Improved Outcomes of Budd-Chiari Syndrome in Paroxysmal Nocturnal Hemoglobinuria with Eculizumab Therapy

Abstract

3478 Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of hematopoietic stem cells characterised by deficiency of cell membrane glycosylphosphatidylinositol-anchored proteins, rendering the cells susceptible to complement attack. Budd-Chiari syndrome (BCS) describes obstruction of the hepatic venous outflow tract. Complications such as ascites and varices often occur at the time of acute thrombosis. Conventional management includes anticoagulation, transjugular intrahepatic portosystemic shunt (TIPSS) placement, peripheral/local thrombolysis and orthotopic liver transplantation (OLT). The morbidity and mortality of PNH patients with BCS is particularly high: a new thrombotic event or thrombosis extension in anticoagulated patients is reported in 27%; a significant proportion of TIPSS fail due to recurrent thromboses; historically, mortality rates of 67% have been reported; hematopoietic stem cell transplantation and OLT have unacceptably high transplant-related mortalities. Eculizumab prevents cleavage of C5 and reduces risk of thrombosis in PNH. The role of this monoclonal antibody in the management of BCS with PNH has yet to be evaluated. Nineteen PNH patients (12 female, 7 male) with a BCS diagnosis who were subsequently given eculizumab, were identified from the Leeds PNH Service. Patients were diagnosed with PNH between 1991–2012 (median follow up from PNH diagnosis 7.5 yrs, range 2 mths – 21 yrs; from BCS diagnosis 3.5 yrs). Median age at PNH diagnosis was 30 yrs (range 19–87) and at BCS 32 yrs (range 19–87). The mean granulocyte clone size at PNH diagnosis (n=14) was 86.3% (range 59.7–99%) and at BCS (n=12) was 93.1% (range 80.9–99.6%). BCS was the presenting feature of PNH in 9 (47.4%). Six were diagnosed as part of diagnostic work-up during the acute BCS. In 3, a diagnosis of PNH was made 1, 6 and 26 months post BCS. Ten (52.6%) were already known PNH at the time of their BCS. None were receiving eculizumab. Median time from PNH to BCS was 30 mths, range 3–132. Seven were anticoagulated (5 primary prophylaxis) prior to BCS. Eight PNH patients (Group 1) developed BCS before the availability of eculizumab and remained alive long enough to receive therapy. Six in Group 1 (75%) developed BCS complications prior to commencing eculizumab including development of varices (n=1), progression of thrombus despite full anticoagulation (n=1), ascites necessitating TIPSS (n=2), hepatomegaly (n=3) and splenomegaly (n=3). Two did not endure BCS complications but suffered cerebral vein thrombotic events on anticoagulation. The median time to first dose of eculizumab therapy in Group 1 was 3 yrs (range 2 mths – 11 yrs). All patients remain on eculizumab (median follow-up 6.9 yrs, range 2.8 – 7.1); there have been no further thrombotic events in this cohort. Group 2 consists of 11 PNH patients in whom BCS was diagnosed during the availability of eculizumab. Four received this less than 14 days from onset of BCS without any subsequent complications. The remaining 7 started eculizumab 2 or more weeks from probable onset of BCS. Complications included ascites necessitating TIPSS and/or gastric/esophageal varices. TIPSS procedures were effective in all patients once on eculizumab with no occlusions. Importantly, 3 of the 19 patients have stopped secondary anticoagulation after starting eculizumab (due to thrombocytopenia, hemorrhage or perceived bleeding risk due to varices). There have been no further thrombotic episodes in these patients. This case series is the first to document 19 patients, managed with eculizumab with both PNH and BCS. Rapid intervention with eculizumab in addition to anticoagulation when safe to administer, appears to prevent the development of BCS associated complications. If complications are established at diagnosis, eculizumab can prevent progression and reoccurrence; it also facilitates successful use of TIPSS. We can conclude: a) primary prophylaxis is not sufficient to prevent BCS in patients with PNH b) prompt treatment with eculizumab may negate long-term complications of BCS and allows effective and safe use of TIPSS c) in selected cases, eculizumab therapy may facilitate the withdrawal of anticoagulation without increasing subsequent risk of thrombosis and d) survival for this cohort is currently 100%. The management of BCS in PNH with immediate commencement of eculizumab and, where appropriate, use of TIPSS, is associated with improved outcomes. Disclosures: Kelly: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Richards:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Arnold:Alexion Pharmaceuticals, Inc: Honoraria. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hill:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria.

Paroxysmal nocturnal hemoglobinuria and vascular liver disease: Eculizumab therapy decreases mortality and thrombotic complications

“…Our results on the role of eculizumab in VLD patients confirm a similar positive effect in the splanchnic territory, mainly due to its impact to reduce thrombosis recurrence. Preliminary results presented in 2012 also support this hypothesis in VLD: survival after eculizumab therapy was a 100% in 19 BCS patients, after a median follow‐up of 7 years with eculizumab therapy, recurrent thrombosis did not occur in 6/19 patients after eculizumab late therapy, while three had recurrent thrombosis prior eculizumab administration 21 . Although it could have been a hypothesis that patients described with other causes for VLD would be at higher risk for thrombosis, this risk was not increased in the 11 patients with another cause.…”

An interesting case of atypical venous thrombosis with low red blood cells

“…From a pathophysiologic point of view, the drug should not have an effect on thrombotic complications of the disease and these patients need to continue heparin or oral anticoagulation if they have had a thrombotic event, but there is some evidence from clinical studies that eculizumab reduces the incidence of thrombotic events in these patients, particularly in the Budd-Chiari syndrome. 16 Finally, because patients who have a deficit in C5 are more at risk of meningitis, patients in therapy with eculizumab have to be prophylactically vaccinated against meningitis B, C and Y.…”