Prevention
Preventive measures for SOS/VOD include:
- Pre-BMT risk assessment
- Reversal of SOS/VOD risk factors where possible
- Pharmacoprophylaxis
Risk assessment
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
- GVHD prophylaxis with sirolimus and tacrolimus
Reversal of SOS/VOD risk factors
Mohty et al. classify risk factors as modifiable or unmodifiable to provide some guidance on reducing risk factors and improving patients’ management.r
Table 2. Unmodifiable and modifiable SOS/VOD risk factors (adults)
Unmodifiable risk factors (In bold the factors with the highest relative risk) |
Modifiable risk factors and recommendable preventive measures |
- Second HCT
- Advanced disease (beyond second CR or relapse)
- Primary immunodeficiency diagnosis
- Genetic factors (GSTM1 polymorphism, C282Y allele, MTHFR 677CC/1298CC haplotype)
- Older patient age
- Increased serum transaminase
- Karnofsky score below 90%
- Metabolic syndrome
- Assigned female at birth receiving norethisterone
- Previous use of gemtuzumab ozogamicin or inotuzumab ozogamicin
- Hepatotoxic drugs
- Iron overload (>1.000 ng/mL)
- Serum bilirubin > 1.5 mg/l (> 26 μmol/l), Transaminase > 2.5 ULN
- Pre‐existing liver disease:
- hepatic fibrosis
- cirrhosis
- active viral hepatitis
- Abdominal or hepatic irradiation
|
Conditioning:
- High dose (myeloablative) regimens
- Oral or high dose busulfan
- High dose treosulfan
- High dose TBI-based regimen
Donor:
- Unrelated donor
- HLA-mismatched donor
GVHD prophylaxis:
- Sirolimus+ methotrexate+ tacrolimus
- Methotrexate+ cyclosporin or tacrolimus
- Non T-cell depleted transplant
Use of parenteral alimentation:
- Use of parenteral nutrition
|
HCT = haematopoietic cell transplantation; CR = complete remission; HLA = human leucocyte antigen; TBI = total body irradiation; ULN = upper limit of normal; GVHD = graft-versus-host disease
©Bone Marrow Transplant 2023
Pharmacoprophylaxis
Ursodeoxycholic acid prophylaxis (UCDA)
A systematic review by Tay et al.r, 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 most commonly reported is 12 mg/kg/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.)
Defibrotide
A number of studies have reported significant reductions in the incidence of post-BMT SOS/VOD following the prophylactic use of defibrotide, however, a recent phase III study found defibrotide plus standard of care did not show a benefit in the prophylaxis of SOS compared with best standard of care alone.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
While it is unclear whether prophylaxis with defibrotide is superior to early treatment, the mortality from established SOS/VOD is sufficiently high to justify prophylaxis in high-risk adult patients.rr
- 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 via 0.2 micron in-line filter. (Final concentration should be between 4 mg/mL to 20 mg/mL).r
- Defibrotide should be commenced on the day of conditioning and continued until day +21.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.
Supportive care
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
- dialysis
- respiratory support
- 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
Pharmacotherapy
Defibrotide
Defibrotide has been shown to improve complete response and survival in patients with severe SOS/VOD, and should be initiated as soon as possible in those patients.rrrr Furthermore, given that early treatment initiation is associated with a higher day +100 overall survival, and that moderate SOS/VOD is associated with significant mortality, EBMT also recommend early initiation of defibrotide in patients with moderate SOS/VOD. Local experience and international evidence supports defibrotide as 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.rrrA 2019 meta-analysis suggests that defibrotide improves survival rate at day + 100 post-HSCT in patients with SOS/VOD.r
Defibrotide is TGA registered for the treatment of severe hepatic SOS/VOD in HSCT therapy.
- 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).rrrThe dose should be based on baseline weight, defined as weight on admission date. Administer as a 2 hour IV infusion in sodium chloride or 5% dextrose via 0.2 micron in-line filter. (Final concentration should be between 4 mg/mL to 20 mg/mL).r
- Current recommendation is for treatment to continue for at least 21 days and until the symptoms of SOS/VOD resolve however further study is necessary to establish the optimal duration of therapy.rrr
- There are no dose adjustments provided by the manufacturer for renal or hepatic impairment. Defibrotide is not removed by haemodialysis.r
- Most common adverse events from defibrotide treatment are haemorrhage and hypotension.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