Vaccination in paroxysmal nocturnal hemoglobinuria patients treated with terminal and proximal complement inhibitors — Polish Expert Consensus

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 Paroxysmal nocturnal hemoglobinuria (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 and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good 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 and 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.

Ethical statement: This study was conducted in accordance with the Declaration of Helsinki. The collection and usage of both patient samples and healthy volunteer samples was approved by the Ethics Committee (Arnhem-Nijmegen, the Netherlands) and the Board of Directors of the Radboudumc (Nijmegen, The Netherlands). Patient samples were obtained during routine outpatient visits and diagnostics. No extra study visits or blood draws were scheduled. All collected samples were coded and informed consents were signed before blood collection.

7087 Background: PNH is a rare bone marrow failure disorder defined by stem cell clones with somatic mutations in the PIG-A gene. These mutations result in peripheral blood cells deficient in GPI-anchored proteins including complement inhibitors CD55 and CD59. Chronic lysis of PNH RBCs leads to severe anemia, life-threatening thrombosis, debilitating fatigue, and impaired quality of life. Previous studies have indicated an increased frequency of myeloproliferative disorders, MDS, and acute leukemias in PNH. In a previous retrospective analysis of 1,760 PNH patients, 6.8% developed either myeloid or lymphoid disorders and 1% developed acute leukemias. Eculizumab (Soliris) is a humanized antibody that prevents terminal complement activation. Long-term eculizumab treatment has been evaluated in 195 PNH patients (>250 patient years of exposure) and shown to significantly restore the endogenous PNH RBC clone resulting in improved anemia, as well as significant improvements in thrombosis, fatigue, and quality of life. Methods: Leukocyte clone sizes were assessed at baseline and 26 weeks for patients receiving eculizumab in the Phase III clinical trials (TRIUMPH and SHEPHERD) using flow cytometry. The frequency of MDS and leukemia was calculated as a percentage of the eculizumab-treated patients across all eculizumab trials. Results: PNH leukocyte clone size did not increase with eculizumab treatment (median 96.1% at baseline vs 95.5% at week 26; P=0.80, signed rank test) suggesting that inhibition of terminal complement does not destroy or result in the proliferation of PNH leukocyte clones. Additionally, the frequency of new MDS (1/195 patients, 0.5%) and CMML (1/195 patients, 0.5%) during the treatment period was not increased over that expected. The single case of CMML occurred in a patient previously diagnosed with and was attributed to high grade myelodysplasia. Conclusions: To date, eculizumab treatment of PNH patients does not increase the risk for the development of myeloproliferative disorders, MDS or acute leukemias. Patients on eculizumab will continue to be followed in a Global PNH Safety Registry. No significant financial relationships to disclose.

Monitoring of patients with paroxysmal nocturnal hemoglobinuria on a complement inhibitor.

Small Molecule Factor D Inhibitors Block Complement Activation in Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome

Terminal Complement Inhibitor Eculizumab Improves Complement-Mediated Platelet Consumption and Thrombocytopenia in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).

Effect of Reducing Intravascular Hemolysis on Ferritin Homeostasis in Eculizumab Treated Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients.

Real-world clinical characteristics and treatment outcomes in PNH patients prescribed pegcetacoplan across europe, the United States and Canada

Emerging evidence suggests that activation of the complement system is critical in the pathogenesis of the novel coronavirus, SARS-CoV-2, the causative agent of COVID-19-related lung injury. Inhibition of the terminal complement pathway by targeting complement protein 5 (C5) may be an effective therapeutic intervention in CoV-mediated disease.1 Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired haematopoietic stem cell (HSC) disease characterised by intravascular haemolysis, increased thromboembolic risk and bone marrow failure.2 The lack of GPI-linked complement regulators, especially CD55 and CD59, makes PNH erythrocytes exquisitely sensitive to complement activation, which can occur continuously, spontaneously and acutely and lead to devastating complications as a result of uncontrolled intravascular haemolysis. Precipitation of haemolysis, both in untreated patients and in those on anti-complement therapy,3 can be induced by any complement-activating events such as infection, trauma, surgery and pregnancy. Although viral infections have been shown to induce haemolysis by activating complement, there has been no published report of COVID-19 in the context of PNH during the ongoing pandemic, and neither has the added benefit of therapeutic complement inhibition, especially with monoclonal antibodies targeting C5 including eculizumab and ravulizumab, been examined. Here we report the clinical course, degree of intravascular haemolysis and outcomes of COVID-19 in four patients with PNH, two well-established on terminal complement inhibitor and two treatment-naïve PNH patients. Our index patient (patient 1, Table I) presented in mid-March 2020 with symptoms of fever (39·1°C), myalgia, dry cough and anosmia. She had a long-standing history of PNH and her disease activity, symptoms and haemolysis were well controlled on a long-acting C5 inhibitor, ravulizumab,4 and prior to this with a first generation monoclonal antibody, eculizumab.3 She was not hypoxic. SARS-CoV2 infection was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) assay. She did not have elevated inflammatory markers and her chest radiology was normal. Interestingly, her haemolytic markers were not significantly elevated, and terminal complement was adequately inhibited, as measured by an undetectable CH50/AH50. Yes Ravulizumab 3300 mg × 8 weekly 6 years Yes Eculizumab 1500 mg × 2 weekly 11 years Subsequently, we identified three additional PNH patients with concurrent presentation with clinical symptoms of COVID-19 and RT-PCR-confirmed COVID-19 (Table I). Two patients naïve to complement inhibitor treatment (patients 3 and 4), both with moderate/large PNH clones accompanied by a degree of haemolysis, required hospitalisation for COVID-19 pneumonia and also showed active signs of inflammation [high C-reactive protein (CRP)] and worsening haemolysis [high lactate dehydrogenase (LDH) compared to baseline], due to uncontrolled complement activation. The clinical course of these two individuals, not on anti-complement therapy but on primary prophylaxis with warfarin, was protracted and needed prolonged hospitalisation, readmission and supplemental oxygen therapy. Patient 2, on a high dose of eculizumab, had a similar presentation to the index patient and was found to be anaemic requiring blood transfusion, but with a clear chest radiograph, normal CRP and normal LDH. It is clear that complement plays a key role and is an integral component of the innate immune response to pathogens and its dysregulation or activation, either due to acquired deficiency of complement regulatory proteins (i.e. PNH) or due to viral infection (i.e. SARS-CoV-2), and can lead to significant tissue damage and importantly thrombosis due to endothelial damage.5 Our patients illustrate the presence of both conditions (PNH and COVID-19) concurrently and the differential response seen in patients already on effective complement inhibition compared to patients not on C5 inhibition. The beneficial effect of complement inhibition in not only controlling the intravascular haemolysis due to PNH, but also dampening the hyperinflammatory lung damage during COVID-19 has been illustrated with our small series. The adverse effect in patients not on C5 inhibitors may be circumstantial, as other known COVID-19 risk factors of mortality and morbidity,6 like older age, comorbidity, high body mass index (BMI) and male gender could have contributed to the worse outcome. SARS-CoV-2 infection,7 like other virus infections such as influenza virus and respiratory syncytial virus, is likely to induce massive complement activation in this ‘vulnerable’ group and can lead to severe life-threatening complications and hospitalisation. Emerging evidence suggests that the activation of the complement system, even in the absence of PNH, is key in the pathogenesis of COVID-19-related lung injury8 and therefore C5 inhibition may be an effective therapeutic strategy in CoV-mediated disease. Trials (SOLID-C19, CORIMUNO19-ECU and ALXN1210-COV-305), are ongoing to test the efficacy of terminal complement inhibition in dampening the progression of complications and improve outcomes in patients with COVID-19·9

NLRP3 inflammasome inhibition fails to prevent red blood cell lysis in PNH

Increased soluble urokinase plasminogen activator receptor (suPAR) is associated with thrombosis and inhibition of plasmin generation in paroxysmal nocturnal hemoglobinuria (PNH) patients

Blockade of Intravascular Hemolysis in PNH with the Terminal Complement Inhibitor Eculizumab Unmasks Low-Level Hemolysis Potentially Occurring through C3 Opsonization.

Lactate dehydrogenase versus haemoglobin: which one is the better marker in paroxysmal nocturnal haemoglobinuria?

Introduction Eculizumab, the first anti-C5 monoclonal antibody approved for patients with paroxysmal nocturnal hemoglobinuria (PNH), has revolutionized the natural history of this disease, blocking intravascular hemolysis, reducing the risk of thromboembolic events, resulting in a significant improvement in survival and quality of life. However, the hematological response to eculizumab is extremely heterogeneous, with only one-third of PNH patients reaching normal hemoglobin levels. Areas covered This article reviews the current new drugs being investigated in phase II and III trials for adult PNH patients. Literature search was performed using Medline and Clinicaltrials.org databases. Expert opinion The new molecules have been classified according to the target of the complement system on which they act; we have novel terminal complement inhibitors, which target C5, and proximal complement inhibitors, which interfere with C3 or even further upstream (factor B and D). Ravulizumab is the first next-generation C5 inhibitor, approved by FDA and EMA, which reproduced the excellent results achieved with eculizumab, trying to improve the convenience of patients. However, unresolved issues remain, such as C3-mediated extravascular hemolysis, on which novel proximal complement inhibitors are showing their efficacy. Pegcetacoplan is the first C3-inihibitor approved by FDA. Long-term safety data for novel complement inhibitors are needed.

Efficacy and Safety of Single Agent Proximal Complement Inhibitors in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients with Residual Anemia Despite of Adequate Terminal Complement Inhibitor Use