Hepatic Veno-occlusive disease/Sinusoidal obstruction syndrome Kristin Wessel, MD

Pre-test Which of the following chemotherapeutic agents used for conditioning is associated with increased risk for VOD? Fludarabine Cyclophosphamide Busulfan Cisplatin Which of the following is NOT evaluated as part of the criteria for VOD? Weight Hepatomegaly Bilirubin ALT/AST What is the mortality rate of VOD? 10% 20% 30% 50% 70%

Pre-test 4. What initial imaging study should you order when you suspect VOD? Abdominal XR CT Ultrasound MRI 5. A patient in which of the following periods surrounding transplant is at greatest risk for developing VOD? Conditioning through day +30 Day +30 to day +50 Day +50 to day +100 After day +100

VOD/SOS: Epidemiology Potentially life-threatening complication of HSCT Incidence in pediatrics 11-31% 3rd leading cause of death in pediatric HSCT patients during post-transplant period Mortality rate up to 50% Usually develops by 30 days post-transplant, but can occur later

VOD/SOS: Pathogenesis Damage to sinusoidal endothelial cells and hepatocytes secondary to toxicity from conditioning regimen and alloreactivity in the case of allogeneic HSCT Damage to sinusoidal endothelial cells Inciting event cytokine release  collagen production  cellular debris accumulates in Space of Disse  venular narrowing and obstruction Pro-thrombotic state also contributes to obstruction Damage to hepatocytes in zone 3 (centrilobular zone) Conditioning regimen toxic metabolites  glutathione depletion  hepatocyte necrosis

VOD/SOS: Risk factors Allogenic HSCT > Autologous HSCT Myeloablative conditioning regimen (MAC) Conditioning regimen including busulfan, especially in combination with cyclophosphamide Immunosuppression, especially with cyclosporine Pre-existing liver disease Second HSCT High-dose TBI Poor performance status (Karnofsky score <90) Pediatric-specific risk factors: Primary HLH, adrenoleucodystrophy, osteopetrosis, thalassemia major, auto-HSCT in neuroblastoma, younger age (<1-2 years)

Modified Seattle Criteria VOD/SOS: Diagnosis Modified Seattle Criteria Baltimore Criteria At least 2 of the following, occurring within 20 days of transplantation: Serum bilirubin >34 umol/L (>2 mg/dl) Hepatomegaly with right upper quadrant pain >2% weight gain from baseline due to fluid retention Serum bilirubin >34 umol/L (>2 mg/dl) within 21 days of transplantation AND at least 2 of the following: Hepatomegaly >5% weight gain from baseline Ascites Source: http://bloodref.com/transplant/other/vodsos-diagnosis-severity

VOD/SOS: Diagnosis As treatment for VOD/SOS is mainly supportive, early detection is critical Patients require strict monitoring from start of conditioning to at least day +40 including daily weights (at least) and strict I/O Pay attention to non-specific complaints of abdominal pain and discomfort

VOD/SOS: Diagnosis Determine severity: Seattle criteria Mild: No adverse effects of liver disease, AND no medications required for diuresis or hepatic pain, AND all symptoms, signs and laboratory features reversible Moderate: Adverse effects of liver disease present, AND sodium restriction/diuretics required, OR medication for hepatic pain required, AND all signs, symptoms and laboratory features reversible Severe: Adverse effects of liver disease present, AND symptoms, signs and laboratory features not resolved by day +100, OR death

VOD/SOS: Treatment Prevention Reversal/reduction of risk factors when possible Ursodiol or low-dose heparin Defibrotide: reduced incidence of VOD/SOS shown in prospective phase III RCT Supportive care: fluid restriction, cautious use of diuretics

Recap: What residents need to do on the floor Knowing where your patient is in relation to transplant is important is key. If they are anywhere between conditioning through day +40, this is a high risk window Order daily weights and strict I/O Bilirubin must be monitored daily If a patient meets the criteria for VOD, let your fellow or attending know immediately. Keep in mind the mortality rate is 50% Order liver U/S when suspecting VOD. Ascites may be present. Reversal of flow is a late sign.

References Mohty, M et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives—a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplantation (2015), 1-9. Barker, CC et al. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients. Bone Marrow Transplantation (2003), 32, 79-81. Lee et al. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: incidence, risk factors and outcome. Bone Marrow Transplantation (2010), 45, 1287-1293. Cefalo et al. Hepatic veno-occlusive disease: a chemotherapy-related toxicity in children with malignancies. Pediatric Drugs (2010)