How we(’ll) treat paroxysmal nocturnal haemoglobinuria: diving into the future

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by complement‐mediated intravascular haemolysis, severe thrombophilia and bone marrow failure. While for patients with bone marrow failure the treatment follows that of immune‐mediated aplastic anaemia, that of classic, haemolytic PNH is based on anti‐complement medication. The anti‐C5 monoclonal antibody eculizumab has revolutionized treatment, resulting in control of intravascular haemolysis and thromboembolic risk, with improved long‐term survival. Novel strategies of complement inhibition are emerging. New anti‐C5 agents reproduce the safety and efficacy of eculizumab, with improved patient convenience. Proximal complement inhibitors have been developed to address C3‐mediated extra‐vascular haemolysis and seem to improve haematological response.

[1]  J. Panse,et al.  3113 – FORTY-EIGHT WEEK EFFICACY AND SAFETY OF PEGCETACOPLAN IN ADULT PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA AND SUBOPTIMAL RESPONSE TO PRIOR ECULIZUMAB TREATMENT , 2021, Experimental Hematology.

[2]  I. Rozenberg,et al.  Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. , 2021, The Lancet. Haematology.

[3]  R. Wells,et al.  One‐year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab , 2020, European journal of haematology.

[4]  J. Maciejewski,et al.  Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria , 2020, Haematologica.

[5]  R. Wells,et al.  One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study , 2020, Therapeutic advances in hematology.

[6]  J. Maciejewski,et al.  C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab , 2020, American journal of hematology.

[7]  R. Wells,et al.  Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies , 2020, British journal of haematology.

[8]  J. Panse,et al.  The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. , 2020, Blood.

[9]  J. Maciejewski,et al.  Characterization of breakthrough hemolysis events observed in the phase III randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria , 2020, Haematologica.

[10]  J. Maciejewski,et al.  A Phase 2 Open-Label Study of Danicopan (ACH-0144471) in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to Eculizumab Monotherapy , 2019, Blood.

[11]  P. Scheinberg,et al.  Hematological Response to Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: Application of a Novel Classification to Identify Unmet Clinical Needs and Future Clinical Goals , 2019, Blood.

[12]  P. Scheinberg,et al.  Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT , 2019, Front. Immunol..

[13]  H. Schrezenmeier,et al.  Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. , 2019, Blood.

[14]  R. Wells,et al.  Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. , 2019, Blood.

[15]  L. Luzzatto,et al.  The “escape” model: a versatile mechanism for clonal expansion , 2019, British journal of haematology.

[16]  J. Maciejewski,et al.  Effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) with or without aplastic anemia in the International PNH Registry , 2018, American journal of hematology.

[17]  R. Wells,et al.  Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. , 2018, Blood advances.

[18]  L. Luzzatto,et al.  Advances in understanding the pathogenesis of acquired aplastic anaemia , 2018, British journal of haematology.

[19]  Zhao-Xue Yu,et al.  Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action , 2018, PloS one.

[20]  A. Risitano,et al.  Toward complement inhibition 2.0: Next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria , 2018, American journal of hematology.

[21]  M. Borowitz,et al.  ICCS/ESCCA Consensus Guidelines to detect GPI‐deficient cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) and related Disorders Part 1 – Clinical Utility , 2018, Cytometry. Part B, Clinical cytometry.

[22]  P. Wallace,et al.  ICCS/ESCCA Consensus Guidelines to detect GPI‐deficient cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) and related Disorders Part 2 – Reagent Selection and Assay Optimization for High‐Sensitivity Testing , 2018, Cytometry. Part B, Clinical cytometry.

[23]  P. Wallace,et al.  ICCS/ESCCA Consensus Guidelines to detect GPI‐deficient cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) and related Disorders Part 4 – Assay Validation and Quality Assurance , 2018, Cytometry. Part B, Clinical cytometry.

[24]  O. Wagner-Ballon,et al.  ICCS/ESCCA Consensus Guidelines to detect GPI‐deficient cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) and related Disorders Part 3 – Data Analysis, Reporting and Case Studies , 2018, Cytometry. Part B, Clinical cytometry.

[25]  P. Chevallier,et al.  Hematopoietic stem cell transplantation for patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a retrospective study of 21 patients from SFGM-TC centers , 2017, Haematologica.

[26]  J. Nezu,et al.  Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases , 2017, Scientific Reports.

[27]  A. Risitano,et al.  Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future. , 2016, Seminars in immunology.

[28]  Pierre-Yves Dumas,et al.  Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no‐treatment study , 2016, American journal of hematology.

[29]  J. Szer,et al.  Eculizumab in Pregnant Patients with Paroxysmal Nocturnal Hemoglobinuria. , 2015, The New England journal of medicine.

[30]  Patrizia Ricci,et al.  Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria. , 2015, Blood.

[31]  J. Nishimura.  [Genetic variants in C5 and poor response to eculizumab]. , 2015, [Rinsho ketsueki] The Japanese journal of clinical hematology.

[32]  R. Porcher,et al.  Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. , 2015, Blood.

[33]  A. Risitano.  Dissecting complement blockade for clinic use. , 2015, Blood.

[34]  B. Leber,et al.  Increased eculizumab requirements during pregnancy in a patient with paroxysmal nocturnal hemoglobinuria: case report and review of the literature , 2014, Clinical case reports.

[35]  A. Risitano,et al.  Hematopoietic stem cell transplantation for aplastic anemia and paroxysmal nocturnal hemoglobinuria: current evidence and recommendations , 2014, Expert review of hematology.

[36]  John D Lambris,et al.  Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. , 2014, Blood.

[37]  P. Hillmen,et al.  Thrombosis in paroxysmal nocturnal hemoglobinuria. , 2013, Blood.

[38]  J. Maciejewski,et al.  Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria , 2013, British journal of haematology.

[39]  A. Risitano,et al.  Paroxysmal nocturnal hemoglobinuria and other complement-mediated hematological disorders. , 2012, Immunobiology.

[40]  D. Blaise,et al.  Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria , 2012, Haematologica.

[41]  M. Imbriaco,et al.  From perpetual haemosiderinuria to possible iron overload: iron redistribution in paroxysmal nocturnal haemoglobinuria patients on eculizumab by magnetic resonance imaging , 2012, British journal of haematology.

[42]  L. Luzzatto,et al.  The complement receptor 2/factor H fusion protein TT30 protects paroxysmal nocturnal hemoglobinuria erythrocytes from complement-mediated hemolysis and C3 fragment. , 2012, Blood.

[43]  H. Thaler,et al.  Thrombolytic therapy is effective in paroxysmal nocturnal hemoglobinuria: a series of nine patients and a review of the literature , 2012, Haematologica.

[44]  B. Bonnotte,et al.  Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: the French experience , 2011, Haematologica.

[45]  L. Luzzatto,et al.  Management of Paroxysmal Nocturnal Haemoglobinuria: a personal view , 2011, British journal of haematology.

[46]  W. Gregory,et al.  Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. , 2010, Blood.

[47]  John D Lambris,et al.  Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency. , 2011, Molecular immunology.

[48]  L. Luzzatto,et al.  correspondence: Pregnancy in PNH: another eculizumab baby , 2010, British journal of haematology.

[49]  G. Khursigara,et al.  Long‐term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria , 2010, American journal of hematology.

[50]  S. Craigo,et al.  Managing a pregnant patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab. , 2010, Leukemia research.

[51]  S. Richards,et al.  Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization , 2010, Haematologica.

[52]  L. Luzzatto,et al.  Paroxysmal nocturnal hemoglobinuria and eculizumab* , 2010, Haematologica.

[53]  R. Porcher,et al.  Evaluation of hemostasis and endothelial function in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab , 2010, Haematologica.

[54]  A. Zanella,et al.  Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. , 2009, Blood.

[55]  G. Khursigara,et al.  Modification of the Eculizumab Dose to Successfully Manage Intravascular Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria. , 2008 .

[56]  M. Mohty,et al.  Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. , 2008, Blood.

[57]  B. Murtaza,et al.  Paroxysmal nocturnal hemoglobinuria. , 2008, Journal of the College of Physicians and Surgeons--Pakistan : JCPSP.

[58]  N. Young,et al.  Eculizumab, a terminal complement inhibitor, improves anaemia in patients with paroxysmal nocturnal haemoglobinuria , 2008, British journal of haematology.

[59]  N. Young,et al.  Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. , 2008, Blood.

[60]  A. Zanella,et al.  Paroxysmal nocturnal hemoglobinuria (PNH) in the eculizumab era: The bedside and beyond. , 2008 .

[61]  P. Hillmen.  The role of complement inhibition in PNH. , 2008, Hematology. American Society of Hematology. Education Program.

[62]  N. Young,et al.  Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. , 2007, Blood.

[63]  R. Brodsky,et al.  Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria , 2007, Nature Biotechnology.

[64]  N. Young,et al.  The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. , 2006, The New England journal of medicine.

[65]  R. Delsignore,et al.  Clinical Management of Paroxysmal Nocturnal Hemoglobinuria in Pregnancy: A Case Report and Updated Review , 2006, Obstetrical & gynecological survey.

[66]  Neal Young,et al.  Diagnosis and management of paroxysmal nocturnal hemoglobinuria. , 2005, Blood.

[67]  S. Richards,et al.  Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. , 2004, The New England journal of medicine.

[68]  K. Haram,et al.  Paroxysmal nocturnal hemoglobinuria in pregnancy , 2003, Acta obstetricia et gynecologica Scandinavica.

[69]  S. Richards,et al.  Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). , 2003, Blood.

[70]  J. Passweg,et al.  Outcome of Pregnancy and Disease Course among Women with Aplastic Anemia Treated with Immunosuppression , 2002, Annals of Internal Medicine.

[71]  J. Ray,et al.  Paroxysmal Nocturnal Hemoglobinuria and the Risk of Venous Thrombosis: Review and Recommendations for Management of the Pregnant and Nonpregnant Patient , 2000, Pathophysiology of Haemostasis and Thrombosis.

[72]  T. Nagasawa,et al.  Inhibition of complement‐mediated haemolysis in paroxysmal nocturnal haemoglobinuria by heparin or low‐molecular weight heparin , 2000, British journal of haematology.

[73]  W. Rosse,et al.  The natural history of paroxysmal nocturnal hemoglobinuria. , 1997, Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion.

[74]  J. Mary,et al.  Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors , 1996, The Lancet.

[75]  T. Miyata,et al.  Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria. , 1994, The New England journal of medicine.

[76]  T. Miyata,et al.  Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG‐A gene. , 1994, The EMBO journal.

[77]  Teizo Fujita,et al.  Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria , 1993, Cell.

[78]  T. Miyata,et al.  Deficient Biosynthesis of N-acetylglucosaminyl- Phosphatidylinositol, the First Hte~iiiediate of Glycosyl Phosphatidylinositol Anchor Biosynthesis, in Cell Lines Established from Patients with Paroxysmal Nocturnal Hemoglobinuria Materials and Methods , 2022 .

[79]  M. Borowitz,et al.  Defective glycosylphosphatidylinositol anchor synthesis in paroxysmal nocturnal hemoglobinuria granulocytes. , 1992, Blood.

[80]  A. Nicholson-Weller,et al.  Decay accelerating factor (CD55). , 1992, Current topics in microbiology and immunology.

[81]  L. Ravi,et al.  Assembly and deacetylation of N-acetylglucosaminyl-plasmanylinositol in normal and affected paroxysmal nocturnal hemoglobinuria cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[82]  W. Rosse,et al.  Relationship between the membrane inhibitor of reactive lysis and the erythrocyte phenotypes of paroxysmal nocturnal hemoglobinuria. , 1989, The Journal of clinical investigation.

[83]  C. Parker,et al.  Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria. , 1989, The Journal of clinical investigation.

[84]  H. Fernandez,et al.  Pregnancy and paroxysmal nocturnal hemoglobinuria. , 1988, Archives of internal medicine.

[85]  J. Atkinson,et al.  Normal polymorphic variations and transcription of the decay accelerating factor gene in paroxysmal nocturnal hemoglobinuria cells. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[86]  K. Austen,et al.  Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[87]  D. Fearon,et al.  Isolation of a human erythrocyte membrane glycoprotein with decay-accelerating activity for C3 convertases of the complement system. , 1982, Journal of immunology.

[88]  J. Spencer.  PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA IN PREGNANCY: CASE REPORT , 1980, British journal of obstetrics and gynaecology.

[89]  P. Lachmann,et al.  The influence of C3b inactivator (KAF) concentration on the ability of serum to support complement activation. , 1975, Clinical and experimental immunology.

[90]  J. Dacie.  Paroxysmal nocturnal haemoglobinuria. , 1972, The Scientific basis of medicine annual reviews.

[91]  J. Dacie,et al.  Immune lysis of normal human and paroxysmal nocturnal hemoglobinuria (PNH) red blood cells. I. The sensitivity of PNH red cells to lysis by complement and specific antibody. , 1966, The Journal of clinical investigation.

[92]  W. Denny.  Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria. , 1963, The Journal of the Arkansas Medical Society.