Advancing therapeutic complement inhibition in hematologic diseases: PNH and beyond.

Complement is an elaborate system of the innate immunity. Genetic variants and autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototype model of complement activation and inhibition. Eculizumab, the first-in-class complement inhibitor, was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting C5 inhibitor, ravulizumab, and a C3 inhibitor, pegcetacoplan have been also now approved with PNH. Novel agents, such as factor B and factor D inhibitors, are under study with very promising results. In this era of several approved targeted complement therapeutics, selection of the proper drug needs to be based on a personalized approach. Beyond PNH, complement inhibition has also shown efficacy and safety in cold agglutinin disease (CAD), primarily with the C1s inhibitor of the classical complement pathway, sutimlimab, but also with pegcetacoplan. Furthermore, C5 inhibition with eculizumab and ravulizumab, as well as inhibition of the lectin pathway with narsoplimab, are investigated in transplant-associated thrombotic microangiopathy (TA-TMA). With this revolution of next-generation complement therapeutics, additional hematologic entities, such as delayed hemolytic transfusion reaction (DHTR) or immune thrombocytopenia (ITP), might also benefit from complement inhibitors. Therefore, this review aims to describe state-of-the-art knowledge of targeting complement in hematologic diseases focusing on: a) complement biology for the clinician, b) complement activation and therapeutic inhibition in prototypical complement-mediated hematologic diseases, c) hematologic entities under investigation for complement inhibition, and d) other complement-related disorders of potential interest to hematologists.