Clinical Effects of Eculizumab in PNH: Extravascular Hemolysis After Eculizumab Treatment

Abstract

The most important advance in the management of paroxysmal nocturnal hemoglobinuria (PNH) has been the introduction of eculizumab, a human monoclonal antibody against the C5 component of complement, that abrogates intravascular hemolysis by preventing the formation of the complement membrane attack complex. Complement blockade by eculizumab has proven to be clinically effective in hemolytic PNH, reducing the transfusion requirement in most of patients. However, in almost all PNH patients on eculizumab, a proportion of PNH red cells become coated with C3 and thus a potential target of phagocytosis by macrophages. This phagocytosis results in a variable degree of extravascular hemolysis that in some patients may limit the clinical benefit from eculizumab: in fact, at least one in four of transfusion-dependent PNH patients remain transfusion dependent even on eculizumab, and these patients may also have a high risk to develop iron overload. Unfortunately, there are not yet established treatments for the cases in which this extravascular hemolysis became clinically relevant: it is possible that new strategies for complement blockade could overcome this condition.