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Review
. 2019 Sep 9:10:2040620719873321.
doi: 10.1177/2040620719873321. eCollection 2019.

Novel insights into the treatment of complement-mediated hemolytic anemias

Sigbjørn Berentsen  1 , Anita Hill  2 , Quentin A Hill  2 , Tor Henrik Anderson Tvedt  3 , Marc Michel  4
Affiliations
Review

Novel insights into the treatment of complement-mediated hemolytic anemias

Sigbjørn Berentsen et al. Ther Adv Hematol. .

Abstract

Complement-mediated hemolytic anemias can either be caused by deficiencies in regulatory complement components or by autoimmune pathogenesis that triggers inappropriate complement activation. In paroxysmal nocturnal hemoglobinuria (PNH) hemolysis is entirely complement-driven. Hemolysis is also thought to be complement-dependent in cold agglutinin disease (CAD) and in paroxysmal cold hemoglobinuria (PCH), whereas warm antibody autoimmune hemolytic anemia (wAIHA) is a partially complement-mediated disorder, depending on the subtype of wAIHA and the extent of complement activation. The pathophysiology, clinical presentation, and current therapies for these diseases are reviewed in this article. Novel, complement-directed therapies are being rapidly developed. Therapeutic terminal complement inhibition using eculizumab has revolutionized the therapy and prognosis in PNH but has proved less efficacious in CAD. Upstream complement modulation is currently being investigated and appears to be a highly promising therapy, and two such agents have entered phase II and III trials. Of these, the anti-C1s monoclonal antibody sutimlimab has shown favorable activity in CAD, while the anti-C3 cyclic peptide pegcetacoplan appears to be promising in PNH as well as CAD, and may also have a therapeutic potential in wAIHA.

Keywords: autoimmune hemolytic anemia; cold agglutinin disease; complement; complement inhibitors; paroxysmal nocturnal hemoglobinuria; therapy.

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Conflict of interest statement

Conflict of interest statement: The authors did not receive any funding for this work. Outside this work, S. Berentsen has received research funding from Mundipharma, consulting fees from Apellis, Bioverativ, Momenta Pharmaceuticals and True North Therapeutics, and travel grants and lecture honoraria from Alexion, Apellis, Bioverativ and Janssen-Cilag. A. Hill has received honoraria from Alexion, Apellis, Bioverativ, and Novartis. Q.A. Hill has received research support from Alexion and honoraria for lecturing or advisory work from Novartis, Shire, and Bioverativ. T.H.A. Tvedt has received advisory board honoraria from Ablynx and Alexion and lecture honoraria from Alexion and Novartis. M. Michel has advisory board honoraria from Alexion, Apellis, and Rigel.

Figures

Figure 1.
Figure 1.
The complement system simplified. Only the relevant pathways and components are shown. C, complement protein; MAC, membrane attack complex.
Figure 2.
Figure 2.
Mechanisms of hemolysis in warm antibody autoimmune hemolytic anemia. C, complement protein; Ig, immunoglobulin.
Figure 3.
Figure 3.
Survival among patients with paroxysmal nocturnal hemoglobinuria (PNH) on eculizumab therapy compared with survival before the eculizumab era. First published in Blood by Kelly and colleagues, reused under general permission. Copyright: Blood, the Journal of the American Society of Hematology.
Figure 4.
Figure 4.
Effect of pegcetacoplan in cold agglutinin disease (CAD). Data from a phase II study, showing normalization of hemoglobin levels within 56 days of medication in the majority of patients and within 84 days in all patients (a). Normalization of indirect bilirubin levels within 1–2 weeks in all patients (b). LLN, lower limit of normal; ULN, upper limit of normal. Originally presented by F. Grossi and colleagues. at the 60. Annual Meeting of the American Society of Hematology, 2018, reproduced with permission. Courtesy of F. Stout and A. Shen. Copyright: Apellis Pharmaceuticals.
See this image and copyright information in PMC

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