The alternative pathway of complement (APC) is in a state of continuous, low-grade activation, and host erythrocytes are normally protected against complement-mediated injury by two glycosyl phosphatidylinositol (GPI)-anchored membrane proteins (Figure). Decay accelerating factor (DAF, CD55) inhibits the formation and stability of the APC C3 and C5 amplification convertases and membrane inhibitor of reactive lysis (MIRL, CD59) block the assembly of the cytolytic membrane attack complex (MAC) (Figure). Coombs-negative, complement-mediated intravascular hemolysis, the clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH), is a consequence of deficiency of CD55 and CD59. A logical strategy for controlling the hemolysis of PNH is to compensate for deficiency of CD55 and CD59 by blocking the APC pharmacologically. In this paper by Hillmen and colleagues, this approach was employed in a phase III, randomized, placebo-controlled trial in which a humanized monoclonal antibody (eculizumab) that binds the fifth component of complement (C5) was used to inhibit formation of the MAC (Figure). Treatment with eculizumab (43 patients vs. 44 in the control group) resulted in a dramatic, sustained decrease in the concentration of plasma LDH (a sensitive surrogate marker for intravascular hemolysis). A marked reduction in red cell transfusion requirement was also observed in the eculizumab-treated group. Patients in the treatment group, however, remained anemic, and an earlier phase II study showed essentially no change in reticulocyte count in patients treated with eculizumab1 . The persistent anemia may be the result of extravascular hemolysis of C3-coated erythrocytes, as the anti-C5 antibody eclulizumab does not inhibit formation of the amplification C3 convertase (Figure). Quality-of-life measurements suggested that inhibition of complement-mediated intravascular hemolysis ameliorates the fatigue associated with PNH, but the effects of eculizumab therapy on such PNH-associated symptoms as dysphagia/odynophagia and abdominal pain2 were not specifically addressed in the study. Neither was the study designed to determine the effects of eculizumab on thromboembolic complications of PNH; however, only one thrombotic event (affecting a patient in the placebo group) was reported. Four serious adverse events (none infectious and none considered treatment-related) were reported among patients in the eculizumab group.
In Brief
Although not yet FDA-approved, eculizumab appears to be an effective, safe treatment for controlling the complement-mediated intravascular hemolysis of PNH. Patients most likely to benefit are those with classical PNH2 . These patients have large PNH clones, and their symptoms are primarily a consequence of uncontrolled hemolysis. As with infusional therapy treatments developed for other orphan diseases, the cost will certainly be high, and treatment must continue indefinitely as eculizumab has no apparent effect on the underlying PIGA-mutant clonal hematopoiesis or on the marrow failure component of the disease. Whether eculizumab therapy will have an impact on thrombosis, the major cause of mortality in PNH, is uncertain. Treatment with eculizumab allows us a glimpse of PNH without its trademark intravascular hemolysis. What we see so far is a relatively benign clonal myeloid disorder3 , distinct from myeloproliferative and myelodysplastic processes. Continued investigation is needed to understand the basis of the clonal selection and clonal expansion of PNH so that strategies can be developed to treat the disease, not just the symptoms.
