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      Characterization of breakthrough hemolysis events observed in the phase III randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria

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          Abstract

          Eculizumab is first-line treatment for paroxysmal nocturnal hemoglobinuria (PNH); however, approximately 11-27% of patients may experience breakthrough hemolysis (BTH) on approved doses of eculizumab. Ravulizumab, a new long-acting C5 inhibitor with a four times longer mean half-life than eculizumab, provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals. In two phase III studies, ravulizumab was non-inferior to eculizumab ( Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with ravulizumab versus eculizumab in both studies (301 [complement inhibitor−naïve patients], 4.0% vs. 10.7%; 302 [patients stabilized on eculizumab at baseline], 0% vs. 5.1%). In the current analysis, patientlevel data were evaluated to assess causes and clinical parameters associated with incidents of BTH reported during the 26-week treatment periods in the ravulizumab phase III PNH studies. Of the five BTH events occurring in ravulizumab-treated patients across the studies, none were temporally associated with suboptimal C5 inhibition (free C5 ≥0.5 mg/mL); four (80%) were temporally associated with complement-amplifying conditions (CAC). Of the 22 events occurring in eculizumab-treated patients, 11 were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant infection. Six events were associated with CAC only. Five events were unrelated to free C5 elevation or reported CAC. These results suggest that the immediate, complete, and sustained C5 inhibition achieved through weight-based dosing of ravulizumab reduces the risk of BTH by eliminating BTH associated with suboptimal C5 inhibition in patients with PNH. (Registered at clinicaltrials.gov identifiers: Study 301, NCT02946463; Study 302, NCT03056040.)

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          Most cited references 29

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          Thrombosis in paroxysmal nocturnal hemoglobinuria.

          The most frequent and feared complication of paroxysmal nocturnal hemoglobinuria (PNH) is thrombosis. Recent research has demonstrated that the complement and coagulation systems are closely integrated with each influencing the activity of the other to the extent that thrombin itself has recently been shown to activate the alternative pathway of complement. This may explain some of the complexity of the thrombosis in PNH. In this review, the recent changes in our understanding of the pathophysiology of thrombosis in PNH, as well as the treatment of thrombosis, will be discussed. Mechanisms explored include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, absence of other glycosylphosphatidylinositol-linked proteins such as urokinase-type plasminogen activator receptor and endothelial dysfunction. Complement inhibition with eculizumab has a dramatic effect in PNH and has a major impact in the prevention of thrombosis as well as its management in this disease.
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            Avian influenza A (H5N1) infection in eastern Turkey in 2006.

            An outbreak of highly pathogenic avian influenza A (H5N1) that had previously been detected throughout Asia, with major economic and health repercussions, extended to eastern Turkey in late December 2005 and early January 2006. We documented the epidemiologic, clinical, and radiologic features of all cases of confirmed H5N1 virus infection in patients who were admitted to Yuzuncu Yil University Hospital in Van, Turkey, between December 31, 2005, and January 10, 2006. H5N1 virus infection was diagnosed in eight patients. The patients were 5 to 15 years of age, and all eight had a history of close contact with diseased or dead chickens. The mean (+/-SD) time between exposure and the onset of illness was 5.0+/-1.3 days. All the patients had fever, and seven had clinical and radiologic evidence of pneumonia at presentation; four patients died. Results of enzyme-linked immunosorbent assay and rapid influenza tests were negative in all patients, and the diagnosis was made by means of a polymerase-chain-reaction assay. H5N1, which causes a spectrum of illnesses in humans, including severe and fatal respiratory disease, can be difficult to diagnose. Copyright 2006 Massachusetts Medical Society.
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              Paroxysmal nocturnal haemoglobinuria

              Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematopoietic stem cell (HSC) disease that presents with haemolytic anaemia, thrombosis and smooth muscle dystonias, as well as bone marrow failure in some cases. PNH is caused by somatic mutations in PIGA (which encodes phosphatidylinositol N -acetylglucosaminyltransferase subunit A) in one or more HSC clones. The gene product of PIGA is required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors; thus, PIGA mutations lead to a deficiency of GPI-anchored proteins, such as complement decay-accelerating factor (also known as CD55) and CD59 glycoprotein (CD59), which are both complement inhibitors. Clinical manifestations of PNH occur when a HSC clone carrying somatic PIGA mutations acquires a growth advantage and differentiates, generating mature blood cells that are deficient of GPI-anchored proteins. The loss of CD55 and CD59 renders PNH erythrocytes susceptible to intravascular haemolysis, which can lead to thrombosis and to much of the morbidity and mortality of PNH. The accumulation of anaphylatoxins (such as C5a) from complement activation might also have a role. The natural history of PNH is highly variable, ranging from quiescent to life-threatening. Therapeutic strategies include terminal complement blockade and bone marrow transplantation. Eculizumab, a monoclonal antibody complement inhibitor, is highly effective and the only licensed therapy for PNH.
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                Author and article information

                Journal
                Haematologica
                Haematologica
                HAEMA
                Haematologica
                Fondazione Ferrata Storti
                0390-6078
                1592-8721
                01 January 2021
                01 January 2021
                : 106
                : 1
                Affiliations
                [1 ]Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, MD, USA
                [2 ]Universite Paris Diderot , Paris, France
                [3 ]French Reference Center for Aplastic Anemia and PNH Hematology-Bone Marrow Transplantation, Hopital Saint-Louis AP-HP, Paris, France
                [4 ]Alexion Pharmaceuticals Inc. , Boston, MA, USA
                [5 ]Department of Hematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen , Essen, Germany
                [6 ]Hematology, Department of Clinical Medicine and Surgery, Federico II University of Naples , Naples, Italy
                [7 ]Jane Anne Nohl Division of Hematology, Keck-USC School of Medicine , Los Angeles, CA, USA
                [8 ]Department of Haematology, St James's University Hospital , Leeds, UK
                [9 ]Department of Translational Hematology and Oncology Research, Taussig Cancer Institute , Cleveland Clinic Foundation, Cleveland, OH, USA
                [10 ]Clinical Haematology, Royal Melbourne Hospital , Melbourne, Victoria, Australia
                [11 ]Department of Hematology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea , Seoul, Republic of Korea
                [12 ]Department of Haematological Medicine, King’s College Hospital , NIHR/Wellcome King’s Clinical Research Facility, London, UK
                [13 ]Institute for Clinical Transfusion Medicine and Immunogenetics , German Red Cross Blood Transfusion Service Baden-Wurttemberg-Hessen, Germany and University Hospital Ulm , Ulm, Germany
                [14 ]Institute of Transfusion Medicine, University of Ulm , Ulm, Germany
                Author notes
                aCurrent address: Principal, Volles Consulting Group, Old Lyme, CT, USA
                bCurrent address: Vista Life Innovations, Madison, CT, USA
                cCurrent address: Alexion Pharmaceuticals, Inc., Boston, MA, USA
                ROBERT A. BRODSKY rbrodsky@ 123456jhmi.edu

                Disclosures

                RAB is a member of the scientific advisory board for and receives grant funding from Alexion Pharmaceuticals, Inc.; RPdL has received honoraria, consulting fees, and research support from Alexion Pharmaceuticals, Inc., Pfizer, and Novartis, and has received research support from Amgen; STR is an employee and stockholder of Alexion Pharmaceuticals, Inc.; AR has received honoraria and consulting fees from Alexion Pharmaceuticals, Inc., Apellis Pharmaceuticals, Novartis, and Roche; AMR has received research support, honoraria, and consulting fees from Alexion Pharmaceuticals, Inc., Novartis, Alnylam, and Ra Pharma, lecture fees from Alexion Pharmaceuticals, Inc., Novartis, Pfizer, and Jazz, and served as an advisory board member for Alexion Pharmaceuticals, Inc., Novartis, Pfizer, and Jazz, as well as consultant for Amyndas; ICW has received honoraria and consulting fees from Alexion Pharmaceuticals, Inc.; PH has received honoraria from and has been a consultant for Alexion Pharmaceuticals, Inc., and has received research support (to the University of Leeds) from Apellis Pharmaceuticals; JPM has received consulting fees from Alexion Pharmaceuticals, Inc., Apellis Pharmaceuticals, and Ra Pharma; has also received speaker fees from and is a member of the Executive Committee of the International PNH Registry for Alexion Pharmaceuticals, Inc.; JS has received research support (to Royal Melbourne Hospital), honoraria, consulting fees, and travel support from Alexion Pharmaceuticals, Inc.; JWL has received honoraria, consulting fees, and research support (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc.; AGK has received honoraria, travel support, and consulting fees from Alexion Pharmaceuticals, Inc.; LV is an employee and stockholder of Alexion Pharmaceuticals, Inc.; AID was an employee and stockholder of Alexion Pharmaceuticals, Inc. at the time of the study analysis and during the development of this manuscript; SO is an employee and stockholder of Alexion Pharmaceuticals, Inc.; LS was an employee and stockholder of Alexion Pharmaceuticals, Inc. at the time of this analysis and during development of the manuscript; PLis an employee and stockholder of Alexion Pharmaceuticals, Inc.; AH has received honoraria and consulting fees from Alexion Pharmaceuticals, Inc.; HS has received honoraria and research support (both to University of Ulm) from Alexion Pharmaceuticals, Inc.

                Contributions

                Study design: AH, AID, AR, PH, HS, RPL, JWL, AK, LS, LV, STR. Study investigator: AH, AR, RAB, RPL, AMR, ICW, PH, JPM, JS, JWL, AK, HS. Enrolled patients: AH, AR, RAB, RPL, AMR, ICW, PH, JPM, JS, JWL, AK, HS. Collection and assembly of data: All authors. Data analysis: AR, AID, HS, PL, SO, STR, RAB. Data interpretation: All authors. Manuscript review and revisions: All authors. Final approval of manuscript: All authors.

                Article
                10.3324/haematol.2019.236877
                7776354
                31949012
                Copyright© 2021 Ferrata Storti Foundation

                This article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

                Page count
                Figures: 0, Tables: 4, Equations: 0, References: 31, Pages: 8
                Funding
                Funding : This study was supported by Alexion Pharmaceuticals, Inc.
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