A feared complication of haematopoietic stem cell transplantation is veno-occlusive disease, a serious condition associated with multi-organ failure and mortality rates ranging up to 98% for severe disease in adults
Tiene Bauters PharmD PhD
Department of Pharmacy and
Department of Pediatric Hematology-Oncology and
Stem Cell Transplantation, Ghent University Hospital, Belgium
Stem Cell Transplantation, Ghent University Hospital, Belgium
Veno-occlusive disease (VOD) of the liver is a serious condition often associated with multi-organ failure and mortality rates ranging up to 90%. It is commonly referred to as hepatic sinusoidal obstructive syndrome due to the associated characteristic histopathological findings. VOD is one of the most feared complications of allogeneic and autologous haematopoietic stem cell transplantation (HSCT).1–5
The term VOD is used to designate a number of signs and symptoms that appear soon after HSCT. It occurs most often in patients undergoing HSCT but can also be induced by ingestion of alkaloid toxins, after high dose radiation therapy to the liver, oral contraceptives, from the use of terbinafine, toxic oil and alcohol.1,3 It has also been reported after solid organ transplantation, particularly after kidney transplantation but also after liver transplantation.
In 1979, the first reported case of VOD was associated with HSCT.3 Since then, HSCT has become the most important and frequent cause of VOD.3
The pathogenesis of VOD is complex. HSCT involves high-dose cytotoxic chemotherapy, which produces endothelial injury in sinusoids and small hepatic venules. This leads to activation of the coagulation cascade.3 Hepatic venous outflow obstruction is the consequence of occlusion of terminal hepatic venules with subendothelial deposition of fibrin, factor VIII and Von Willebrand factor multimers. This leads to centrilobular necrosis, post-sinusoidal obstruction and portal hypertension. Fibrosis usually occurs several weeks after onset of the disease.1–3
Other factors contributing to the damage in VOD are the release of cytokines (TNF-a, interleukin-1 and -2) and the use of cyclosporine in patients with graft-versus-host disease.3
Genetic and secondary susceptibility of the liver play a major role.1,3
Incidences of hepatic VOD vary between studies depending upon baseline risk factors, type of HSCT transplantation and conditioning regimen, and the criteria used for diagnosis. Reported incidences in paediatrics are between 27 and 40%.4 The mean prevalence in adults is estimated at 14% with rates from 5–60%1,5 ranging in severity from mild, reversible disease to a severe syndrome associated with multi-organ failure and even death.1,3–6
Risk factors for development of VOD
- Conditioning regimens given prior to HSCT that are associated with a higher incidence of VOD include those with high doses radiotherapy and chemotherapy including busulfan (oral more than intravenous), busulfan with cyclophosphamide, fludarabine, cytarabine, cyclophosphamide, carmustine, melphalan, 6-mercaptopurine, azathioprine and dacarbazine.
- The risk of VOD is higher after allogeneic transplantation than after autologous transplantation.
- Pre-existing hepatic disease: Hepatic dysfunction may be the result of previous treatments, including abdominal irradiation or use of gemtuzumab ozogamicin.6
- Pre-existing hepatic dysfunction impairing drug metabolism, hypoalbuminemia, hyperbilirubinemia, and a history of pancreatitis or viral hepatitis infection may also contribute to hepatic toxicity.1
- Patient factors such as young age in children (less than six to seven years) and older age in adults.
- Disease factors including acute leukaemia, neuroblastoma, advanced malignancy, presence of graft versus host disease and thalassaemia major.
- Treatment factors such as allogeneic HSCT, unrelated donor, mismatched donor, second or subsequent transplants etc.
- Choice of prophylaxis against graft versus host disease: Regimens using a combination of tacrolimus, sirolimus and methotrexate are associated with a higher rate of VOD compared to the combination of tacrolimus and methotrexate.1,3
- Less established potential risk factors such as use of vancomycin, acyclovir prior to or during HSCT, abnormal lung diffusing capacity and female gender (possibly due to use of progesterone) and use of sirolimus.
Hepatic VOD usually presents in the early post-transplantation period with patients developing signs and symptoms within the first three weeks after HSCT although VOD has been reported to occur after this period.1–5
The classic presentation of the condition is characterised by the triad of weight gain caused by fluid retention, tender hepatomegaly and hyperbilirubinemia without any known cause.1,3,7
Classical VOD occurs within days after conditioning (from day –1 to day +14) and is characterised by the presence of jaundice (in almost all patients), hepatomegaly and/or right upper quadrant pain and weight gain with oedema and ascites.7
Late VOD has the same clinical manifestations as classical VOD but develops late after HSCT. This is mostly observed in conditioning regimens including several alkylating agents in combination (for example, busulfan, melphalan, thiotepa).7
VOD with multiple organ failure means that patients can have the clinical manifestations as described above plus thrombocytopenia, pleural effusion/pulmonary infiltrates, progressive renal, cardiac, pulmonary failure, confusion, encephalopathy and coma.7
The diagnosis of VOD must be established clinically. Two sets of criteria are used to diagnose VOD based on clinical criteria: the modified Seattle criteria and the Baltimore criteria.1,3,6,7
The modified Seattle criteria define hepatic VOD by occurrence of two or more of the following events within 20 days of HSCT:
- Hyperbilirubinemia (≥2mg/dl).
- Hepatomegaly or right upper quadrant pain of liver origin.
- Unexplained weight gain (>2% from the pre-transplant weight) because of fluid accumulation.
The Baltimore criteria define hepatic VOD by:
Elevated total serum bilirubin (≥2mg/dl) within 21 days of HSCT plus at least two of the following criteria:
– Painful hepatomegaly
– Weight gain (>5% from the pre-transplant weight)
To establish the diagnosis of VOD, all the possible causes of similar clinical features should be excluded, including infections (fungal, viral etc.), immune dysfunctions (acute graft versus host disease of the liver), drug toxicity (caused by cyclosporine, azoles, methotrexate, trimethoprim/sulfamethoxazole, total parenteral nutrition), reduction of venous outflow/increased volume and others like pancreatic ascites and infiltration of the liver.
Additional investigations that can aid the diagnosis are a haemodynamic study of the liver, liver biopsy, biological markers and ultrasounds.
Prognosis and outcome
Milder cases of hepatic VOD usually resolve spontaneously. Between 50–80% of patients with VOD may recover without any treatment other than supportive care. Severe VOD has been associated with mortalities of up to 98% in adults3,8 and 62% in children.8 Prognosis depends on the extent of hepatic injury, liver dysfunction and the presence of multiple organ failure.
Prevention of VOD
Certain pre-transplant factors and characteristics are associated with an increased risk of VOD as described above.1,3,6,7
Physicians can minimise risk factors, for example, by minimising exposure to hepatotoxic agents (overuse of paracetamol, alcohol) and considering the conditioning regimen. Patients with liver cirrhosis receiving myeloablative conditioning are at particular risk. Reduced intensity conditioning regimens should be considered if possible.
When a busulfan-containing regimen is necessary in high-risk patients, pharmacokinetic monitoring of busulfan should be considered.1–3
The choice of graft versus host disease prophylaxis should also be considered.
Although there is no general accepted standard for prophylaxis of VOD, most prophylactic regimens include ursodeoxycholic acid (allogeneic patients) and low dose heparins (autologous patients). The use of these products in the respective patient populations is supported by results of randomised trials demonstrating good tolerability and reduced incidence of VOD compared to placebo.1
Ursodeoxycholic acid, being an antioxidant and an anti-apoptotic agent, is a hydrophilic bile acid that results in the reduction of hydrophobic bile acids, which can be toxic to hepatic parenchymal cells. Ursodeoxycholic acid is used in a total daily dose of 12mg/kg or 600mg, divided into two doses. It is started from the day preceding the conditioning regimen and continued for the first three months post-transplantation.
Ursodeoxycholic acid is generally well tolerated and has limited side effects, such as headache, diarrhoea and constipation.1
Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have been studied in the prophylaxis of VOD.1,6 Unfractionated heparin (low dose, 100IU/kg per day by continuous infusion) is suggested for most patients undergoing autologous transplantation. UFH is started on the first day of the conditioning regimen and continued until haematopoietic engraftment.1
A systematic review and meta-analysis on the use of LMWH or UFH in the prophylaxis of VOD reported that anticoagulation did not significantly reduce the risk of VOD.6
The Haemato-oncology Task Force of British Committee for Standards in Haematology (BCSH) and British Society for Blood and Marrow Transplantation (BSBMT) do not suggest heparins (UFH and LMWH) for use in the prophylaxis of VOD due to the risk of increased toxicity.6
Although retrospective studies in adults and children and randomised trials in children have reported significant reduction in the incidence of VOD when using defibrotide in prophylaxis, it is mostly reserved for treatment of VOD.1,9 The BCSH and the BSBMT recommend defibrotide for prophylaxis (in specific patient populations) and treatment of VOD.6
Antithrombin is not suggested for prophylaxis of VOD due to a lack of efficacy.1,6
Prostaglandin E1 is a vasodilator with protective properties for the endothelium and with anti-thrombotic activity. Its use is not recommended for the prophylaxis of VOD due to a lack of efficacy and toxicity.3,6
Pentoxifylline is not recommended for the prophylaxis of VOD due to a lack of efficacy.6
Apart from pharmacological treatment, classical VOD also needs supportive measures. Early discussion with critical care unit specialists and hepatology unit specialists is recommended.6
Defibrotide is a single stranded poly-deoxyribonucleotide adenosine receptor agonist derived from porcine mucosa. The exact mechanism of action has not been fully clarified.1,10,11 It increases endogenous prostaglandin E2, prostacyclin and thrombomodulin and inhibits fibrin deposition. It has anti-inflammatory, anti-ischaemic and anti-thrombotic properties but lacks systemic anti-coagulant effects.2,6,10–13 It has a protective effect against endothelial injury.6
The efficacy of defibrotide in severe hepatic VOD after HSCT is supported by results of a Phase II dose-finding study, data of an international compassionate use programme, information provided from an independent transplant registry and a pivotal multicentre Phase III trial.6,12,13
Intravenous defibrotide is generally well tolerated and is not associated with an increased risk of haemorrhagic adverse events.6,1,13
The frequency of reported adverse reactions was less than 9% and there were no serious adverse events. The most reported side effects during pre-marketing use were haemorrhage, hypotension and coagulopathy.
Defibrotide has not been associated with an increased bleeding risk despite reducing pro-coagulant activity, increasing fibrinolysis and modulating platelet activity.6 Gastrointestinal disturbances were also recorded.1,6,10,13,14
In July 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) gave a positive opinion for marketing authorisation under exceptional circumstances for the medicinal product Defitelio® (Gentium, division of Jazz Pharmaceuticals) intended for the treatment of severe VOD.13,14
Defitelio® (80mg/ml concentrate for solution for infusion) is indicated in adults, adolescents, children and infants aged one month to 18 years. The recommended dose is 6.25mg/kg body weight every six hours (25mg/kg/day). As there are limited efficacy and safety data on doses above this level, it is not recommended to increase the dose above 25mg/kg/day. Defitelio® should be administered for a minimum of 21 days and continued until the symptoms and signs of severe VOD resolve.13,14 Defitelio® is administered by intravenous infusion over two hours and should always be diluted prior to use.
Patients who do not improve with defibrotide treatment may be considered for transjugular intrahepatic portosystemic shunt or hepatic transplantation.1
Tissue plasminogen activator
Tissue plasminogen activator is not recommended for the treatment of VOD due to an associated risk of haemorrhage, while N-acetylcysteine is not recommended due to a lack of efficacy.
High dose methylprednisolone has been used in treatment of VOD. It may be considered with caveats of caution regarding infection.6
Supportive care is the key factor in the management of all patients with VOD. The mainstay of supportive care is the management of fluid balance. Physicians should take care of the total amount of fluids and diuretic therapy must be administered in case of severe fluid overload.6
- Daily weight of patients and measures of fluid intake and output are critical to maintain euvolaemia.
- Exposure to hepatotoxic drugs, ethanol, non-steroidal anti-inflammatory drugs, and excessive use of paracetamol and use of certain herbs should be minimised.
- If the patient suffers from right upper quadrant pain, adequate pain management must be established.
- Severe veno-occlusive disease (VOD) is a complex and unpredictable disease. Its impact on patients, physicians and resources is substantial. Early and effective intervention is crucial.
- VOD occurs as a result of the conditioning treatment administered prior to haematopoietic stem cell transplantation (HSCT).
- Identification of patients at risk, prompt diagnosis and initiation of appropriate supportive care and pharmacologic therapy are key components in the management of all patients with VOD.
- VOD accounts for a significant fraction of HSCT-related mortality. Severe VOD is almost always fatal.
- Ursodeoxycholic acid is suggested for use in the prophylaxis of VOD.
- Defibrotide is the only product that has been granted marketing authorisation by the European Medicines Agency for the treatment of severe VOD in adults and children.
It can be used safely and is well tolerated with mild adverse effects.
- Negrin R, Bonis P. Diagnosis of hepatic sinusoidal obstruction syndrome (veno-occlusive disease) following hematopoietic cell transplantation. UpToDate, Waltham, MA, USA.
- Qureshi A, Marshall L, Lancaster D. Defibrotide in the prevention and treatment of veno-occlusive disease in autologous and allogeneic stem cell transplantation in children. Pediatr Blood Cancer 2008;50:831–2.
- Senzolo M et al. Veno occlusive disease: Update on clinical management. World J Gastroenterol 2007;13(29):3918–24.
- Miano M et al. Early complications following haematopoietic SCT in children. Bone Marrow Transplant 2008;41:S39–S42.
- Coppell J et al. Hepatic veno-occlusive disease following stem cell transplantation: Incidence, clinical course, and outcome. Biol Blood Marrow Transplant 2010;16:157–68.
- Dignan F et al. Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol 2013;163(4):444–57.
- Carreras E. EBMT guidelines. Early complications after HSCT. EBMT handbook 2008;181–8.
- Bulley S et al. Defibrotide for the treatment of hepatic veno-occlusive disease in children. Pediatr Blood Cancer 2007;48(7):700-4.
- Corbacioglu S et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet 2012;379(9823).
- Morabito F et al. Insights into defibrotide: an updated review. Expert Opin Biol Ther 2009;9(6):763–72.
- Pescador R et al. Defibrotide: properties and clinical use of an old/new drug. Vascul Pharmacol 2013;59(1–2):1–10.
- Keating GM. Defibrotide: A review of its use in severe hepatic veno-occlusive disease following haematopoietic stem cell transplantation. Clin Drug Investig 2014;34(12):895–904.
- European Medicines Agency. Defibrotide. www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002393/WC500146653.pdf (accessed 21 April 2015).
- Defitelio.Summary of product characteristics. www.gentium.com/~/media/Files/G/Gentium-V2/pdf/SPCS%20and%20Package%20Insert%20Information%20Defitelio.pdf (accessed 21 April 2015).