Treatment of paroxysmal nocturnal hemoglobinuria with the anti-complement antibody eculizumab helps prevent thromboembolism

November 19, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

A new study published in the journal Blood has evaluated the efficacy of long-term treatment with eculizumab for prevention of thromboembolism in patients with paroxysmal nocturnal hemoglobinuria (PNH). They demonstrate that 900 mg infusion of eculizumab every 14 days reduced rates of thromboembolism compared to pre-treatment rates.

Patients with PNH lack glycosylphosphatidylinositol (GPI)-bound membrane proteins in their hematopoietic cells. Absence of the GPI-linked membrane protein CD55, in particular, makes red blood cells susceptible to lysis by complement proteins. Patients with PNH experience hemolysis, anemia, risk for myelodysplasia or acute leukemia, and venous or even arterial thrombosis. Thromboembolism is the leading cause of death from this disorder, accounting for upwards of two-thirds of the mortality. Eculizumab is a monoclonal antibody against C5, a complement component of the membrane attack complex that mediates cell lysis in PNH. Previous phase III randomized placebo-controlled trials have demonstrated that PNH patients treated with eculizumab required fewer blood transfusions, had less hemolysis, and report better quality of life. Patients appear to tolerate treatment well, but require vaccination against Neisseria meningitidis because complement-deficient patients are at increased risk of infection.

The current study included 195 patients. It was an extension of previous clinical trials including the phase II pilot study, two phase III studies called TRIUMPH and SHEPHERD, and a common phase III extension study. In general, these studies included patients 18 years of age and older who had a PNH clone greater than 10% and required blood transfusions in the past. Patients on immunosuppresion, anticoagulants and iron supplementation were included in these studies. Pre- and post-eculizumab treatment rates of thromboembolism were compared.

Patients treated with eculizumab showed rapid decreases in rate of hemolysis as demonstrated by a significant drop in lactate dehydrogenase (LDH) levels. LDH levels remained just above the lower limit of detection for over 50 weeks of follow-up. Rates of thromboembolism following eculizumab treatment were 1.07 per 100 patient-years, compared with 7.37 per 100 patient-years prior to treatment (p<0.001). In patients on anti-coagulation, the thromboembolism event rate dropped from 10.61 to 0.62 per 100 patient-years.

This study was funded by Alexion Pharaceuticals, which markets eculizumab under the brand name Soliris. The initial report of the placebo-controlled trial TRIUMPH trial did not analyze rates of thromboembolism. The current comparison of pre- and post-treatment thromboembolic rates could be influenced by many factors other than eculizumab. As the authors mention, such a large impact on rates of thromboembolism would be expected to improve survival, although no mortality data was included in this analysis. PNH is a rare disease, which certainly limits the ability to power studies. The current study shows a dramatic impact of eculizumab on a meaningful clinical outcome, and supports the use of this immunotherapy in patients with PNH.

1.''Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. '' Peter Hillmen, Petra Muus, Ulrich Dührsen, Antonio M. Risitano, Jörg Schubert, Lucio Luzzatto, Hubert Schrezenmeier, Jeffrey Szer, Robert A. Brodsky, Anita Hill, Gerard Socié, Monica Bessler, Scott A. Rollins, Leonard Bell, Russell P. Rother, and Neal S. Young

Blood 2007 110: 4123-4128. Prepublished online August 16, 2007; DOI 10.1182/blood-2007-06-095646