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Dysregulated complement is thought to mediate atypical hemolytic–uremic syndrome (aHUS), a clinical constellation consisting of hemolytic anemia, thrombocytopenia, and renal failure. Eculizumab, a humanized monoclonal antibody that binds to the C5 complement protein, blocks the terminal activation of the complement system.
To evaluate the effects of eculizumab in aHUS, investigators conducted two manufacturer-sponsored, phase II trials involving a total of 37 patients with either clinical evidence of progressive disease (trial 1) or long-duration aHUS resulting in chronic renal failure (trial 2). Patients received meningococcal vaccination prior to eculizumab initiation. Eculizumab was given in intravenous doses of 900 mg per week for 4 weeks, followed by maintenance doses of 1200 mg every 2 weeks for 26 weeks and then for a median of 62 to 64 weeks during an extension study. The outcomes were as follows:
The mean increase in platelet count in 15 patients in trial 1 was 73×109/L (95% confidence interval, 40–105; P<0.001); 13 of these patients (87%) had platelet counts that were normal at week 26 and remained normal at week 64.
Lactate dehydrogenase declined and the glomerular filtration rate (GFR) improved for patients in both trials; 4 of 5 patients in trial 1 were able to discontinue dialysis. Patients in trial 2 had smaller increases in GFR, perhaps because their disease was of longer duration (median 48.0 vs. 9.7 months). Earlier initiation of eculizumab was associated with greater improvement in GFR in both trials (P≤0.007).
Eculizumab was associated with a significant improvement in quality-of-life scores in both trials; previous treatment with plasma exchange/infusion could be discontinued in 88% of patients in trial 1 and 100% of patients in trial 2.
Complement activity was reduced within 1 hour of dosing and completely inhibited though week 26 in both trials.
Adverse events were infrequent, but severe infections (influenza and peritonitis) occurred in 2 patients in trial 2.
Legendre CM et al. Terminal complement inhibitor eculizumab in atypical hemolytic–uremic syndrome. N Engl J Med 2013 Jun 6; 368:2169. (http://dx.doi.org/10.1056/NEJMoa1208981)
Comment
Eculizumab was previously shown to prolong survival in patients with paroxysmal nocturnal hemoglobinuria (JW Oncol Hematol Aug 16 2011). The current study demonstrates that eculizumab also improves the management of patients with atypical hemolytic–uremic syndrome. Early diagnosis and prompt initiation of therapy are required to prevent renal damage, dialysis, and the need for kidney transplantation. Still unknown in aHUS patients is when doses of eculizumab can be safely tapered or discontinued.