disease (VOD) and multi-system organ failure (MOF) post-SCT: final results of a phase II, multicenter, randomized study and preliminary analyses of surrogate markers and ultrasound findings. Blood. 2004;104
  86. Richardson P, Soiffer RJ, Antin JH, et al. Defibrotide (DF) for the treatment of veno-occlusive disease (VOD) and multi-system organ failure (MOF) post-SCT: analysis of response and survival according to degree and type of MOF. Blood. 2005;106:399
  87. Strasser SI, McDonald GB. Gastrointestinal and hepatic complications. In:  Thomas ED,  Blume KG,  Forman SJ editor. Hemopoietic Cell Transplantation. Malden, MA: Blackwell; 1999;p. 627–658
  88. Aversa F, Terenzi A, Felicini R, et al. Haploidentical stem cell transplantation for acute leukemia. Int J Hematol. 2002;76(Suppl 1):165–168
  89. Olavarria E, Kanfer E, Szydlo R, et al. High-dose busulphan alone as cytoreduction before allogeneic or autologous stem cell transplantation for chronic myeloid leukaemia: a single-centre experience. Br J Haematol. 2000;108:769–777
  90. Russell JA, Tran HT, Quinlan D, et al. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant. 2002;8:468–476
  91. Ramasamy K, Lim ZY, Pagliuca A, et al. Incidence and management of hepatic veno-occlusive disease in 237 patients undergoing reduced-intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT). Bone Marrow Transplant. 2006;38:823–824
  92. Olavarria E, Hassan M, Eades A, et al. A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation. Leukemia. 2000;14:1954–1959
  93. Clopes A, Sureda A, Sierra J, et al. Absence of veno-occlusive disease in a cohort of multiple myeloma patients undergoing autologous stem cell transplantation with targeted busulfan dosage. Eur J Haematol. 2006;77:1–6
  94. Spitzer TR, Ambinder RF, Lee JY, et al. Dose-reduced busulfan, cyclophosphamide, and autologous stem cell transplantation for human immunodeficiency virus–associated lymphoma: AIDS Malignancy Consortium study 020. Biol Blood Marrow Transplant. 2008;14:59–66
  95. Soiffer RJ, Dear K, Rabinowe SN, et al. Hepatic dysfunction following T-cell–depleted allogeneic bone marrow transplantation. Transplantation. 1991;52:1014–1019
  96. Girinsky T, Benhamou E, Bourhis JH, et al. Prospective randomized comparison of single-dose versus hyperfractionated total body irradiation in patients with hematologic malignancies. J Clin Oncol. 2000;18:981–986
  97. Cosset JM, Baume D, Pico JL, et al. Single-dose versus hyperfractionated total body irradiation before allogeneic bone marrow transplantation: a non-randomized comparative study of 54 patients at the Institut Gustave-Roussy. Radiother Oncol. 1989;15:151–160
  98. Locasciulli A, Bacigalupo A, Alberti A, et al. Predictability before transplant of hepatic complications following allogeneic bone marrow transplantation. Transplantation. 1989;48:68–72
  99. Ayash LJ, Hunt M, Antman K, et al. Hepatic veno-occlusive disease in autologous bone marrow transplantation of solid tumors and lymphomas. J Clin Oncol. 1990;8:1699–1706
  100. Resbeut M, Altschuler C, Blaise D, et al. Results of fractionated TBI prior to bone marrow transplantation in standard-risk leukaemia at Marseille. Radiother Oncol. 1990;18(Suppl 1):132–134
  101. Atkinson K, Biggs J, Noble G, et al. Preparative regimens for marrow transplantation containing busulfan are associated with hemorrhagic cystitis and hepatic veno-occlusive disease but a short duration of leucopenia and little oro-pharyngeal mucositis. Bone Marrow Transplant. 1987;2:385–394
  102. Holler E, Kolb HJ, Moller A, et al. Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. Blood. 1990;75:1011–1016
  103. Morgan M, Dodds A, Atkinson K, et al. The toxicity of busulphan and cyclophosphamide as the preparative regimen for bone marrow transplantation. Br J Haematol. 1991;77:529–534
  104. Petersdorf EW. HLA matching in allogeneic stem cell transplantation. Curr Opin Hematol. 2004;11:386–391
  105. Bartelink IH, Bredius RG, Ververs TT, et al. Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2008;14:88–98
  106. Nabhan C, Mehta J, Tallman MS. The role of bone marrow transplantation in acute promyelocytic leukemia. Bone Marrow Transplant. 2001;28:219–226
  107. Goldman JM, Marin D, Olavarria E, et al. Clinical decisions for chronic myeloid leukemia in the imatinib era. Semin Hematol. 2003;40:98–103
  108. Cutler C, Stevenson K, Kim HT, et al. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood. 2008;112:4425–4431
  109. Platzbecker U, von Bonin M, Goekkurt E, et al. Graft-versus-host disease prophylaxis with everolimus and tacrolimus is associated with a high incidence of sinusoidal obstruction syndrome and microangiopathy: results of the EVTAC trial. Biol Blood Marrow Transplant. 2009;15:101–108
  110. Richardson P, Guinan E. Hepatic veno-occlusive disease following hematopoietic stem cell transplantation. Acta Haematol. 2001;106:57–68
  111. Mahmoud HK. Schistosomiasis as a predisposing factor to veno-occlusive disease of the liver following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1996;17:401–403
  112. Bearman SI, Lee JL, Baron AE, et al. Treatment of hepatic veno-occlusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood. 1997;89:1501–1506
  113. Chopra R, Eaton JD, Grassi A, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol. 2000;111:1122–1129
  114. Brugieres L, Hartmann O, Benhamou E, et al. Veno-occlusive disease of the liver following high-dose chemotherapy and autologous bone marrow transplantation in children with solid tumors: incidence, clinical course and outcome. Bone Marrow Transplant. 1988;3:53–58
  115. Richardson PG, Elias AD, Krishnan A, et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood. 1998;92:737–744
  116. Corbacioglu S, Greil J, Peters C, et al. Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicenter study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant. 2004;33:189–195
  117. Gordon B, Tarantolo S, Ruby E, et al. Increased platelet transfusion requirement is associated with multiple organ dysfunctions in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 1998;22:999–1003
  118. Haire WD. Multiple organ dysfunction syndrome in hematopoietic stem cell transplantation. Crit Care Med. 2002;30:S257–S262
  119. Haire WD. The multiple organ dysfunction syndrome in cancer patients undergoing hematopoietic stem cell transplantation. Semin Thromb Hemost. 1999;25:223–237
  120. Haire WD, Ruby EI, Gordon BG, et al. Multiple organ dysfunction syndrome in bone marrow transplantation. JAMA. 1995;274:1289–1295
  121. Khassawneh BY, White P, Anaissie EJ, et al. Outcome from mechanical ventilation after autologous peripheral blood stem cell transplantation. Chest. 2002;121:185–188
  122. Diaz de Heredia C, Moreno A, Olive T, et al. Role of the intensive care unit in children undergoing bone marrow transplantation with life-threatening complications. Bone Marrow Transplant. 1999;24:163–168
  123. Rossi R, Shemie SD, Calderwood S. Prognosis of pediatric bone marrow transplant recipients requiring mechanical ventilation. Crit Care Med. 1999;27:1181–1186
  124. Haire WD, Ruby EI, Stephens LC, et al. A prospective randomized double-blind trial of antithrombin III concentrate in the treatment of multiple-organ dysfunction syndrome during hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 1998;4:142–150
  125. Morris JD, Harris RE, Hashmi R, et al. Antithrombin-III for the treatment of chemotherapy-induced organ dysfunction following bone marrow transplantation. Bone Marrow Transplant. 1997;20:871–878
  126. Rubenfeld GD, Crawford SW. Withdrawing life support from mechanically ventilated recipients of bone marrow transplants: a case for evidence-based guidelines. Ann Intern Med. 1996;125:625–633
  127. Afessa B, Tefferi A, Hoagland HC, et al. Outcome of recipients of bone marrow transplants who require intensive care unit support. Mayo Clin Proc. 1992;67:117–122
  128. Letourneau I, Dorval M, Belanger R, et al. Acute renal failure in bone marrow transplant patients admitted to the intensive care unit. Nephron. 2002;90:408–412
  129. Keenan HT, Bratton SL, Martin LD, et al. Outcome of children who require mechanical ventilatory support after bone marrow transplantation. Crit Care Med. 2000;28:830–835
  130. Zager RA, O'Quigley J, Zager BK, et al. Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients. Am J Kidney Dis. 1989;13:210–216
  131. Lane PH, Mauer SM, Blazar BR, et al. Outcome of dialysis for acute renal failure in pediatric bone marrow transplant patients. Bone Marrow Transplant. 1994;13:613–617
  132. Kist-van Holthe JE, van Zwet JM, Brand R, et al. Bone marrow transplantation in children: consequences for renal function shortly after and 1 year post-BMT. Bone Marrow Transplant. 1998;22:559–564
  133. Gruss E, Bernis C, Tomas JF, et al. Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome. Am J Nephrol. 1995;15:473–479
  134. Wingard JR, Mellits ED, Jones RJ, et al. Association of hepatic veno-occlusive disease with interstitial pneumonitis in bone marrow transplant recipients. Bone Marrow Transplant. 1989;4:685–689
  135. Merouani A, Shpall EJ, Jones RB, et al. Renal function in high-dose chemotherapy and autologous hematopoietic cell support treatment for breast cancer. Kidney Int. 1996;50:1026–1031
  136. Kist-van Holthe JE, Goedvolk CA, Brand R, et al. Prospective study of renal insufficiency after bone marrow transplantation. Pediatr Nephrol. 2002;17:1032–1037
  137. Torrecilla C, Cortes JL, Chamorro C, et al. Prognostic assessment of the acute complications of bone marrow transplantation requiring intensive therapy. Intens Care Med. 1988;14:393–398
  138. Todd K, Wiley F, Landaw E, et al. Survival outcome among 54 intubated pediatric bone marrow transplant patients. Crit Care Med. 1994;22:171–176
  139. Jacobe SJ, Hassan A, Veys P, et al. Outcome of children requiring admission to an intensive care unit after bone marrow transplantation. Crit Care Med. 2003;31:1299–1305
  140. McDonald GB, Hinds MS, Fisher LB, et al. Liver toxicity following cytoreductive therapy for marrow transplantation: risk factors, incidence and outcome. Hepatology. 1991;14:162A
  141. Klaesson S, Ringden O, Ljungman P, et al. Does high-dose intravenous immune globulin treatment after bone marrow transplantation increase mortality in veno-occlusive disease of the liver?. Transplantation. 1995;60:1225–1230
  142. Gooley TA, Rajvanshi P, Schoch HG, et al. Serum bilirubin levels and mortality after myeloablative allogeneic hematopoietic cell transplantation. Hepatology. 2005;41:345–352

 Financial disclosure: See Acknowledgments on page 164.

PII: S1083-8791(09)00418-2

doi:10.1016/j.bbmt.2009.08.024

Biology of Blood and Marrow Transplantation
Volume 16, Issue 2 , Pages 157-168, February 2010

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