VENO-OCCLUSIVE DISEASE AND OTHER ACUTE COMPLICATIONS OF HSCT

Dr Sunday OcheniConsultant Haematologist,

Department of Haematology & ImmunologyUniversity of Nigeria, Enugu Campus,

Mobile Nos: +234-7039222313, +234-8185766742E-mails: kcjsocheni@yahoo.com, sunday.ocheni@unn.edu.ng

ACUTE COMPLICATIONS OF HSCT

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

Early complications resulting from damage to the vascular endothelium include: Hepatic veno-occlusive diseaseCapillary leak syndromeEngraftment syndromeDiffuse alveolar haemorrhageThrombotic microangiopathyIndiopathic pneumonia syndromeMulti-organ dysfunction syndrome

ACUTE COMPLICATIONS OF HSCT

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

INTRODUCTIONThe 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

VENO-OCCLUSIVE DISEASE

EPIDEMIOLOGYIncidence: 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 DISEASEPATHOGENESIS 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 DISEASEPATHOGENESIS 2This 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

PATHOGENESIS 3The 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 DISEASEPretransplantation factorsPreexisting liver dysfunction (elevated transaminases, fibrosis or cirrhosis, or low albumin levelPresence of hepatic metastasesAdvanced agePrior radiation treatment of the liver17Use of vancomycin or acyclovir in the pretransplantation period17Previous stem cell transplantation17Prior therapy with gemtuzumab ozogamicin (Mylotarg)14? Viral hepatitis C39-41? Decreased protein C42? Factor V Leiden mutation, prothrombin 20210 mutation

VENO-OCCLUSIVE DISEASETransplantation-related factorsHigh-dose conditioning regimensAllogeneic transplantation (compared with autologoustransplantation)Busulfan for conditioning, and combined with cyclophosphamideTotal body irradiation, especially combined with cyclophosphamide (depends on total dose and fractionation)Grafts from unrelated donors or related HLA mismatched transplantsMethotrexate as part of graft-vs-host disease prophylaxis? Cytomegalovirus infection

VENO-OCCLUSIVE DISEASECLASSICAL VODUsually occurs from days – 1 to + 21 after SCT with regimens containing cyclophosphamideTriad of:Weight gain with oedema and ascites caused by fluid retention not attributable to an excessive fluid administrationTender hepatomegaly and/or right upper quadrant painHyperbilirubinaemia/jaundice without anyknown cause

VENO-OCCLUSIVE DISEASE

LATE VODSame clinical manifestations as Classical VODUsually after conditioning with agents such as busulphan, melphalan or thiotepaMay occur after patient’s discharge

CHRONIC VODOccurs outside of the HSCT setting eg following chronic assumption of pyrrolizidine alkaloids contained in Senecio tea (South Africa).

VENO-OCCLUSIVE DISEASE

VOD WITH MULTI-ORGAN FAILURESame clinical manifestations plusThrombocytopaenia (refractoriness to platelet transfusions)Pleural effusionPulmonary infiltratesProgressive renal, cardiac and pulmonary failure, confusion, encephalopathy, and coma

VENO-OCCLUSIVE DISEASE: Diagnosis

DIAGNOSTIC CRITERIA OF VENO OCCLUSIVE DISEASE AFTER SCT

SEATTLE CRITERIAWithin 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 origin3 Unexplained weight gain (> 2% of baseline bodyweight) because offluid accumulation

BALTIMORE CRITERIAIn the first 21 days after HSCT:Elevated total serum bilirubin at ≥ 34mmol/L (≥ 2 mg/dL) ANDtwo or more of the following three criteria:1 Tender hepatomegaly2 Weight gain ≥ 5% from baseline3 Ascites

VENO-OCCLUSIVE DISEASE: Severity

Classification of severity of VOD after HSCT according to weight increase (%), bilirubin concentration peak, presence of peripheral edema and ascites (mean ± sd) Mild Moderate SevereWeight 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: Differential DiagnosisOther liver diseases are common after BMTHowever, 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 GVHD2. Cyclosporine-induced hepatotoxicity

B) After autologous or allogeneic BMT:1. Fungal infiltration of the liver2. Viral hepatitis3. Cholangitis lenta, e.g. during sepsis4. Drug (trimethoprim-sulfamethoxazole, some third-generationpenicillins, fluconazole and itraconazole) induced liver dysfunction5. Constrictive pericarditis and right congestive heart failure6. Persistent tumor infiltration of the liver

VENO-OCCLUSIVE DISEASE: Therapy

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: Therapy2Treatment 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) replacementATIII 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: Therapy3Defibrotide----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 effectsSYMPTOMATIC TREATMENT:Restriction of salt and water intake ± diureticsMaintain intravascular volume and renal perfusion by means of albumin, plasma expanders and transfusions (PCV ˃30%)AnalgesiaParacentesis/thoracocentesisHaemodialysis/haemofiltrationMechanical VentilationSurgical shuntLiver Transplantation

VENO-OCCLUSIVE DISEASE: Prophylaxis

Because there in no effective treatment for the syndrome, its prevention is critical:Substitution of fludarabine for cyclophosphamideUse of RIC regimens decreases the risk of VODLow-dose heparin decreases the overall incidence of VOD100 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: Prophylaxis2When 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: Conclusion

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

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