How I treat paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal blood disorder that manifests with hemolytic anemia, bone marrow failure, and thrombosis. Many of the clinical manifestations of the disease result from complement-mediated intravascular hemolysis. Allogeneic bone marrow transplantation is the only curative therapy for PNH. Eculizumab, a monoclonal antibody that blocks terminal complement activation, is highly effective in reducing hemolysis, improving quality of life, and reducing the risk for thrombosis in PNH patients. Insights into the relevance of detecting PNH cells in PNH and other bone marrow failure disorders are highlighted, and indications for treating PNH patients with bone marrow transplantation and eculizumab are explored.

Figure 1

Multiparameter flow cytometry analysis of peripheral blood in PNH. (A-D) Aplastic anemia patient with small (2%) PNH clone; (E-H) classic PNH patient. (A,E) Forward scatter (FSC)/side scatter (SSC) display showing initial gate to exclude lymphocytes and debris. (B,F) Granulocytes (green) are identified as bright CD15 and low CD33, whereas monocytes (blue) are bright CD33 and low CD15. (C,G) Population of GPI anchor protein–deficient granulocytes showing lack of staining with both anti-CD24 and FLAER. (D,H) Population of GPI anchor protein–deficient monocytes showing lack of staining with both anti-CD14 and FLAER.

Figure 2

Structure of eculizumab. Eculizumab was engineered to reduce immunogenicity and eliminate effector function. Human IgG2 and IgG4 heavy-chain sequences were combined to form a hybrid constant region that is unable to bind Fc receptors or to activate the complement cascade. Eculizumab exhibits high affinity for human C5, effectively blocking its cleavage and downstream proinflammatory and cell lytic properties. Reprinted from Rother et al with permission.

Figure 3

Overview of the complement cascade. Classic, alternative, and lectin pathways converge at the point of C3 activation. The lytic pathway is initiated with the formation of C5 convertase and leads to the assembly of the C5, C6, C7, C8, (n) C9 membrane attack complex. Eculizumab is a monoclonal antibody that binds to C5, thereby preventing the formation of C5a and C5b. C5b is the initiating component of the MAC. Reprinted from Brodsky with permission.

Figure 4

Reduction in intravascular hemolysis during treatment with eculizumab. Mean levels of lactate dehydrogenase reflect the degree of hemolysis from baseline to week 52. The dashed line represents the upper limit of the normal range for lactate dehydrogenase (normal range, 103-223 U/L). In eculizumab-treated patients, the mean level of lactate dehydrogenase was rapidly reduced to just above the upper limit of the normal range. In the placebo group, the mean level of lactate dehydrogenase remained highly elevated. The arrow represents the transition of placebo-treated patients to eculizumab treatment in the phase 3 extension study, at which time levels of lactate dehydrogenase rapidly reduced to near normal values. Reprinted from Rother et al with permission.