Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: Risk Factors and Stratification, Prophylaxis, and Treatment

Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: Risk Factors and Stratification, Prophylaxis, and Treatment

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Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org

Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: Risk Factors and Stratification, Prophylaxis, and Treatment Jean-Hugues Dalle 1, Sergio A. Giralt 2, * 1 2

Department of Paediatric Haematology, Paris Diderot University, Sorbonne Paris Cité, Hôpital Robert Debré, APHP, Paris, France Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York

Article history: Received 15 July 2015 Accepted 24 September 2015 Key Words: Hepatic veno-occlusive disease Prophylaxis Risk factors Sinusoidal obstruction syndrome Stem cell transplantation Treatment

a b s t r a c t Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), can develop in a subset of patients, primarily after myeloablative hematopoietic stem cell transplantation, but it also may occur after reduced-intensity conditioning. Severe VOD/SOS, typically characterized by multiorgan failure, has been associated with a mortality rate greater than 80%. Therefore, an accurate and prompt diagnosis of VOD/SOS is essential for early initiation of appropriate therapy to improve clinical outcomes. Moreover, some studies have support the use of prophylaxis for patients who are at high risk of developing VOD/SOS. This review summarizes risk factors associated with development of VOD/SOS, including pretransplantation patient characteristics and factors related to stem cell transplantation, that can facilitate patient stratification according to risk. The incidence of VOD/SOS, clinical features, and diagnostic criteria are reviewed. Data on emerging treatment strategies for patients with VOD/SOS are discussed in the context of recent treatment guidelines. Additionally, options for prophylaxis in individuals who are at increased risk are presented. Although historically only those patients with moderate to severe VOD/SOS have been treated, early therapy and prophylaxis may be appropriate for many patients and may have the potential to improve patients’ outcomes and survival, including for those with nonsevere disease. Ó 2015 American Society for Blood and Marrow Transplantation.

INTRODUCTION Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a well-recognized and potentially life-threatening complication that occurs primarily after myeloablative hematopoietic stem cell transplantation (HSCT), but it also has been observed in patients after reduced-intensity conditioning (RIC) and rarely after exposure to hepatotoxic chemotherapies outside the transplantation framework [1]. VOD/SOS was initially described in patients who had ingested bush tea containing pyrrolizidine alkaloids. Although associated with multiple clinical settings, such as hepatic irradiation and use of azathioprine, or more recently gemtuzumab ozogamicin, VOD/SOS is most commonly seen in the context of high-dose chemotherapy with HSCT, where it was first described in 1979 [2]. Initial case series reported fatality rates of 50%

Financial disclosure: See Acknowledgments on page 8. * Correspondence and reprint requests: Sergio A. Giralt, MD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 235, New York, NY 10065. E-mail address: [email protected] (S.A. Giralt).

or higher [3]. VOD/SOS has been reported as a leading cause of death in the post-transplantation period, with interstitial pneumonia, infections, and graft-versus-host disease (GVHD) as the other leading causes [4]. Patients with moderate or severe VOD/SOS (sVOD/sSOS; typically characterized by multiorgan failure [MOF]) with ascites and hypertension, can have significant morbidity and mortality. sVOD/sSOS is associated with a mortality rate higher than 80% [1]. During the past 10 years, our understanding of the risk factors for developing VOD/SOS has improved, and new therapeutic strategies have emerged that allow for better prevention and treatment of this devastating complication. Herein, we provide a review of the current understanding of VOD/SOS, its prevention, and treatment.

PATHOPHYSIOLOGY OF VOD/SOS VOD/SOS arises from endothelial cell damage and hepatocellular injury due to the transplantation conditioning regimen. Although its pathophysiology is not completely understood, the complex pathogenesis begins with injury

http://dx.doi.org/10.1016/j.bbmt.2015.09.024 1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.

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to sinusoidal endothelial cells and hepatocytes due to toxic metabolites generated by high-dose alkylating chemotherapy conditioning regimens, such as busulfan (BU), cyclophosphamide (CY), melphalan, 6-mercaptopurine, and possibly thiotepa [5]. Ionizing radiation may induce the same type of damage. In addition, locally released cytokines induce activation of cell adhesion molecules on endothelial cells, resulting in local cell damage and detachment and activation of the coagulation pathway [6]. Subsequent activation of the fibrinolytic pathway leads to fibrosis of sinusoids, followed by perivascular hepatocyte necrosis and the venular blockage characteristic of VOD/SOS [7]. Other mediators of VOD/SOS pathogenesis may include soluble intercellular adhesion molecule 1, von Willebrand factor, thrombomodulin, and plasminogen activator inhibitor-1 [7,8]. INCIDENCE AND RISK FACTORS The reported incidence of VOD/SOS varies, in part because of the use of different diagnostic criteria, conditioning regimens, patient populations, types of transplantation, and prior therapies. Its overall mean incidence typically ranges from 8% to 14%, depending on the clinical diagnostic criteria used [1]. Although rates of up to 60% have been reported, few studies cite an incidence of more than 40%. A retrospective analysis reported an incidence of approximately 25% in pediatric patients after myeloablative conditioning that occurred before allogeneic or autologous HSCT [9]. In 1 literature review encompassing 135 published reports, the mean incidence of VOD/SOS was found to be 13.7%, with a range of 0% to 40% reported in most of the studies [1]. The incidence now appears to be relatively stable, despite recent advances in HSCT, such as new agents for GVHD prophylaxis and more widespread use of RIC. It should be noted, however, that VOD/SOS still can occur with RIC regimens. For example, 1 recent prospective study evaluating 271 patients who received a BU-containing RIC regimen (BU, fludarabine, and antithymocyte globulin) for allogeneic HSCT found that 24 (8.8%) developed moderate to severe VOD/SOS (4 cases of sVOD/sSOS) [10]. On the other hand, we now perform transplantations in greater numbers of older patients and in more heavily pretreated patients (ie, those with higher potential for liver injury before HSCT and conditioning regimens). In reality, the incidence and prevalence of VOD/SOS will depend on the proportion of patients who are at high risk of developing this complication, as well as their exposure to predisposing agents. Understanding risk factors associated with the development of VOD/SOS is critical for early initiation of treatment or for VOD/SOS prophylaxis to prevent the occurrence of sVOD/ sSOS, MOF, other morbidities, and potentially death. In some studies, selected risk factors were associated with a higher VOD/SOS-related mortality rate at day 100 after transplantation [3,11]. For example, a study of pediatric post-HSCT patients identified several predictors of mortality, including donors other than autologous or matched siblings, GVHD, maximal weight gain > 9%, pleural effusion, intensive care unit admission, and elevated bilirubin; mortality was higher with more than 3 such risk factors [11]. In general, risk factors can be divided into 2 categories: pretransplantation patient characteristics and transplantation-related factors (Table 1). These factors affect all patients, although they may have been identified initially in either pediatric or adult populations.

Table 1 Risk Factors for Development of VOD/SOS Risk Factors Pretransplantation Risk Factors Age [11,12] Increased transaminase levels [4,13,14] Pre-existing liver disease [14,15] Viral hepatitis CMV positivity Underlying disease/advanced malignancy [11,15] Myelodysplasia Inborn errors of metabolism Leukemia CML Immunodeficiency Thalassemia Interval between diagnosis of malignancy and transplantation >12 mo [11] Deteriorated health status within 30 days before transplantation [3] Diarrhea Fever Parenteral nutrition before transplantation Previous stem cell transplantation [14,15] Prior abdominal radiation [14] Prior treatment with gemtuzumab ozogamicin [16,17] Prior treatment with norethisterone [18] Poor performance status (Karnofsky score <90%) [14,19-21] Genetic factors [22-24] GSTM1-null genotype Impaired pulmonary function [25] Infection/antibiotic/antiviral use [3,26] Sepsis Vancomycin during cytoreductive therapy Pretransplantation acyclovir Ferritin levels >1000 ng/mL [15,19,27] Bilirubin >26 mmol/L before BMT [18,28] Transplantation-related Risk Factors Allogeneic versus autologous SCT [14,15] Sibling Parental Unrelated donor/HLA mismatch [3,14,15] Haploidentical High-dose/myeloablative therapy [11,13,14,26,29,30] BU regimen versus others BU þ CY Fludarabine BCNU þ CY þ etoposide High-dose total body irradiation >12 Gy þ CY [3,13,14,29-31] GVHD prophylaxis [11,20,32] Sirolimus þ methotrexate þ tacrolimus Methotrexate þ cyclosporine Cyclosporine NoneT celledepleted grafts [17,20] Peripheral blood SCT versus BMT [33] Acute hepatic/gut GVHD [11]

Patient Population

Odds Ratio

Ped, adults Ped, adults Ped, adults

5.2-9.5 2.4-4.6 3.4 2.0 3.0

Ped, adults

Ped

1.5 1.8 2.2 3.0 3.3 4.0 2.3

Ped Ped Ped

3.2 2.9 3.0

Adults Ped, adults

1.9 2.9 19.8

Adults Ped, adults

10.1 2.7

Ped, adults Adults Ped

4.1 2.4 4.1 2.4

Ped Ped, adults Ped, adults

4.8 3.1 23.5

Ped, adults

2.8 2.8 4.6 1.4 1.9 2.3-7.9

Ped, adults

2.6-4.5 3.9-5.1 4.0 2.8 2.8

Ped, adults

Ped, adults

Ped Ped

w3 3.3 4.2 2.2 1.3 w2.0

Ped indicates pediatric; CMV, cytomegalovirus; CML, chronic myeloid leukemia; BCNU, 1,3-bis(2-chloroethyl)1-nitrosourea; BMT, bone marrow transplantation; SCT, stem cell transplantation.

Pretransplantation Patient-related Risk Factors Common pretransplantation patient-related factors associated with increased risk of VOD/SOS include young recipient age (eg, in patients <1 year of age, arising from immature liver metabolism), liver damage or prior liver transplantation in non-HSCT patients, Karnofsky

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performance scale score lower than 90, underlying disease (especially advanced malignancy), abdominal or liver radiation, and exposure to certain hepatotoxic drugs, particularly the anti-CD33 monoclonal antibodyecalicheamicin conjugate gemtuzumab ozogamicin [8,11,19,26,29,34]. Increased baseline levels of transaminase and bilirubin before HSCT are the most commonly identified risk factors for VOD/SOS [13,18]. Other associations have been noted with impaired pulmonary function, renal impairment after renal transplantation, and infection (eg, active viral hepatitis) or antibiotic use (some third-generation antibiotics such as cephalosporin can induce biliary sludge, which is a minor risk factor for VOD/SOS) [3,15,25]. Prior use of total parenteral nutrition (such as some antibiotics, total parenteral nutrition, and fasting can induce slow bile flow) also may increase risk. In adult females, use of progestin and norethisterone increases the risk of VOD/SOS [35]. Elevated serum ferritin levels also are associated with elevated risk [15,27]. Genetic factors, such as the GSTM1-null genotype, the hemochromatosis C282Y allele [24], and the MTHFR 677CC/1298CC haplotype in patients receiving high-dose oral BU for myeloablative conditioning [22,23], have been implicated in some cases. In addition, children with osteopetrosis have a very high risk of VOD/SOS. In 1 study of 20 pediatric patients undergoing HSCT for osteopetrosis, the VOD/SOS rate was 40% (8 of 20 patients) for the entire study group and nearly 64% (7 of 11 patients) for the historical control group [36]. Familial lymphohistiocytosis and juvenile myelomonocytic leukemia may also represent high-risk VOD/SOS-associated diseases. Transplantation-related Factors The risk of VOD/SOS also varies with the type of transplant a patient receives (Table 1). For example, the risk is substantially elevated for allogeneic HSCT, matched unrelated donors, and noneT celledepleted transplantations [3,11,33,37]. Donor human leukocyte antigen mismatch is also a factor in some studies. In the pediatric setting, use of multiple sequential autologous transplantations for verypoor prognosis tumors, such as stage IV neuroblastoma or other selected brain tumors, presents a substantial risk for developing sVOD/sSOS [38]. Certain conditioning agents and regimens, such as CY and BU (particularly oral BU) are associated with increased risk of VOD/SOS after HSCT [10,30,39]. In vitro, BU and CY metabolites deplete hepatic glutathione levels, inducing oxidative stress and hepatotoxicity [40]. High-intensity conditioning regimens, such as those based on full or high-dose BU or high-dose melphalan, significantly increase the risk of VOD/ SOS. Compared with oral BU, intravenous administration is associated with a lower risk of VOD/SOS when used as part of a RIC regimen or in myeloablative conditioning for allogeneic HSCT, a difference that seems likely to be due to better and more stable bioavailability and interpatient exposure [10,39]. Use of pharmacokinetic-based individualized dosing of BU (Bayesian individualization of dosage) to adjust for interpatient variability may lower the rate of VOD/SOS in pediatric patients undergoing autologous or allogeneic bone marrow transplantation [41]. Additionally, at least in adults, eligible patients may benefit from use of RIC regimens. These may result in a lower cumulative incidence of VOD/SOS compared with the incidence after myeloablative regimens (2.1% versus 8.4% since 1997 in a single-center retrospective analysis), although such differences may be due in part to less frequent use of BU in low-intensity regimens [29].

3

In a retrospective study of 193 HSCT patients, use of nonmyeloablative conditioning regimens (eg, total body irradiation 2 Gy with or without fludarabine) with allogeneic HSCT resulted in no cases of VOD/SOS [42], although, as noted earlier, a prospective study reported a VOD/SOS rate of 8.8% with a BU-based regimen [10]. In some reports, certain drugs used as GVHD prophylaxis during HSCT, such as cyclosporine A, sirolimus, and methotrexate (but not tacrolimus), may increase VOD/SOS risk, [15,20,32]. On the other hand, T cell depletion for prevention of GVHD may reduce risk, presumably by downregulating immune response integral to VOD/SOS [20]. This correlation may relate to the common mechanism of action for VOD/SOS and GVHD (ie, endothelial damage) [1]. Use of gemtuzumab ozogamicin shortly before HSCT raises risk of VOD/SOS, because it binds to CD33 on sinusoidal endothelial cells, inducing vasoconstriction and hepatocyte necrosis [16]. Likewise, treatment with inotuzumab ozogamicin, a novel anti-CD22ecalicheamicin conjugate active in acute lymphoblastic leukemia, was associated with a 17% risk of developing VOD/SOS after HSCT [43]. Finally, prior abdominal radiation and high-dose total body irradiation as part of myeloablative conditioning for HSCT conditioning both have been associated with an elevated risk of VOD/SOS [13,31]. Symptoms of VOD/SOS are typically observed within 30 days after HSCT and have been reported as early as day 1 after transplantation (Figure 1) [11]; however, later onset has also been observed [28]. In 1 study, VOD/SOS developed in 190 of 355 patients after transplantation; some symptoms of VOD/SOS (hepatomegaly or liver tenderness and weight gain >2% of baseline weight) occurred on the day of the transplantation [26]. These results suggest that early detection (and subsequent treatment) of VOD/SOS may be possible, supporting the need for prompt diagnosis before irreversible damage occurs. Before and after VOD/SOS diagnosis, patients undergoing either autologous or allogeneic transplantation should be monitored daily for weight gain, ascites, fluid overload, hepatomegaly, and fluid balance [34,44]. Liver function tests (eg, alkaline phosphatase, alanine aminotransferase, bilirubin, gamma glutamyl transpeptidase) should be checked several times per week. Monitoring should start with the conditioning regimen and be maintained for at least 14 to 21 days after HSCT [44]. CLINICAL PRESENTATION, DIAGNOSIS, AND RISK STRATIFICATION OF VOD/SOS VOD/SOS is clinically characterized by fluid retention and ascites, jaundice, weight gain (5%), and painful hepatomegaly, in the absence of other identifiable causes of liver disease (Table 2) [6,26,45]. Patients with sVOD/sSOS frequently have comorbidities, such as respiratory, renal, and cardiac failure, representing MOF. The presence of MOF is commonly used as a prospective indicator of sVOD/sSOS [34]. These clinical criteria may be complemented by noninvasive testing, such as ultrasonography, to identify ascites, hepatomegaly, gallbladder wall thickening, and attenuated or reversed hepatic venous flow; however, none of these symptoms are specific to VOD/SOS. The use of invasive testing (eg, percutaneous or transjugular liver biopsy) must be weighed against the risk of bleeding associated with such procedures [6]. Diagnosis of VOD/SOS is largely based on retrospectively developed clinical criteria, primarily the Baltimore and modified Seattle criteria (Table 3), which differ slightly from Q 1 each another in the number and magnitude of clinical

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Figure 1. Timing of VOD/SOS onset in transplantation patients [6,13]. HSCT, hematopoietic stem cell transplantation; PB, peripheral blood; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.

features required for a positive diagnosis and in the time of assessment after HSCT [4,6,45]. Laboratory findings associated with VOD/SOS include elevated aminotransferases, hyperbilirubinemia (conjugated), prolonged prothrombin time, and signs of decreased synthetic function (eg, low albumin) [19]. The triad of weight gain (often ascites), right upper quadrant pain or hepatomegaly, and elevated bilirubin is common in sVOD/sSOS but variable in less severe cases and may be either incomplete or delayed in pediatric patients compared with adults. A bilirubin level of 20 mg/dL by day 20 (the “20 by 20” rule) predicts a poor outcome. However, a recent study found that 5 of 17 (29%) of pediatric patients who developed VOD/SOS after HSCT did not have hyperbilirubinemia at diagnosis, so elevated bilirubin is not a prerequisite for a diagnosis of VOD/SOS [47]. VOD/SOS has been classified retrospectively as mild, moderate, or severe based on severity of the disease, including degree of hepatic dysfunction and the need for therapy [26]. These criteria are loosely defined, however, and they cannot be used to predict risk or guide VOD/SOS treatment. Chao has proposed classifying VOD/SOS severity based on a combination of bilirubin levels and baseline parameters and their rate of change, emphasizing that patient status may change quickly, and this classification has been further adapted by Carreras (Table 4) [19,44]. Other clinical data that might suggest VOD/SOS include elevated serum ALT, esophQ 2 ageal varices, and thrombocytopenia and consumption of transfused platelets [44]. Clinical signs that could be consistent with the presence of MOF (ie, sVOD/sSOS) are confusion, encephalopathy, renal insufficiency or failure, pleural effusion or infiltrates, and hypoxia. Differential diagnosis of VOD/SOS is critical because other syndromes may present a similar clinical profile and should

be excluded (eg, hyperacute hepatic GVHD, autoimmune hepatitis, cholestasis of sepsis, biliary obstruction, infection such as fungal abscess and viral hepatitis, drug toxicity, right heart failure) [44]. Additional factors that may contribute to the clinical profile of VOD/SOS, including reduction of venous outflow due to fluid overload or renal failure, comorbidities, pancreatic or chylous ascites, and infiltration of the liver, also should be evaluated [31]. Various imaging techniques, such as ultrasound imaging with Doppler studies or computed tomography, although not highly specific or highly sensitive for VOD/SOS, may be helpful when used in conjunction with clinical criteria for diagnosis, risk stratification, severity grading, and assessment of treatment response [6,19,34]. Abnormalities suggestive of VOD/SOS on ultrasound (the primary imaging modality) include reversal of portal vein flow; abnormal portal vein waveform; ascites; morphologic changes, such as gallbladder wall thickening and hepatomegaly; and hepatic artery resistance index of .75 or greater. Although these tests are not diagnostic, they can suggest a diagnosis of VOD/SOS. In 1 study, a multivariate analysis demonstrated that 2 ultrasound criteria (splenomegaly and ascites) and 1 Doppler criterion (flow recorded in paraumbilical vein) correlated with VOD/SOS severity, and this method could differentiate between VOD/SOS and hepatic GVHD [48]. Other investigators also found a positive prognostic value of ultrasound [49]. However, some studies reported that this technique did not show any benefit over clinical criteria in diagnosing VOD/SOS [50]. Other imaging techniques, such as magnetic resonance imaging, can be of value in diagnosing VOD/SOS [34]. A transjugular liver biopsy with hemodynamic evaluation is recommended by some authors when VOD/SOS is suspected, although this should be reserved for patients in

Table 2 Clinical Features Associated with Hepatic Veno-occlusive Disease, According to Severity [26]. Severity

Weight Gain, % increase

Maximum Total Serum Bilirubin before Day 20, mg/dL

Patients with Peripheral Edema, %

Patients with Ascites, %

Day 100 Mortality (all causes), %

Mild Moderate Severe

7.0  3.5 10.1  5.3 15.5  9.2

4.7  2.9 7.9  6.6 26.0  15.2

23 70 85

5 16 48

9 23 98

Data expressed as mean  standard deviation.

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5

Table 3 Clinical Criteria for Hepatic Veno-occlusive Disease [4,6,46]. Modified Seattle Criteria* [4]

Baltimore Criteria [45]

In the first 20 days after HSCT, the presence of 2 of the following:  Bilirubin >2 mg/dL (>34 mmol/L)  Hepatomegaly or pain in right upper quadrant  Weight gain (>2% basal weight)

In the first 21 days after HSCT, the presence of bilirubin >2 mg/dL (>34 mmol/L) plus 2 of the following:  Painful hepatomegaly  Ascites  Weight gain (>5% basal weight)

*

The Seattle criteria have been further modified in some studies, which have used unexplained weight gain of >5% from baseline [46].

whom this diagnosis is unclear, because of the risk of this technique [6]. Transvenous liver biopsy, to assess transhepatic wedge pressure, and wedged hepatic venous pressure gradient measurement are usually definitive for this diagnosis. In wedged hepatic venous pressure gradient measurement, a gradient of >10 mm has been associated with a specificity of 91% and a positive predictive value of 86% for VOD/SOS [6]. However, with rare exceptions, these invasive techniques should be avoided because of the risk for hemorrhage [13,44,45]. For most patients, VOD/SOS with a maximum severity of mild is typically self-limiting and does not require treatment. Those with a maximum VOD/SOS of moderate severity require pain medication, diuretics, and/or supportive care, but usually recover [26,44]. It should be noted, however, that the risk of morbidity and mortality with retrospectively classified mild to moderate VOD/SOS is still substantial. A retrospective analysis found that 67% of confirmed VOD/SOS cases were mild to moderate in severity per the Seattle criteria [29], although this percentage varied among studies [26,32]. In general, mortality rates increase as VOD/SOS progresses. For example, in a cohort of patients who underwent bone marrow transplantation and then developed VOD/SOS, the mortality rates for mild, moderate, and severe forms of the disease were 9%, 23%, and 98%, respectively [26]. Moreover, patients with mild or moderate disease can still experience significant clinical issues, such as peripheral edema (70%), renal insufficiency (38%), pulmonary infiltrates (36%), ascites (20%), and need for oxygen support (31%) [13,32]. Other studies have found that such patients can progress to interstitial pneumonitis, thrombocytopenia refractory to platelet transfusion, and/or progressive decline in hepatic function leading to prolonged prothrombin time and deficiencies in coagulation factors [51,52]. Because VOD/ SOS is a dynamic process and patients can progress rapidly from milder forms to more severe disease, early identification is essential. Some cases of sVOD/sSOS occur in which symptoms do not resolve. Characteristics of sVOD/sSOS include a rapid increase in the severity of VOD/SOS symptoms compared with mild VOD/SOS, and a significantly higher risk of Table 4 Proposed Grading of VOD/SOS Severity [19,44]. Endpoints

VOD/SOS Grade Mild*

Moderate*

Severe*

Bilirubin (mg/dL) Liver function Weight above baseline Renal function Rate of change, d

2.0-3.0 <3  normal 2%

3.1-5.0 3-5  normal 2.1%-5%

>5.0 >5  normal >5%

Normal Slow (over 6-7 days)

<2  normal Moderate (over 4-5 days)

2  normal Rapid (over 2-3 days)y

* y

Two or more of the following. Or creatinine clearance 50%.

mortality (sVOD/sSOS mortality rate is >80% by day þ100) [1,26]. Death due to sVOD/sSOS can result from kidney or heart failure, respiratory failure and pleural effusion, encephalopathy, bleeding in lungs or intestines, infection, or MOF [1,26]. In a cohort of 845 patients who underwent allogeneic HSCT, 32% to 48% of those who developed VOD/ SOD were judged to have sVOD/sSOS by modified Seattle and Baltimore criteria, respectively [29]. PREVENTION AND MANAGEMENT OF VOD/SOS Historically, management of VOD/SOS involved primarily supportive care (diuretics, dialysis, oxygen) and use of anticoagulants or antifibrinolytics; however, their efficacy is often limited, and adverse events can be significant (eg, fatal bleeding with heparin). For patients with VOD/SOS, the goal of supportive care should be to minimize extracellular fluid overload without worsening renal function. Maintenance of baseline weight should be a goal of treatment. Some patients may develop ascites with or without pleural effusion, or pulmonary infiltrates in the absence of ascites, and become hypoxemic. Hemodialysis may be necessary for patients with renal failure after VOD/SOS. Those with MOF require a high level of intensive care. Currently, pharmacologic options for VOD/SOS are very limited. Defibrotide is the only agent in the European Union that is approved for treatment of sVOD/sSOS and no agents in the United States are approved for treatment or prevention of any severity of VOD/SOS, highlighting a significant unmet clinical need. Agents with distinct mechanisms of action, including ursodeoxycholic acid (UDCA), defibrotide, and antithrombin, have shown varying degrees of promise for treatment and/or prophylaxis of VOD/SOS. Key pharmacological approaches for treatment of VOD/SOS and its prophylaxis are discussed below. Heparin for Prophylaxis of VOD/SOS Unfractionated heparin and low-molecular-weight heparin were shown to be effective when used as VOD/SOS prophylaxis in some trials but not in others [21,53-55]. Heparin was found to be effective in some studies of patients undergoing HSCT, used alone or in combination with lipo-prostaglandin E1 or UDCA [56,57]. Conversely, a metaanalysis and systematic review, which included 12 studies of prophylactic low-molecular-weight heparin or unfractionated heparin, found no significant reduction in risk of VOD/ SOS, although 2 of 3 eligible randomized controlled trials suggested prophylactic heparin may help prevent VOD/SOS [58]. Because of the significant risk of hemorrhage and lack of consistent efficacy among studies, heparin is no longer recommended for VOD/SOS prophylaxis [34]. UDCA Acid for Prophylaxis of VOD/SOS UDCA is a hydrophilic bile acid that may be useful in the prophylaxis and treatment of certain liver conditions. In

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randomized controlled trials and historically controlled studies, UDCA resulted in a reduction in VOD/SOS and mortality. Several small studies and a meta-analysis of 3 randomized controlled trials demonstrated significant reductions in risk of VOD/SOS with UDCA therapy [59-61]. Consequently, prophylaxis with UDCA is recommended by the European Society for Blood and Marrow Transplantation Handbook and the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines [6,34]. Additionally, the combination of UDCA and defibrotide can be considered for prophylaxis in patients at high risk for VOD/SOS [34]. Data for the combination of UDCA and heparin are mixed [61]. Antithrombin for Prophylaxis of VOD/SOS Antithrombin may be beneficial as VOD/SOS prophylaxis when used early in the course of the disease to prevent or slow pathologic progression [62]. However, it is seldom used for VOD/SOS treatment because of the increased risk of hemorrhage, and is contraindicated for patients with MOF. A retrospective study of 48 post-HSCT patients treated early with antithrombin reported no significant treatment-related morbidity, with an overall mortality rate of 17% [63]. In a prospective study of antithrombin prophylaxis in pediatric patients, no difference in the incidence of VOD/SOS was observed versus historical controls [64]. Defibrotide Defibrotide is a sodium salt of complex single-stranded oligodeoxyribonucleotides derived from porcine intestinal mucosa DNA [65]. Its mechanism of action is complex and not completely elucidated but is thought to involve endothelial protection and restoration of the thrombofibronolytic balance. Defibrotide is approved in the European Union for the treatment of sVOD/sSOS in HSCT therapy, in adults and in adolescents, children, and infants older than 1 month of age [66]. In the United States, defibrotide is not currently licensed and is available only through an expanded-access, protocol-directed treatment as an investigational new drug (IND; ClinicalTrials.gov identifier NCT00628498). Current British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines support use of defibrotide for VOD/SOS prevention and treatment in pediatric and adult patients [34], and it is recommended by the European Society for Blood and Marrow Transplantation as therapy for VOD/SOS [6,34,66]. Defibrotide for treatment of sVOD/sSOS In the pivotal phase 3 trial of defibrotide for treatment of sVOD/sSOS (as characterized by MOF), a higher day þ100 complete response (CR) (defined as total bilirubin <2 mg/dL and resolution of MOF) and lower day þ100 mortality rate were observed with defibrotide compared with historical controls [67,68]. The phase 3 trial enrolled 102 adult and pediatric patients treated with 25 mg/kg/day of defibrotide who were compared with 32 matched historical control patients selected by an independent medical review committee. Day þ100 CR was observed in 24 of 102 (24%) of treated patients and 3 of 32 (9%) of historical controls (chi-square test, P ¼ .013). Baseline characteristics were quite similar between these 2 rigorously selected, relatively contemporaneous groups of patients receiving HSCT at the same group of centers. Day þ100 survival rates were 38% and 25%, respectively (log-rank test, P ¼ .034) (Figure 2); the

Figure 2. Phase 3 trial of defibrotide treatment in a phase 3 trial for severe VOD/SOS [67]. Difference in CR rate based on 99% confidence interval. CR, complete response; DF, defibrotide; HC, historical controls; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.

treatment group survival rate was comparable to that observed in other defibrotide trials. It should be noted that in the setting of high mortality and initial favorable results in an early defibrotide studies [32,37], a placebo-controlled randomized trial was considered to be ethically problematic given the sound option of a historical control for comparison. An expanded-access treatment IND initiated in the United States in 2007 is evaluating defibrotide in both patients with sVOD/sSOS (characterized by MOF) and those with nonsevere VOD/SOS after HSCT or VOD/SOS after chemotherapy [69]. This trial is the largest prospective study of defibrotide in these patient populations and it is the only current mechanism for US patients to receive this agent. To date, the study has enrolled 641 patients in the expanded-access treatment IND. Interim results indicate that at day þ100, the survival rate among 526 patients (283 ages  16 years; 243 ages > 16 years) after HSCT was 58% for pediatric and 45% for adult patients (Table 5) [69]. Higher survival rates in the subgroups of patients with nonsevere VOD (67% for pediatric and 52% for adult patients) suggest that further study may be warranted to determine the impact of treatment earlier in the course of VOD. Survival in the small group of postchemotherapy patients was also favorable (83% for pediatric and 60% for adult patients). Treatment-related adverse events were reported in <25% of patients. In an international compassionate use program, data were voluntarily provided for 710 patients who received at least 1 documented dose (recommendation: 10 mg/kg/day to 60 mg/kg/day) of defibrotide; the Kaplan-Meier estimated day þ100 survival was 54%, with a survival rate of 58% in patients receiving 25/mg/kg/day (the approved dose in the European Union) [70].

Table 5 Day þ100 Survival in Defibrotide Treatment-IND Study [69].

After HSCT, all patients sVOD/sSOS only Nonsevere VOD/SOS only After chemotherapy, all patients sVOD/sSOS only

Q5

Pediatric, % (n/N)

Adult, % (n/N)

58 50 67 83 77

45 38 52 60 67

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(163 of 283) (79 of 157) (84 of 126) (39 of 47) (20 of 26)

(109 of 243) (46 of 122) (63 of 121) (9 of 15) (4 of 6)

712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776

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777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841

Defibrotide for VOD/SOS prophylaxis In high-risk patients, defibrotide was found to be effective as prophylaxis for pediatric VOD/SOS and demonstrated a favorable safety profile. In a phase 3 randomized trial, 356 pediatric HSCT patients were treated prophylactically with defibrotide or received standard care in the context of either autologous or allogeneic transplantation [46]. VOD/SOS occurred in 22 (12%) of 180 defibrotide patients versus 35 (20%) of 176 controls, with less morbidity on the defibrotide arm (risk difference, 7.7%; 95% confidence interval 15.3 to .1; log-rank test P ¼ .0507). In allogeneic HSCT patients (intent-to-treat analysis), the incidence and severity of acute GVHD were significantly lower in the defibrotide arm compared with the control group (day 30: incidence P ¼ .0057 and severity P ¼ .0062; day 100: incidence P ¼ .0046 and severity P ¼ .0034). The incidences of nonsevere and severe adverse events and events leading to study discontinuation were comparable between the study arms. The study was not designed to assess mortality, and patients in either arm who developed VOD/SOS received treatment with defibrotide. High-dose Methylprednisolone for Treatment of VOD/SOS Several small studies have evaluated high-dose methylprednisolone in patients with VOD/SOS, which in some cases was followed by defibrotide maintenance therapy. A trial in 48 patients with VOD/SOS (w30% with sVOD/sSOS) undergoing allogeneic HSCT assessed response to high-dose methylprednisolone. Responses were seen in 63% of patients, with a 58% survival rate among responders [71]. In a study of pediatric HSCT patients, early treatment with high-dose steroids resulted in responses in 6 of 9 patients, occurring within 3 to 6 days [72]. The side effects of methylprednisolone may be dose limiting, however. High-dose methylprednisolone may be considered for treatment of VOD/SOS but should be used with caution due to risk of infection [34]. Tissue Plasminogen Activator for Treatment of VOD/SOS Use of tissue plasminogen activator (tPA) for treatment of VOD/SOS has been evaluated mostly in small studies. Treatment data for tPA in combination with heparin are mixed, with a risk of bleeding complications [73,74]. The largest study retrospectively evaluated recombinant human tPA plus heparin for treatment of VOD/SOS in 42 HSCT patients (10 with sVOD/sSOS); a 29% response rate was reported, but bleeding occurred in 88% of patients (severe in 28%) [75]. In studies of tPA, bleeding complications were more common in patients with moderate/severe VOD/SOS [76]. It is no longer recommended for treatment of VOD/SOS because of the risk of hemorrhage [34]. Other Therapies Use of transjugular intrahepatic porto-systemic shunt has been shown to reduce ascites in some patients with VOD/SOS but not in others [35,40,77]. Similarly, liver transplantation can be beneficial in some patients, but it is only appropriate for those with severe liver failure. It is usually contraindicated in patients with cancer because of high recurrence rates, and the risk of rejection and GVHD must be weighed [35]. CURRENT PRACTICE Risk Stratification and Strategic Treatment Options for Patients at Risk of Developing VOD/SOS At present, there is a lack of clear and strong risk stratification or risk scoring to identify patients requiring

7

prophylaxis for VOD/SOS, select the optimal type of prophylaxis, and identify those patients needing early intervention versus those whose condition will resolve without treatment. Bearman et al. developed a logistic regression model to predict development of sVOD/sSOS and MOF at various times after HSCT when used with intensive conditioning regimens (eg, CY þ total body irradiation, CY þ BU) [78]. This model, based on total serum bilirubin level and early percent weight gain, estimated 50% or higher probability of developing sVOD/sSOS. Use of such a model could allow for better decision-making regarding early identification and treatment of patients at high risk for developing sVOD/sSOS and MOF. The limitations of this model were that it only identified a proportion of patients developing VOD/SOS (ie, in the initial 16 days), although late VOD/SOS can develop in some patients, especially in those receiving alkylating agents [79]. Additionally, it only applied to CY-based intensive preparative regimens and did not account for patients with liver disease of unknown etiology. Some current specific and supportive VOD/SOS therapies were not available at the time of study (1993), and no prophylaxis was given. However, the findings that the likelihood of sVOD/sSOS is increased if weight gain and jaundice occur early after transplantation, or if the degree of weight gain or rise in bilirubin are marked, are likely to remain true today. Identification of VOD/SOS risk factors in these patient populations thus may better identify which patients are at high risk and should receive prophylaxis for VOD/SOS. Treatment/Prophylaxis of High-Risk Patients The absence of both consensus and labeling for VOD/SOS prophylaxis preclude the development of definitive treatment recommendations. Indeed, each hematological team should carefully consider and develop their own guidelines, depending on the evolution of medical knowledge and the kind of patients they treat. The foremost preventive measure is probably to minimize or avoid, for as long as possible, any additional risk factors in patients who are at elevated risk to develop VOD/SOS (eg, less risk with RIC versus myeloablative conditioning regimens, pharmacologic monitoring of BU dosing). However, this approach is not always possible for all patients. Recommendations to minimize the occurrence of VOD/SOS are provided in Table 6. The authors assume that every patient presenting with at least 1 of the risk factors described above should receive prophylaxis. To date, no drugs have received such a label indication. Prior available data led us to prescribe either UDCA or low-dose heparin therapy as prophylactic treatment, although some physicians may decide to follow the wider and stronger British guidelines indicating defibrotide as VOD/SOS prophylaxis. Defibrotide is the only drug in the European Union currently indicated for treatment of sVOD/sSOS after HSCT (it is investigational in the United States), based on the Table 6 Recommendations for the Prevention of VOD/SOS in Hematopoietic Stem Cell Transplantation Recipients  Avoid the use of hepatotoxins during conditioning (eg, azoles, acetaminophen).  Identify drug-drug interactions in preparative regimens and modify as appropriate.  Risk-adjust preparative regimen intensity according to hematopoietic cell transplantation-comorbidity index.  Pharmacologic monitoring of busulfan.  Avoid the use of progesterone and estrogen if possible.

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842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906

8

907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971

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results of the pivotal phase 3 trial discussed above, where a significantly higher proportion of patients in the defibrotidetreated group achieved a CR. Day þ100 survival rate was improved in the defibrotide group, with 38.2% of the patients surviving versus 25% in the historical control group [66]. IMPORTANCE OF EARLY INTERVENTION AND TREATMENT OF MILD TO MODERATE VOD/SOS Several studies support early identification and treatment before progression to sVOD/sSOS [11,68,80]. In a retrospective pediatric defibrotide study, the average delay from diagnosis of VOD/SOS to specific treatment initiation was 1 day in the CR group compared with 5.5 days in those who did not respond (P < .01) [80]. In a separate interim analysis of the treatment IND study in 425 patients who had undergone HSCT, a delay of >2 days (versus 2 days) in the start of defibrotide after VOD/SOS diagnosis resulted in reduced CR rate (25% versus 39%, P ¼ .0052) and survival rate (KaplanMeier estimate) (38% versus 61%, P < .0001) [81]. A study by McDonald and colleagues found that clinical onset of VOD/ SOS was observed in many patients before bone marrow transplantation [26]. Consequently, early treatment of VOD/ SOS may be superior to delayed therapy. Prompt identification of patients at increased risk of sVOD/sSOS is possible because of early onset of key clinical signs and symptoms (eg, greater weight gain and higher total serum bilirubin by day 20, and often respiratory, renal, and cardiac failure) [13,26]. Therefore, treatment should be initiated as soon as possible and is recommended for patients at risk of developing moderate to severe VOD/SOS to prevent disease progression and development of sVOD/sSOS [11,72]. Preliminary data suggest that some patients may progress to VOD/SOS even if they do not meet all current diagnostic criteria at presentation. For example, in a study of nearly 800 pediatric HSCT patients, 17 developed VOD/SOS, 5 (29%) of whom lacked elevated bilirubin at VOD/SOS diagnosis and reversal of portal venous flow [47]. For patients with some diagnostic criteria of VOD/SOS, such as hepatomegaly, weight gain, ascites, or abdominal pain but in the absence of increased bilirubin, a diagnosis of VOD/SOS should be considered. Waiting for such patients to meet prespecified diagnostic criteria could delay the benefits of subsequent VOD/SOS therapy. One proposal is that early ultrasound evaluation in such patients might facilitate a diagnosis of VOD/SOS, and thus allow for earlier and more effective therapeutic interventions [47]. CONCLUSIONS Recent changes in the management of patients requiring HSCT, including RIC regimens, more effective agents, and better supportive care, have resulted in reduced toxicity and improved outcomes. However, VOD/SOS remains an important cause of post-HSCT mortality, and identification of patient-specific and transplantation-specific risk factors for the development of VOD/SOS can help guide treatment decisions. Although the use of the Baltimore and Seattle criteria have been helpful, it may be worthwhile to consider additional factors that could improve differential diagnosis. These factors include, but are not limited to, elevation of serum alanine aminotransferase, thrombocytopenia with rapid platelet consumption, attenuated or reversed hepatic venous flow by ultrasound, esophageal varices, and their rates of change [44]. Rapid, accurate diagnosis and risk assessment, and early initiation of effective treatment, are key to preventing

progression to MOF and sVOD/sSOS and to improving outcomes and survival. Indeed, although treatment has historically been reserved for patients with moderate to severe VOD/SOS, early and/or increased use of VOD/SOS treatment and prophylaxis may be especially warranted in patients at high risk of VOD/SOS (eg, sirolimus or gemtuzumab treatment, patients with mismatched/unrelated allogeneic HSCT). ACKNOWLEDGMENTS The Curry Rockefeller Group, LLC, provided editorial assistance in developing this manuscript, which was funded by Jazz Pharmaceuticals, Inc. Jazz Pharmaceuticals, Inc., did Q 3 not influence or control the content of the publication. Financial disclosure statement: S.G. has a financial interest/ relationship or affiliation in the form of honoraria from Celgene Corporation, Jazz Pharmaceuticals plc, and Takeda Pharmaceuticals U.S.A., Inc. and membership on an advisory board for Celgene Corporation, Jazz Pharmaceuticals plc, and Takeda Pharmaceuticals U.S.A., Inc. J-H.D. received honoraria and/or research support from Jazz Pharmaceuticals plc. Conflict of interest statement: ---. Q4 REFERENCES 1. Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16:157-168. 2. 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 leukemia. S Afr Med J. 1979;55:5-10. 3. 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. 4. McDonald GB, Sharma P, Matthews DE, et al. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4:116-122. 5. Ho VT, Revta C, Richardson PG. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies. Bone Marrow Transplant. 2008; 41:229-237. 6. Carreras E. Early complications after HSCT. In: Apperley J, Carreras E, Gluckman E, Masszi T, editors. The EBMT-ESH Handbook on Haemopoietic Stem Cell Transplantation (Chapter 11). Available at: http:// ebmtonline.forumservice.net/media/11/tex/content_alt/EBMT_Handbook 2012_CHAP11.pdf; 2012. Accessed May 13, 2015. 7. Pihusch M, Wegner H, Goehring P, et al. Diagnosis of hepatic venoocclusive disease by plasminogen activator inhibitor-1 plasma antigen levels: a prospective analysis in 350 allogeneic hematopoietic stem cell recipients. Transplantation. 2005;80:1376-1382. 8. Cutler C, Kim HT, Ayanian S, et al. Prediction of veno-occlusive disease using biomarkers of endothelial injury. Biol Blood Marrow Transplant. 2010;16:1180-1185. 9. Corbacioglu S, Kernan N, Lehmann L, et al. Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Expert Rev Hematol. 2012;5:291-302. 10. Tsirigotis PD, Resnick IB, Avni B, et al. Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen. Bone Marrow Transplant. 2014;49:1389-1392. 11. 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. 12. 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. 13. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85:3005-3020. 14. Carreras E, Bertz H, Arcese W, et al. 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. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood. 1998;92:35993604. 15. Maximova N, Ferrara G, Minute M, et al. Experience from a single paediatric transplant centre with identification of some protective and risk factors concerning the development of hepatic veno-occlusive

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1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101

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