Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Despite the availability of safe, effective targeted therapy that controls intravascular hemolysis, the management of paroxysmal nocturnal hemoglobinuria (PNH) remains complicated because of disease heterogeneity and close association with BM failure syndromes. The purpose of this review is to provide a framework for individualizing treatment based on disease classification. According to the recommendations of the International PNH Interest Group, patients can be placed into one of the following 3 categories: (1) classic PNH, (2) PNH in the setting of another BM failure syndrome, or (3) subclinical PNH. The PNH clone in patients with subclinical disease is insufficiently large to produce even biochemical evidence of hemolysis, and consequently, patients who fit into this category require no PNH-specific therapy. Patients with PNH in the setting of another BM failure syndrome (usually aplastic anemia or low-risk myelodysplastic syndrome) have at least biochemical evidence of hemolysis, but typically the PNH clone is small (< 10%) so that hemolysis does not contribute significantly to the underlying anemia. In these cases, the focus of treatment is on the BM failure component of the disease. Intravascular hemolysis is the dominant feature of classic PNH, and this process is blocked by the complement inhibitor eculizumab. The thrombophilia of PNH also appears to be ameliorated by eculizumab, but the drug has no effect on the BM failure component of the disease. Low-grade extravascular hemolysis due to complement C3 opsonization develops in most patients treated with eculizumab, and in some cases is a cause for suboptimal response to treatment. Allogeneic BM transplantation can cure classic PNH, but treatment-related toxicity suggests caution for this approach to management.