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Nature Reviews. Disease Primers May 2017Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematopoietic stem cell (HSC) disease that presents with haemolytic anaemia, thrombosis and smooth muscle... (Review)
Review
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.
Topics: Antibodies, Monoclonal, Humanized; Bone Marrow Transplantation; CD55 Antigens; CD59 Antigens; Complement Inactivator Proteins; Hemoglobinuria, Paroxysmal; Humans; Membrane Proteins; Mutation; Treatment Outcome
PubMed: 28516949
DOI: 10.1038/nrdp.2017.28 -
British Journal of Haematology Jan 2016
Topics: Aged; Anemia, Aplastic; Benzoates; Blood Component Transfusion; Female; Hematopoietic Stem Cell Transplantation; Hemoglobinuria, Paroxysmal; Humans; Hydrazines; Immunosuppressive Agents; Opportunistic Infections; Pregnancy; Pregnancy Complications, Hematologic; Pyrazoles; Severity of Illness Index
PubMed: 26568159
DOI: 10.1111/bjh.13853 -
British Journal of Haematology Jan 2022Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by complement-mediated intravascular haemolysis, severe thrombophilia and bone marrow failure. While for... (Review)
Review
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.
Topics: Algorithms; Clinical Decision-Making; Combined Modality Therapy; Disease Management; Disease Susceptibility; Genetic Predisposition to Disease; Hemoglobinuria, Paroxysmal; Humans; Phenotype; Prognosis; Standard of Care; Treatment Outcome
PubMed: 34355382
DOI: 10.1111/bjh.17753 -
Hematology, Transfusion and Cell Therapy 2021Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and life-threatening disease characterized by intravascular hemolysis, thrombotic events,...
Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and life-threatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.
PubMed: 32713742
DOI: 10.1016/j.htct.2020.06.006 -
Lancet (London, England) Jan 2024The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated... (Review)
Review
The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated complement activity is associated with unwanted or non-resolving immune responses and inflammation, which induce or exacerbate the pathogenesis of a broad range of inflammatory and autoimmune diseases. Although the merit of targeting complement clinically has long been acknowledged, the overall complement drug approval rate has been modest. However, the success of the humanised anti-C5 antibody eculizumab in effectively treating paroxysmal nocturnal haemoglobinuria and atypical haemolytic syndrome has revitalised efforts to target complement therapeutically. Increased understanding of complement biology has led to the identification of novel targets for drug development that, in combination with advances in drug discovery and development technologies, has resulted in a surge of interest in bringing new complement therapeutics into clinical use. The rising number of approved drugs still almost exclusively target rare diseases, but the substantial pipeline of up-and-coming treatment options will possibly provide opportunities to also expand the clinical targeting of complement to common diseases.
Topics: Humans; Complement Inactivating Agents; Complement System Proteins; Hemoglobinuria, Paroxysmal; Autoimmune Diseases; Drug Discovery
PubMed: 37979593
DOI: 10.1016/S0140-6736(23)01524-6 -
British Journal of Haematology Jul 2013Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and...
Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long-term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time-dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Transfusion; Female; Hemoglobins; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Thrombosis; Treatment Outcome; Young Adult
PubMed: 23617322
DOI: 10.1111/bjh.12347 -
Drugs Dec 2022Subcutaneous pegcetacoplan (EMPAVELI in the USA and ASPAVELI in the EU) is the first complement component 3 (C3) inhibitor approved for the treatment of adults with... (Review)
Review
Subcutaneous pegcetacoplan (EMPAVELI in the USA and ASPAVELI in the EU) is the first complement component 3 (C3) inhibitor approved for the treatment of adults with paroxysmal nocturnal haemoglobinuria (PNH) in the USA, and in adults with PNH who are anaemic after ≥ 3 months of treatment with a C5 inhibitor in the EU. In the phase III PRINCE trial in adults with PNH who were anaemic and naïve to a complement inhibitor therapy, pegcetacoplan was superior to the control group (supportive care, excluding complement inhibitors) in achieving haemoglobin stabilization and reducing lactate dehydrogenase levels. Similarly, in the phase III PEGASUS trial in adults with PNH who had a haemoglobin level < 10.5 g/dL despite eculizumab therapy, pegcetacoplan was superior to eculizumab in improving haemoglobin levels. In both trials, pegcetacoplan also improved other clinical and haematological parameters of haemolysis, as well as quality of life (QOL) outcomes. Clinical benefits of pegcetacoplan were sustained for up to 48 weeks of treatment. Pegcetacoplan was generally well tolerated in patients with PNH, with its tolerability profile being similar in patients previously treated with eculizumab and in complement inhibitor-naïve patients. Long-term data would be beneficial to further support the safety profile of pegcetacoplan. Current evidence indicates that pegcetacoplan is a valuable treatment option for adults with PNH.
Topics: Adult; Humans; Hemoglobinuria, Paroxysmal; Quality of Life; Complement Inactivating Agents; Hemolysis; Hemoglobins
PubMed: 36459381
DOI: 10.1007/s40265-022-01809-w -
Transfusion Jun 2017
Topics: Cold Temperature; Complement System Proteins; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Hemolysis; Humans
PubMed: 28594143
DOI: 10.1111/trf.14128 -
Australian Prescriber Apr 2022
Review
PubMed: 35592364
DOI: 10.18773/austprescr.2022.018 -
British Journal of Haematology Nov 2020Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH.
Topics: Antibodies, Monoclonal, Humanized; Biomarkers; Complement C5; Complement Inactivating Agents; Female; Hemoglobinuria, Paroxysmal; Humans; Male; Molecular Targeted Therapy; Treatment Outcome
PubMed: 32449174
DOI: 10.1111/bjh.16711