ANZTCT Guidelines Guidelines SOS/VOD Guidelines Published: September 23, 2022 Hepatic Sinusoidal Obstruction Syndrome (SOS), also known as hepatic Veno-occlusive Disease (VOD) is a serious and potentially fatal complication that can occur following Blood or Marrow Transplantation (BMT) in both adult and paediatric patients. Background Definition Hepatic Sinusoidal Obstruction Syndrome (SOS), also known as hepatic Veno-occlusive Disease (VOD) is a serious and potentially fatal complication that can occur following Blood or Marrow Transplantation (BMT) in both adult and paediatric patients. Pathophysiology SOS/VOD is caused by toxic injury to hepatic venuls and sinusoidal endothelial cells from the conditioning therapy of BMTand manifests with hepatomegaly and/or right upper quadrant pain, jaundice and fluid retention. This toxic injury causesa cascade of events, leading to platelet and coagulative material deposition in the sub endothelium and occlusion causedby fibrosis of the terminal venous venuls and sinusoids. These processes can lead to hepatocellular necrosis, liver failure,multi-organ dysfunction and death. Incidence/prevalence Incidence rates for SOS/VOD are varied but are reported to occur in 5-15%of patients undergoing BMT – being more common after myeloablative allogeneic BMT (5-15%) than after allogeneic BMT with reduced-intensity conditioning or autologous transplant (< 5%). The severity of SOS/VOD varies from mild disease, which resolves without specific therapy, to a more severe from, characterised by progression to multi-organ failure and a mortality rate of over 80% if left untreated. Onset/duration SOS/VOD typically occurs in the first 30 days post BMT (and often in the first 7-14 days post-BMT), although it can occur later. Risk factors The probability and severity of SOS/VOD can be influenced by a range of patient-related, donor-related and transplant-related factors.Risk factors include: >Patient Related age greater than 60 or less than 1-2 yearspoor performance status (Karnovsky <90%)advanced disease (beyond second CR or relapsed/refractory disease)female (especially if receiving norethisterone)underlying haemoglobinopathy (thalassaemia or sickle-cell disease)diagnosis of primary haemophagocytic lymphohistiocytosis, adrenoleucodystrophy or osteopetrosisprior abdominal or hepatic irradiationreduced DLCO (less than 70% predicted)pre-existing liver disease including cirrhosiselevated AST (>2.5 upper limit of normal) or bilirubin (>1.5 upper limit of normal)active viral hepatitis B or Cpre-existing hepatic fibrosis or elevated serum ferritinprior autologous or allogeneic transplantprior treatment with gemtuzumab ozogamicin, inotuzumab ozagomicin or PD-1 inhibitors (pembrolizumab or nivolumab)metabolic syndromegenetic factors (GSTM1 polymorphism, C282Y allele, MTHFR 677CC/1298CC haplotype) Donor Related Haematopoietic Progenitor sourceperipheral blood stem cells (PBSC) confer a lower risk than bone marrow sourced stem cells in autologous transplant (ASCT)allogeneic BMT has a higher risk of SOS/VOD than autologous transplantdonor-recipient HLA disparity Transplant Related (type and intensity of transplant conditioning and GvHD prophylaxis) reduced intensity conditioning regimens have a lower risk compared to myeloablative regimens (<5% vs 5-15%)non T-cell depleted transplant has a higher risk than T-cell depleted transplantautologous SCT has a lower risk than allogeneic BMT (<5% vs 5-15%)second transplant has a higher risk than first transplantmultiple sequential ASCT (eg. for neurological solid tumours) has a higher risk than single ASCTTBI-based conditioning is associated with a higher risk than non-TBI-based conditioningbusulfan-based conditioning has a higher risk than other chemotherapy agents, with; oral busulfan associated with a higher risk of SOS/VOD than intravenous busulfan (including with autologous regimens) and busulfan followed by cyclophosphamide conditioning associated with a higher risk of SOS/VOD than cyclophosphamide followed by busulfanGvHD prophylaxis with sirolimus and tacrolimus Assessment and Diagnosis Symptoms and signs Early diagnosis of SOS/VOD is important so that treatment can be initiated. Clinical assessment and diagnostic interventionsplay a crucial role in identifying patients as high risk of SOS/VOD and detecting the symptoms of SOS/VOD. Assessment should be conducted and documented at baseline and then throughout treatment in order to identify anychanges. Clinical assessment should include: risk assessment for SOS/VOD prior to commencing therapybaseline and then twice daily weightstrict fluid balance monitoring including input, output and balancebaseline measurement of abdominal girth followed by daily measurements if any suspicion of SOS/VOD, to detect fluid retention and ascites. Ensure the same area is measured and the area is marked i.e. 2.5 cm under the umbilicusdaily urinalysisskin integrity for signs of breakdown and jaundiceabdomen for right upper quadrant pain and distensionsigns of bleedingbaseline blood tests and then daily or as clinically indicated: EUC, LFT, bilirubin, FBC, coagulation profile and drug levels for hepatotoxic and nephrotoxic drugsrespiratory assessment to detect pulmonary oedemaregular vital signs, including blood pressure Investigations and diagnosis The differential diagnosis of deranged liver function tests following BMT is wide and includes graft-versus-host disease (GvHD), infection and drug toxicity. The main role of diagnostic techniques including histopathology and imaging investigations is to exclude other diagnoses as the diagnosis of SOS/VOD can primarily be based on clinical criteria. Hepatic ultrasound (specifically reversed hepatic venous flow with new onset of hepatomegaly and ascites) may assist in the diagnosis of SOS/VOD and be useful in excluding other causes of deranged liver function post-BMT. More definitive diagnostic tests, including liver biopsy and measurement of hepatic venous gradient pressure through the jugular vein are far more accurate but are more invasive and as such are uncommonly used. Clinical algorithms for diagnosis and staging of SOS/VOD A number of clinical algorithms have been used to diagnose SOS/VOD. The most well-validated, the Seattle and Baltimore criteria, are both based on the presence of clinical findings (jaundice, weight gain, hepatomegaly and ascites) not attributable to any other cause in the first 3 weeks after BMT. More recently the EBMT (Mohty et al, 2016) have released revised diagnosis and severity criteria for adults in an era of effective early treatment options. These criteria are yet to be validated in prospective studies, but go some way towards addressing the apparent lack of specificity and sensitivity of previous clinicalalgorithms. CriteriaDefinitionSeattleAt least 2 of the following within 30 days after transplant: hepatomegaly and right upper quadrant pain jaundice unexplained weight gain or ascitesModified SeattleAt least 2 of the following within 20 days after transplant hepatomegaly and right upper quadrant pain ascites unexplained weight gain of more than 2% from baselineBaltimoreBilirubin greater than or equal to 34µmol/L within 21 days after transplant and at least 2 of the following: painful hepatomegaly ascites weight gain of more than 5% from baselineEBMT 2016Classical SOS/VOD (In the first 21 days post-BMT)Bilirubin 34µmol/L and two of the following criteria must be present: Painful hepatomegaly Weight gain >5% from baseline AscitesLate onset SOS/VOD (>21 Days post-BMT) Classical VOD/SOS beyond day 21 OR Histologically proven SOS/VOD OR Two or more of the following criteria must be present: Bilirubin > 34µmol/L Painful hepatomegaly Weight gain>5% Ascites AND Hemodynamic or/and ultrasound evidence of SOS/VOD Grading SOS/VOD can be classified into mild, moderate or severe disease depending on the clinical course within the first 100 dayspost BMT : Mild stage meets diagnostic criteriarequires no specific interventionis self limiting Moderate stage evidence of liver injuryrequires active treatment for excess fluid and pain managementresolves in most patients Severe stage persistent hepatic dysfunction with severe hyperbilirubinaemiadoes not resolve within 100 days post BMTassociated with multi organ failurecan lead to:renal insufficiencyconfusion/disorientationcardiac failurebleeding requiring transfusion supportuntreated SOS/VOD may be associated with a mortality rate of over 80% (it must be noted however, that these outcomes were reported prior to the development of effective therapies for SOS/VOD, such as defibrotide) In an effort to develop an aid to estimate prognosis, Bearman et al used a Cox regression analysis to generate risk curves predictive of severe SOS/VOD based upon a large cohort of patients from the Seattle Transplant Registry. More recently, the EBMT (Mohty et al, 2016) developed criteria for severity grading of suspected SOS/VOD based principally on the time since first onset of clinical symptoms of SOS/VOD, the bilirubin level and kinetics, transaminases, weight increase and renal function (below). 2016 EBMT Criteria for Severity Grading of Suspected SOS/VOD in adultsMildModerateSevereVery severe (MOD/MOF)Time since first clinical symptoms of SOS/VOD>7 days5-7 days<4 daysAny timeBilirubin (µmol/L)≥ 34 and <51≥ 51 and <85≥ 85 and <136≥ 136Bilirubin kineticsDoubling within 48 hoursTransaminases≤ 2 x normal>2 and ≤ 5 x normal>5 and ≤ 8 x normal>8 x normalWeight increase<5%≥ 5% and <10%≥ 5% and <10%≥ 10%Renal function<1.2 x baseline at transplant≥ 1.2 and >1.5 x baseline at transplant≥ 1.5 and <2 x baseline at transplant≥ 2 x baseline at transplant or other signs of MOD/MOFInterpretation: MOD = Multi-organ dysfunction MOF = Multi-organ failure Patients belong to the category that fulfils two or more criteria. If patients fulfil two or more criteria in two different categories they must be classified in the most severe category. Patients weight increase ≥ 5% and <10% is considered by default as a criterion of severe SOS/VOD unless they fulfil no other criteria for severe SOS/VOD – in which case they are classified as having moderate SOS/VOD. Patients with multi-organ dysfunction must be classified as very severe. Time from the date when the first signs/symptoms of SOS/VOD began to appear (retrospectively determined) to the date when the symptoms/signs fulfilled SOS/VOD diagnostic criteria. Management: Prevention and Treatment Prevention Preventive measures for SOS/VOD include: Pre-BMT risk assessmentReversal of SOS/VOD risk factors where possiblePharmacoprophylaxis 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: pre-existing liver disease (cirrhosis or elevated ALT/AST – 2 x upper limit of normal)prior autologous or allogeneic transplantallogeneic transplant for leukaemia beyond second relapseconditioning 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, inotuzumab ozagomicin or PD-1 inhibitors (pembrolizumab or nivolumab)diagnosis of primary haemophagocytic lymphohistiocytosis,adrenoleucodystrophy or osteopetrosishaemoglobinopathy (thalassaemia or sickle cell disease)prior abdominal irradiationreduced DLCO (less than 70% predicted)hepatitis B or C positive (not Ab positive)pre-existing hepatic fibrosis or iron overloadGVHD prophylaxis with sirolimus and tacrolimus Reversal or remediation 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 resolvedUse of reduced intensity conditioning for allogeneic transplant in preference to myeloablative conditioningUse of non-TBI-based conditioningUse of intravenous rather than oral busulfan as conditioningChange in conditioning chemotherapy sequencing to CyBU rather than BuCyAvoidance of hepato-toxins Pharmacoprophylaxis 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 al, pooled the results from three randomised studies 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. 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 unfractionated and 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. Defibrotide 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. 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. 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. recommended dose is 6.25 mg/kg intravenously four times a day, every 6 hourly (total daily dose of 25mg/kg) 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. 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. In this regard it is important to note that as of May 2018 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. The cost of defibrotide is also substantial: for an average 70kg adult patient defibrotide costs $4696/day – $65,000 for a 14 day course. 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 analgesiamaintenance of intravascular volumeavoidance of nephrotoxinsdiuretics and salt restriction, to avoid and treat fluid overloaddialysisrespiratory supportdrainage 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 Transjugular Intrahepatic Portosystemic Shunt (TIPS). Pharmacotherapy 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. Defibrotide has been shown in phase II and III trials to improve complete response and survival in patients with severe post-BMT SOS/VOD. 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. The recommended dose for the treatment of SOS/VOD is 6.25 mg/kg intravenously four times a day (total daily dose of 25mg/kg). 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. References Richardson, P. G., V. T. Ho, C. Cutler, et al. 2013. “Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions.” Biol Blood Marrow Transplant 19(1 Suppl):S88-90. Zhang, L., Y. Wang and H. 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