The importance of terminal complement inhibition in paroxysmal nocturnal hemoglobinuria

Author:

Kulasekararaj Austin G.12ORCID,Brodsky Robert A.3,Nishimura Jun-ichi4,Patriquin Christopher J.5,Schrezenmeier Hubert6

Affiliation:

1. Department of Haematological Medicine, King’s College Hospital, Denmark Hill, London SE5 9RS, UK

2. National Institute of Health Research/Wellcome King’s Clinical Research Facility and King’s College London, London, UK

3. Division of Hematology, Johns Hopkins Medicine, Baltimore, MD, USA

4. Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Suita, Japan

5. Division of Medical Oncology & Hematology, University Health Network – Toronto General Hospital, University of Toronto, Toronto, ON, Canada

6. Institute of Transfusion Medicine, University of Ulm, and Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, and University Hospital Ulm, Ulm, Germany

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic hematologic disorder associated with inappropriate terminal complement activity on blood cells that can result in intravascular hemolysis (IVH), thromboembolic events (TEs), and organ damage. Untreated individuals with PNH have an increased risk of morbidity and mortality. Patients with PNH experiencing IVH often present with an elevated lactate dehydrogenase (LDH; ⩾ 1.5 × the upper limit of normal) level which is associated with a significantly higher risk of TEs, one of the leading causes of death in PNH. LDH is therefore used as a biomarker for IVH in PNH. The main objective of PNH treatment should therefore be prevention of morbidity and mortality due to terminal complement activation, with the aim of improving patient outcomes. Approval of the first terminal complement inhibitor, eculizumab, greatly changed the treatment landscape of PNH by giving patients an effective therapy and demonstrated the critical role of terminal complement and the possibility of modulating it therapeutically. The current mainstays of treatment for PNH are the terminal complement component 5 (C5) inhibitors, eculizumab and ravulizumab, which have shown efficacy in controlling terminal complement-mediated IVH, reducing TEs and organ damage, and improving health-related quality of life in patients with PNH since their approval by the United States Food and Drug Administration in 2007 and 2018, respectively. Moreover, the use of eculizumab has been shown to reduce mortality due to PNH. More recently, interest has arisen in developing additional complement inhibitors with different modes of administration and therapeutics targeting other components of the complement cascade. This review focuses on the pathophysiology of clinical complications in PNH and explores why sustained inhibition of terminal complement activity through the use of complement inhibitors is essential for the management of patients with this chronic and debilitating disease.

Funder

astrazeneca

Publisher

SAGE Publications

Subject

Hematology

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