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Front. Immunol. | doi: 10.3389/fimmu.2019.01157

Anti-complement treatment for Paroxysmal Nocturnal Hemoglobinuria: time for proximal complement inhibition? A position paper from the SAAWP of the EBMT.

 Antonio Maria Risitano1*,  Serena Marotta1,  Patrizia Ricci1, Luana Marano1,  Camilla Frieri1,  Fabiana Cacace1, Michela Sica2, Austin Kulasekararaj3,  Rodrigo T. Calado4, Philip Scheinberg5,  Rosario Notaro2 and Regis Peffault de Latour6
  • 1University of Naples Federico II, Italy
  • 2Istituto per lo Studio e la Prevenzione Oncologica (ISPO), Italy
  • 3King's College London, United Kingdom
  • 4University of São Paulo, Brazil
  • 5Beneficência Portuguesa de São Paulo, Brazil
  • 6Paris Diderot University, France

The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for PNH, and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (major and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). Different factors contribute to residual anemia during eculizumab treatment: underlying bone marrow dysfunction, residual intravascular hemolysis and the emergence of C3-mediated extravascular hemolysis. These two latter pathogenic mechanisms are the target of novel strategies of anti-complement treatments, which can be split into terminal and proximal complement inhibitors. Many novel terminal complement inhibitors are now in clinical development: they all target C5 (as eculizumab), potentially paralleling the efficacy and safety profile of eculizumab. Possible advantages over eculizumab are long-lasting activity and subcutaneous self-administration. However, novel anti-C5 agents do not improve hematological response to eculizumab, even if some seem associated with a lower risk of breakthrough hemolysis caused by pharmacokinetic reasons (it remains unclear whether more effective inhibition of C5 is possible and clinically beneficial). Indeed, proximal inhibitors are designed to interfere with early phases of complement-activation, eventually preventing C3-mediated extravascular hemolysis in addition to intravascular hemolysis. At the moment there are three strategies of proximal complement inhibition: anti-C3 agents, anti-factor D agents and anti-factor B agents. These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible, apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.

Keywords: Paroxysmal nocturnal hemoglobinuria, intravascular hemolysis, Extravascular hemolysis, complement, Complement inhibition therapy, Compstatin, eculizumab therapeutics

Received: 16 Mar 2019; Accepted: 08 May 2019.

Edited by:

John D. Lambris, University of Pennsylvania, United States

Reviewed by:

Trent M. Woodruff, University of Queensland, Australia
Ronald P. Taylor, University of Virginia, United States
Gowthami Arepally, Duke University Medical Center, United States
Christoph Q. Schmidt, University of Ulm, Germany  

Copyright: © 2019 Risitano, Marotta, Ricci, Marano, Frieri, Cacace, Sica, Kulasekararaj, Calado, Scheinberg, Notaro and Peffault de Latour. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Antonio Maria Risitano, University of Naples Federico II, Napoli, Italy,