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>>[154] Eculizumab, a C5 Complement–Blocking Antibody, Abolishes Hemolysis
and Renders Hemolytic Patients with Paroxysmal Nocturnal Hemoglobinuria
(PNH) Transfusion Independent.
Peter Hillmen, Claire Hall, Judith Marsh, Dupe Elebute, Christopher F. Mojcik, Scott A.
Rollins, Stephen Richards, Russell P. Rother. Haematology, Leeds Teaching Hospitals
NHS Trust, Leeds, United Kingdom; Haematology, St. George's Hospital Medical
School, London, United Kingdom; Alexion Pharmaceuticals, Inc., Cheshire, CT, USA
Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by intravascular hemolysis,
venous thrombosis and is associated with aplastic anemia. The complement-mediated
hemolysis is due to the deficiency of complement-regulatory proteins on the surface of
PNH red cells, particularly the terminal complement inhibitor CD59. The high risk of
venous thrombosis results from PNH platelet activation by complement. Therefore
complement inhibition in PNH should control the hemolysis and reduce the risk of venous
thrombosis. Eculizumab is a humanized monoclonal antibody that binds to C5 and inhibits
terminal complement activation. Ten transfusion-dependent PNH patients have been
entered into an ongoing open label Pilot study of eculizumab and all patients will have
completed the study by November 2002. Patients receive 600 mg eculizumab by
intravenous infusion over 30 minutes weekly for 4 doses and then 900 mg every other
week. To date, 4 patients have completed therapy and all have been entered into an
extension study. Response data for at least 4 weeks of therapy is available for 6 of the
10 patients. Eculizumab has been well tolerated with no serious adverse events. No
episodes of thrombosis have occurred although follow-up is short and 4 of 6 patients are
on warfarin. The biochemical parameters of hemolysis dramatically improved or
normalised for all patients within a week of starting therapy. Mean LDH decreased from
4494 +/- 3380 U/L prior to treatment to 636 +/- 166 U/L following treatment while
mean AST decreased from 106 +/- 66 U/L to 24 +/- 9 U/L during the same interval. In
addition, a progressive increase in the PNH type III red cells occurred during the
treatment period. While hemoglobinuria was common in this patient group before
treatment, no patient has had an episode of hemoglobinuria since commencing
eculizumab therapy and patients report a marked improvement in symptoms related to
hemolysis, such as dysphagia and lethargy. One patient began treatment during a severe
acute hemolytic episode when she was passing nearly black urine and within 24 hours
there was a complete resolution of her hemoglobinuria. Patients who had purely
hemolytic disease (macroscopic hemoglobinuria with a normal platelet count; n=3)
appeared to have the best response to eculizumab with cessation of hemolysis and an
increase in mean hemoglobin from 9.4 +/- 1.6 g/dL to 10.3 +/- 0.6 g/dL at four weeks,
obtained without transfusion. These hemolytic patients without cytopenias also showed a
more pronounced increase in the proportion of PNH red cells (mean increase equal to
62%) presumably due to a prolongation of PNH red cell survival. None of these patients
have required transfusions to date. Cytopenic patients with laboratory evidence of
hemolysis but minimal hemoglobinuria (n=3) had a marked improvement in hemolytic
parameters but less effect on transfusion requirements. There was no change in the
proportion of PNH neutrophils, monocytes or platelets in any of the patients whilst on
eculizumab. In summary, the preliminary results from this pilot study demonstrate that
eculizumab was well tolerated, decreased hemolysis and improved symptoms in PNH
patients. This study suggests that blocking complement at C5 is an effective therapeutic
strategy for hemolytic PNH resulting in control of hemolysis and a reduction in
transfusion dependency.
Keywords: PNH\ Therapy\ Eculizumab<<
Cheers, Tuck |
