VENO-OCCLUSIVE DISEASE AND OTHER ACUTE COMPLICATIONS OF HSCT

1. Dr Sunday Ocheni Consultant Haematologist, Department of Haematology & Immunology University of Nigeria, Enugu Campus, Mobile Nos: +234-7039222313, +234-8185766742 E-mails: kcjsocheni@yahoo.com, sunday.ocheni@unn.edu.ng VENO-OCCLUSIVE DISEASE AND OTHER ACUTE COMPLICATIONS OF HSCT

2. Several complications occur following HSCT • These complications arise primarily from the effects of A: Pre-transplant high dose chemotherapy  radiotherapy conditioning strategies. • Such complications include mucositis, pain, nausea, vomiting, haemorrhagic cystitis, hair loss, pancytopaenia, and those resulting from damage to the vascular endothelium ACUTE COMPLICATIONS OF HSCT

3. Early complications resulting from damage to the vascular endothelium include: • Hepatic veno-occlusive disease • Capillary leak syndrome • Engraftment syndrome • Diffuse alveolar haemorrhage • Thrombotic microangiopathy • Indiopathic pneumonia syndrome • Multi-organ dysfunction syndrome ACUTE COMPLICATIONS OF HSCT

4. B: Complications due to the genetic and immunologic disparities between the host and the donor. • These include graft rejection, grant-versus-host disease (GvHD) and prolonged immune system dysfunctions. ACUTE COMPLICATIONS OF HSCT

5. INTRODUCTION • The high doses of RT and/or CT included in conditioning regimens affect all the pt’s organs and tissues→→several early & late secondary effects of variable intensity • VOD is a potentially fatal syndrome of painful hepatomegaly, jaundice and fluid retention occurring 35-40 days post-HSCT as a result of conditioning regimen-related hepatic toxicity • The term “Sinusoidal obstruction syndrome” is preferred because damaged sinusoidal endothelium sloughs and then obstructs the hepatic circulations, injuring centrilobular hepatocytes ACUTE COMPLICATIONS OF HSCT

6. EPIDEMIOLOGY • Incidence: 5-70% in different reports, depending on the diagnostic criteria used, the population studied (eg, pediatric vs adult), and the differences in conditioning therapy used. • Contributes to considerable mortality & morbidity VENO-OCCLUSIVE DISEASE

7. PATHOGENESIS • After SCT the high dose cytoreductive therapy used in patients who have a particular susceptibility, produces endothelial injury in both sinusoids and small hepatic venules. • This leads to activation of the coagulation cascade, and clot formation. • Fibrin-related plugs, intracellular fluid entrapment and cellular debris progressively occlude sinusoids VENO-OCCLUSIVE DISEASE

8. PATHOGENESIS 2 • This leads to intrahepatic post sinusoidal portal hypertension, responsible for the clinical signs of fluid retention (weight increase), hepatomegaly, ascites and jaundice. • Usually fibrosis occurs several weeks after the onset of the disease. • Post mortem studies have shown that hepatic venules are partially or completely obliterated by subendothelial collagen fibers VENO-OCCLUSIVE DISEASE

9. PATHOGENESIS 3 The pathogenesis is complex, involving cytokine release, endothelial injury, hemostatic activation, and hepatic drug detoxification through the glutathione pathway. Hepatocellular necrosis, fibrosis, and vascular occlusion ultimately lead to liver failure, hepatorenal syndrome, MOF, and death. VENO-OCCLUSIVE DISEASE

10. Pretransplantation factors • Preexisting liver dysfunction (elevated transaminases, fibrosis or cirrhosis, or low albumin level • Presence of hepatic metastases • Advanced age • Prior radiation treatment of the liver17 • Use of vancomycin or acyclovir in the pretransplantation period17 • Previous stem cell transplantation17 • Prior therapy with gemtuzumab ozogamicin (Mylotarg)14 • ? Viral hepatitis C39-41 • ? Decreased protein C42 • ? Factor V Leiden mutation, prothrombin 20210 mutation VENO-OCCLUSIVE DISEASE

11. Transplantation-related factors • High-dose conditioning regimens • Allogeneic transplantation (compared with autologous • transplantation) • Busulfan for conditioning, and combined with cyclophosphamide • Total body irradiation, especially combined with cyclophosphamide (depends on total dose and fractionation) • Grafts from unrelated donors or related HLA mismatched transplants • Methotrexate as part of graft-vs-host disease prophylaxis • ? Cytomegalovirus infection VENO-OCCLUSIVE DISEASE

12. CLASSICAL VOD • Usually occurs from days – 1 to + 21 after SCT with regimens containing cyclophosphamide • Triad of: • Weight gain with oedema and ascites caused by fluid retention not attributable to an excessive fluid administration • Tender hepatomegaly and/or right upper quadrant pain • Hyperbilirubinaemia/jaundice without any • known cause VENO-OCCLUSIVE DISEASE

13. LATE VOD Same clinical manifestations as Classical VOD Usually after conditioning with agents such as busulphan, melphalan or thiotepa May occur after patient’s discharge CHRONIC VOD Occurs outside of the HSCT setting eg following chronic assumption of pyrrolizidine alkaloids contained in Senecio tea (South Africa). VENO-OCCLUSIVE DISEASE

14. VOD WITH MULTI-ORGAN FAILURE • Same clinical manifestations plus • Thrombocytopaenia (refractoriness to platelet transfusions) • Pleural effusion • Pulmonary infiltrates • Progressive renal, cardiac and pulmonary failure, confusion, encephalopathy, and coma VENO-OCCLUSIVE DISEASE

15. DIAGNOSTIC CRITERIA OF VENO OCCLUSIVE DISEASE AFTER SCT SEATTLE CRITERIA Within the first 20 days following HSCT, the presence of two or more of the following: 1 Hyperbilirubinaemia: ≥ 34mmol/L (≥ 2 mg/dL) 2 Hepatomegaly or right upper quadrant pain of liver origin 3 Unexplained weight gain (> 2% of baseline bodyweight) because of fluid accumulation BALTIMORE CRITERIA In the first 21 days after HSCT: Elevated total serum bilirubin at ≥ 34mmol/L (≥ 2 mg/dL) AND two or more of the following three criteria: 1 Tender hepatomegaly 2 Weight gain ≥ 5% from baseline 3 Ascites VENO-OCCLUSIVE DISEASE: Diagnosis

16. Classification of severity of VOD after HSCT according to weight increase (%), bilirubin concentration peak, presence of peripheral edema and ascites (mean ± sd) Mild Moderate Severe Weight gain (% increase) 7.0 ± 3.5 10.1 ± 5.3 15.5 ± 9.2 Maximum bilirubin (mg/dL) 4.7 ± 2.9 7.9 ± 6.6 26.6 ± 15.2 Percentage with peripheral edema 23 70 85 Percentage with ascites 5 16 48 Day 100 mortality (all causes) (%) 3 20 98 VENO-OCCLUSIVE DISEASE: Severity

17. Other liver diseases are common after BMT • However, the presence of weight gain and fluid retention is usually sufficient to differentiate VOD from other causes of early liver dysfunction. • Differentials : • A) After allogeneic BMT: • 1. Acute liver GVHD • 2. Cyclosporine-induced hepatotoxicity • B) After autologous or allogeneic BMT: • 1. Fungal infiltration of the liver • 2. Viral hepatitis • 3. Cholangitis lenta, e.g. during sepsis • 4. Drug (trimethoprim-sulfamethoxazole, some third-generation • penicillins, fluconazole and itraconazole) induced liver dysfunction • 5. Constrictive pericarditis and right congestive heart failure • 6. Persistent tumor infiltration of the liver VENO-OCCLUSIVE DISEASE: Differential Diagnosis

18. No specific standard treatment modality for VOD • Studies on the use of many drugs to treat VOD are limited to case reports and small series. • The primary goal of treatment is to normalize the flow in the sinusoidal vessels and veins by controlling the vasculitis and fibrin deposition. VENO-OCCLUSIVE DISEASE: Therapy

19. Treatment Strategies so far: • Low-dose tissue plasminogen activator (t-PA) has been used to increase fibrin degradation. Response only in < one third of pts • Antithrombin III (ATIII) replacement • ATIII administered in combination with heparin/t-PA • Promising experimental drug is defibrotide---- a single-stranded polydeoxyribonucleotide derived from porcine tissue that possesses antithrombotic, thrombolytic, anti-inflammatory, and anti-ischemic properties. VENO-OCCLUSIVE DISEASE: Therapy2

20. Defibrotide----6.25mg/kg iv in 2 h infusion q 6 h x 14 days → 50-55% CR in severe VOD with MOF and 47-60% of survival at day +100 with no secondary effects • SYMPTOMATIC TREATMENT: • Restriction of salt and water intake ± diuretics • Maintain intravascular volume and renal perfusion by means of albumin, plasma expanders and transfusions (PCV ˃30%) • Analgesia • Paracentesis/thoracocentesis • Haemodialysis/haemofiltration • Mechanical Ventilation • Surgical shunt • Liver Transplantation VENO-OCCLUSIVE DISEASE: Therapy3

21. Because there in no effective treatment for the syndrome, its prevention is critical: • Substitution of fludarabine for cyclophosphamide • Use of RIC regimens decreases the risk of VOD • Low-dose heparin decreases the overall incidence of VOD • 100 U/ kg/d of unfractionated heparin started 1 week before transplantation and continued until day 30 decreases the overall incidence of VOD by nearly 10%. VENO-OCCLUSIVE DISEASE: Prophylaxis

22. When possible, delay HSCT if an acute hepatitis exists • Adjust Busulfan dose or use iv • Fractionate TBI • Minimize exposure to potential hepatotoxic (ie, cyclosporine) and nephrotoxic agents (ie, aminoglycosides). • Judiciously manage the sodium and water balance. • Use of LMWH: Enoxaparin 40mg/day in place of unfractionated heparin decreases the risk of bleeding episodes and has the advantage of intermittent dosing. VENO-OCCLUSIVE DISEASE: Prophylaxis2

23. Hepatic VOD is a formidable challenge both for patients undergoing HSCT and for their physicians. • Hepatic VOD contributes considerably to transplantation-related morbidity and mortality. • A high clinical index of suspicion is needed to correctly and consistently identify patients with VOD. • Prophylactic interventions are very critical • Therapeutic agents such as defibrotide still under trial VENO-OCCLUSIVE DISEASE: Conclusion

24. YOU ARE A WONDERFUL AUDIENCE