Non-infectious hepatic complications in patients with GVHD

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1 Non-infectious hepatic complications in patients with GVHD Tapani Ruutu Helsinki University Central Hospital

2 Liver dysfunction in allogeneic stem cell transplantation injury secondary to the cytoreductive therapy (conditioning) or preceding treatment toxicity caused by post-transplant therapy infections graft-versus-host disease

3 Liver GVHD Overall incidence of acute GVHD % depending on the type of transplantation and prophylaxis Overall incidence of chronic GVHD % Liver involvement common in both types

4 Acute GVHD, liver jaundice increases in bilirubin, alkaline phosphatase and gamma glutamyl transferase also ALAT, ASAT Early jaundice related to cholestasis caused by cytokines such as interleukin-6

5 Liver biopsy in acute GVHD Histology: lymphocytic infiltration of small bile ducts nuclear pleomorphism, epithelial cell dropout cholestasis in zone 3 of the liver acinus ductopenia Inflammatory infiltrates may be minimal because of immune suppression A hepatitis-like form with marked elevation of ALAT - most commonly seen in allograft recipients on minimal immunosuppression or after donor lymphocyte infusion

6 Histological diagnosis Liver biopsy may be risky. Therefore the diagnosis of liver GVHD is usually established based on histological confirmation from another affected organ (particularly gut) combined with a typical clinical picture.

7 Chronic GVHD Liver abnormalities include asymptomatic elevation of serum ALAT, alkaline phosphatase and gammaglutamyltransferase slowly progressive cholestatic jaundice sometimes more acute hepatocellular injury (hepatitic GVHD)

8 Prophylaxis and treatment of (liver) GVHD Prophylaxis with ursodeoxycholic acid has been shown to reduce liver problems, including severe GVHD Otherwise the general approach to GVHD prophylaxis No specific treatment for liver GVHD; general GVHD treatment approach

9 Ruutu et al Blood 2002

10 Ruutu et al Blood 2002

11 Ruutu et al Blood 2002

12 Treatment of acute GVHD Corticosteroid first line treatment No standard second line treatment, numerous approaches Components of second line treatment in use, often in combinations: ECP MMF anti-tnf-antibodies other monoclonal antibodies ATG ECP MTX mesenchymal stem cells

13 Treatment of chronic GVHD First line treatment corticosteroid and/or calcineurin inhibitor depending on the history No standard second line treatment, numerous approaches Components of second line treatment in use, often in combinations ECP MMF rituximab calcineurin inhibitors mtor inhibitors

14 Veno-occlusive diseases of the liver (VOD) (Sinusoidal obstruction syndrome, SOS) Occlusion/thrombosis of liver sinusoids A relatively common complication of HSCT, 5-20% (0-60%) A life threatening disorder in severe cases Recently the incidence and mortality seem to have been declining

15 Clinical findings of VOD Enlarged liver (hepatomegaly) Right upper quadrant pain Ascites Weight gain Increased bilirubin levels Within days from the transplantation

16 Baron et al, Haematologica 1997

17 Risk factors for VOD Advanced disease (burden of preceding treament) Prior stem cell transplantation Busulfan, especially when combined with melphalan/ and or cyclophosphamide Hepatic diseases (severe hemosiderosis, viral hepatitis, fibrosis, transaminitis ) Gemtuzumab ozogamicin (Mylotarg ) Abdominal irradiation

18 Severity of VOD Mild no apparent adverse effects of liver disease no need for medications for diuresis or hepatic pain completely reversible signs, symptoms and laboratory abnormalities Moderate adverse effects from liver disease requirement of sodium restriction and diuretics requirement of medication for pain from hepatomegaly complete resolution of all signs of liver damage Severe adverse effects from liver disease signs, symptoms and laboratory values do not resolve before day +100 multiorgan failure (MOF) - Seattle group

19 Outcome of VOD Depends largely on the severity grade (which again is defined by the outcome..) Severe VOD is a serious disorder, usually with poor outcome Patients often have other concomitant complications

20 Coppell JA 2010

21 Prophylaxis of VOD No conclusively documented effective prophylaxis Heparin? Ursodeoxycholic acid? Defibrotide

22 Treatment of VOD Table 3.- VOD treatment First line therapy Symptomatic (a) restriction of salt and water intake diuretics maintain intravascular volume and renal perfusion by means of albumin, plasma expanders and transfusions (haematocrit >30%) Specific Symptomatic (a) Specific Defibrotide: 6.25 mg/kg IV in 2 h infusion q 6 h x 14 d 50-55% CR in severe VOD with MOF and 47-60% of survival at day +100 with no secondary effects (15). Other agents b, c Other measures - Analgesia - Paracentesis / thoracocentesis - Haemodialysis / Haemofiltration - Mechanical ventilation - TIPS (transvenous intrahepatic portosystemic shunt) (d) - Surgical shunt - Liver transplantation Carreras E. EBMT Handbook 2012

23 Defibrotide Sodium salt of a mixture of single-stranded polydeoxyribonucleotides Prepared by controlled depolymerisation of deoxyribonucleic acid (DNA) obtained from porcine intestinal mucosa Can be administered orally and intravenously

24 Survival Treatment IND trial / long term survival DF (n=68) HC (n=32) Confidence Interval * p value *** CR (Day +100) 34% (23/68) 9% (3/32) 95% CI: % (adjusted) ** (unadjusted) Survival (Day +100) 34% (23/68) 25% (8/32) % 80 % 60 % 40 % 20 % 0% Time since SCT 00 Defibrotide Historical control p value < Richardson et al. Blood (ASH Annual Meeting Abstracts) 2010

25 Liver injury caused by drugs trimethoprim-sulfamethoxazole itraconazole voriconazole posaconazole cyclosporine methotrexate etc.

26 Iron overload Common in transplantation patients Can aggravate liver problems