Preventive measures for SOS/VOD include:
- Pre-BMT risk assessment
- Reversal of SOS/VOD risk factors where possible
Most low-risk patients do not require specific prophylaxis for SOS/VOD.
Patients at high risk of SOS/VOD include those who are receiving an allogeneic stem cell transplant AND have at least one of the following additional risk factors for SOS/VOD:rr
- pre-existing liver disease (cirrhosis or elevated ALT/AST - 2 x upper limit of normal),
- prior autologous or allogeneic transplant,
- allogeneic transplant for leukaemia beyond second relapse,
- conditioning with busulfan containing regimens; with a greater risk of SOS/VOD associated with oral busulfan than with IV busulfan (including with autologous regimens),
- prior treatment with gemtuzumab ozogamicin,
- diagnosis of primary haemophagocytic lymphohistiocytosis, adrenoleucodystrophy or osteopetrosis,
- haemoglobinopathy (thalassaemia or sickle cell disease),
- prior abdominal irradiation,
- reduced DLCO (less than 70% predicted),
- hepatitis B or C positive (not Ab positive),
- pre-existing hepatic fibrosis or iron overload, or
- GVHD prophylaxis with sirolimus and tacrolimus.
Reversal of SOS/VOD risk factors
The majority of patient-related risk factors are difficult or impossible to reverse (particularly within the time constraints of BMT). Where possible the following strategies can be considered in patients at high risk of SOS/VOD:
- delay of BMT until reversible conditions have resolved,
- use of reduced intensity conditioning for allogeneic transplant in preference to myeloablative conditioning,
- use of non-TBI-based conditioning,
- use of intravenous rather than oral busulfan as conditioning,
- change in conditioning chemotherapy sequencing to CyBU rather than BuCy, and
- the avoidance of hepatoxins.
Ursodeoxycholic acid prophylaxis (UCDA)
Should a decision be made that prophylaxis is necessary, ursodeoxycholic acid (UCDA) can be used. A systematic review by Tay et alr, pooled the results from three randomised studiesrrr comparing UDCA to no treatment and demonstrated a reduced risk of SOS/VOD in patients receiving UDCA (relative risk, 0.34; 95% confidence interval 0.17–0.66). EBMT position statements have also recognised the potential benefits of UCDA in preventing SOS/VOD.r
The dose of UCDA is 12 mg per kg per day orally given in 2 to 4 divided doses, commencing the day prior to conditioning and continuing until day +90. (UCDA prophylaxis may be ceased before day +90 in patients who have stable engraftment and no signs of SOS/VOD as ‘late’ SOS/VOD is extremely uncommon in these patients.)
Heparin (unfractionated and low molecular weight)
While low molecular weight heparins may be useful for prevention of venous thromboembolic events, there is no evidence that they have any role in the prevention of SOS/VOD.r
A number of studies in both adults and children have reported significant reductions in the incidence of post-BMT SOS/VOD following the prophylactic use of defibrotide.rrr Defibrotide is a sodium salt of complex single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA that appears to stabilise endothelial cells, reduce endothelial-cell activation and restore the thrombofibrinolytic balance. Importantly, defibrotide is not associated with a significantly increased bleeding risk despite reducing procoagulant activity, increasing fibrinolysis and modulating platelet activity.rr
At the current time defibrotide has been registered by the FDA in the United States and is approved in the EU for treatment of SOS/VOD but is not TGA registered in Australia or listed on the PBS.
While the optimal dose, duration of prophylaxis and route of administration remains unknown, and it is uncertain whether prophylaxis with defibrotide is superior to early treatment, the mortality from established SOS/VOD is sufficiently high to justify prophylaxis in high-risk paediatric (where evidence is strongest) and adult patients.r
- Recommended dose is 6.25 mg/kg intravenously four times a day, every 6 hourly (total daily dose of 25 mg/kg)r given as a 2 hour IV infusion in sodium chloride or 5% dextrose. (Maximum concentration is 4 mg/mL).
- Defibrotide should be commenced on the day prior to conditioning and continued until day +14 or until engraftment has occurred.r
The use of defibrotide in combination with UDCA in patients at high risk of developing VOD may be considered at the discretion of the treating physician.r
Treatment (of established SOS/VOD)
The management of established SOS/VOD includes supportive care and specific pharmacotherapy.
It is vitally important to provide adequate supportive care for patients with SOS/VOD. This includes:
- adequate analgesia,
- maintenance of intravascular volume,
- avoidance of nephrotoxins,
- diuretics and salt restriction, to avoid and treat fluid overload,
- respiratory support, and
- drainage of ascites and pleural effusions.
Early consultation with a specialist hepatology unit is advised regarding the medical and surgical management of severe SOS/VOD, including consideration of a transjugular intrahepatic portosystemic shunt (TIPS).r
Systemic anticoagulants or thrombolytics such as tissue plasminogen activator (tPA) have been associated with significant bleeding complications, including fatal events, thus limiting their utility, and do not demonstrate any survival benefit and so cannot be recommended.rr
Defibrotide has been shown in phase II and III trials to improve complete response and survival in patients with severe post-BMT SOS/VOD.rrrr It is currently the most effective agent available for the treatment of SOS/VOD with approximately ~50% of patients with severe SOS/VOD, including those with multi-organ failure, achieving a complete response.r
The recommended dose for the treatment of SOS/VOD is 6.25 mg/kg intravenously four times a day (total daily dose of 25 mg/kg).rrr The dose should be based on baseline weight, defined as weight on admission date. Although further study is necessary to establish the optimal duration of therapy it is currently recommended that treatment should continue for at least 21 days and until the symptoms of SOS/VOD resolve.