Navigating the paroxysmal nocturnal hemoglobinuria (PNH) landscape.

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder in which a somatic mutation in PIGA leads to reduced or absent expression of glycosylphosphatidylinositol-anchored complement regulatory proteins. PNH presents with the central manifestations of complement-mediated hemolytic anemia, bone marrow failure, and thrombosis. The introduction of terminal complement inhibitors that block complement protein 5 (C5) has revolutionized the management of PNH by reducing the risk for thrombosis, extending survival to be similar to that of healthy controls, and improving quality of life. C5 inhibitors approved by the US Food and Drug Administration (FDA) include eculizumab (administered intravenously every 2 weeks), ravulizumab (administered intravenously every 8 weeks), and, most recently, crovalimab (administered subcutaneously every 4 weeks). Given the chronic nature and life-threatening complications of PNH, longterm efficacy and safety data of treatment approaches are invaluable. The most extensive experience has been gained with eculizumab, and now 6-year data with ravulizumab point to its durable control of terminal complement activity and intravascular hemolysis. Although terminal complement inhibitors effectively control intravascular hemolysis, approximately 30% of patients receiving C5 inhibitors develop clinically significant extravascular hemolysis with ongoing transfusion requirements or symptomatic anemia. Upstream complement inhibitors that inhibit components of the alternative complement system have been developed with the goal of addressing both intravascular and extravascular hemolysis. The C3 inhibitor pegcetacoplan (administered subcutaneously twice weekly) and the factor B inhibitor iptacopan (administered orally twice daily), both used as single agents, have demonstrated effective control of hemolysis with increased hemoglobin and transfusion avoidance in both C5 inhibitor-naive and C5 inhibitor-experienced patients with clinically significant extravascular hemolysis. The factor D inhibitor danicopan (administered orally 3 times a day) is used as an add-on to ravulizumab or eculizumab and offers a combination approach by targeting both terminal complement and the alternative pathway. Breakthrough hemolysis in the event of a strong complement trigger is possible on any complement inhibitor, but these breakthrough events could be more severe with alternative pathway inhibitor monotherapy. Rates of breakthrough hemolysis and whether they differ between the alternative pathway inhibitors remain to be determined in the real-world setting.