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Complement C5 inhibitors bring an increased risk for Neisseria infections. A novel complement C3 inhibitor, pegcetacoplan, was recently approved to treat paroxysmal nocturnal hemoglobinuria, a condition commonly treated with complement C5 inhibitors. We present a case of meningococcal sepsis in a pegcetacoplan-treated patient with aplastic anemia and paroxysmal nocturnal hemoglobinuria.

To evaluate disease burden among paroxysmal nocturnal hemoglobinuria (PNH) patients prescribed C5 inhibitors (C5i). Data were drawn from the Adelphi Real World PNH Disease Specific Programme, a cross-sectional survey of physicians and PNH patients in Australia, Canada, France, Germany, Italy, Spain, the United Kingdom, and Japan from January-December 2022. Physicians reported patient demographics, laboratory parameters, and treatments. Patients completed the EQ-5D-5L, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment (WPAI) questionnaire. Analyses were descriptive. Overall, 81 physicians reported on 288 patients receiving C5i. Median (IQR) age was 50.0 (38.3-65.0) years, 79.2% were white, and 54.5% were male. Median (IQR) C5i duration was 1.0 (0-3.0) years; 77.4% received eculizumab, 22.6% ravulizumab. At time of survey, median (IQR) hemoglobin (Hb) was 11.0 (9.9-12.0) g/dL, 73.5% of patients had Hb < 12 g/dL. Lactate dehydrogenase was >1.5× upper limit of normal for 16.7% of patients. Mean (SD) EQ-5D-5L was 0.76 (0.20), FACIT-Fatigue was 36.1 (9.7), WPAI work impairment was 27.5% (22.3) and activity impairment was 35.3% (24.6). Despite C5i treatment, a notable proportion of patients remained anemic and reported impaired quality of life, indicating the need for novel, efficacious therapies.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disease characterized by intravascular hemolysis, thrombosis, and bone marrow (BM) failure. Although PNH is caused by excessive proliferation of hematopoietic stem cell (HSC) clones with loss of function mutations in phosphatidylinositol N-acetylglucosaminyltransferase subunit A ( ) genes, what drives PNH clones to expand remains elusive. We present a case of a 26-year-old female who presented with hemolytic anemia, thrombocytopenia, and leukopenia. Flow cytometry analysis of peripheral blood showed that 71.9% and 15.3% of the granulocytes and erythrocytes were glycosylphosphatidylinositol-anchored protein deficient (GPI[-]) cells. The patient was diagnosed with PNH with non-severe aplastic anemia. Deep-targeted sequencing covering 390 different genes of sorted GPI(-) granulocytes revealed three different mutations (p.I69fs, variant allele frequency (VAF) 24.2%; p.T192P, VAF 5.8%; p.V300fs, VAF 5.1%) and no other mutations. She received six cycles of eculizumab and oral cyclosporine. Although the patient's serum lactate dehydrogenase level decreased, she remained dependent on red blood cell transfusion. Six months after diagnosis, she received a syngeneic bone marrow transplant (BMT) from a genetically identical healthy twin, following an immune ablative conditioning regimen consisting of cyclophosphamide 200 mg/kg and rabbit anti-thymocyte globulin 10 mg/kg. After four years, the patient's blood count remained normal without any signs of hemolysis. However, the peripheral blood still contained 0.2% GPI (-) granulocytes, and the three mutations that had been detected before BMT persisted at similar proportions to those before transplantation (p.I69fs, VAF 36.1%; p.T192P, VAF 3.7%; p.V300fs, VAF 8.6%) in the small PNH clones that persisted after transplantation. The PNH clones that had increased excessively before BMT decreased, but persisted at low percentages for more than four years after the immunoablative conditioning regimen followed by syngeneic BMT. These findings indicate that as opposed to conventional theory, immune pressure on HSCs, which caused BM failure before BMT, was sufficient for -mutated HSCs to clonally expand to develop PNH.

Abstract Objectives To determine fluorescently labeled aerolysin (FLAER) binding and glycophosphatidylinositol–anchored protein expression in bone marrow (BM) cells of healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH) detected in peripheral blood (PB); compare PNH clone size in BM and PB; and detect PNH in BM by commonly used antibodies. Methods Flow cytometry analysis of FLAER binding to leukocytes and expression of CD55/CD59 in erythrocytes. Analysis of CD16 in neutrophils and CD14 in monocytes in BM. Results FLAER binds to all normal BM leukocytes, and binding increases with cell maturation. In PNH, lymphocytic clones are consistently smaller than clones of other BM cells. PNH clones are detectable in mature BM leukocytes with high specificity and sensitivity using common antibodies. Conclusions PNH clone sizes measured in mature BM leukocytes and in PB are comparable, making BM suitable for PNH assessment. We further demonstrate that commonly used reagents (not FLAER or CD55/CD59) can reliably identify abnormalities of BM neutrophils and monocytes consistent with PNH cells.

The complement component 5 (C5)-binding antibody eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). As recently reported there is a need for a precise classification of eculizumab responsive patients to allow for a safe and cost-effective treatment. To allow for such stratification, knowledge of the precise binding site of the drug on its target is crucial. Using a structural epitope mapping strategy based on bacterial surface display, flow cytometric sorting and validation via haemolytic activity testing, we identified six residues essential for binding of eculizumab to C5. This epitope co-localizes with the contact area recently identified by crystallography and includes positions in C5 mutated in non-responders. The identified epitope also includes residue W917, which is unique for human C5 and explains the observed lack of cross-reactivity for eculizumab with other primates. We could demonstrate that Ornithodorus moubata complement inhibitor (OmCI), in contrast to eculizumab, maintained anti-haemolytic function for mutations in any of the six epitope residues, thus representing a possible alternative treatment for patients non-responsive to eculizumab. The method for stratification of patients described here allows for precision medicine and should be applicable to several other diseases and therapeutics.

Anemia associated with PNH is caused by hemolysis. The C5 inhibitor eculizumab blocks intravascular hemolysis, but anemia often persists owing to extravascular hemolysis. Pegcetacoplan, an inhibitor of C3, prevents extravascular hemolysis. After 16 weeks of treatment, hemoglobin increased nearly 4 g per deciliter in 41 patients treated with pegcetacoplan, and 85% no longer needed transfusion.

Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Eculizumab has been developed as a breakthrough treatment for paroxysmal nocturnal hemoglobinuria (PNH). Not only for breakthroughs, eculizumab therapy is also known to increase the risk of invasive meningococcal infection. It has also been recently reported that, although rarely, administration of eculizumab may result in disseminated gonococcal infection (DGI). We report here a case in which a young patient who had used eculizumab for PNH developed DGI. A 22-year-old Japanese male with PNH who had been treated with eculizumab complained of high fever, mild nausea, headache and right knee joint pain. The patient was admitted and suspected to have sepsis due to meningococcal infection and began to receive ceftriaxone (CTRX). Gonococci were detected in a venous blood culture a few days later, and this case was diagnosed as DGI. CTRX was effective, and the patient was discharged. However, four weeks later, he complained of the same subjective symptoms as at the beginning and was hospitalized again. The presence of gonococcus was proven by venous blood culture, CTRX was re-administered and the patient responded. After discharge, he was counseled on safer sexual activity, including accurate and consistent use of condoms, by urologists. He has not relapsed with DGI for more than one year. When serious signs of infection occur in patients receiving eculizumab, it is recommended to consider DGI as well as invasive meningococcal infection, and CTRX should be given. Keywords: disseminated gonococcal infection, DGI, eculizumab, paroxysmal nocturnal hemoglobinuria, PNH, ceftriaxone

Patients with paroxysmal nocturnal hemoglobinuria who had a poor response to eculizumab therapy were found to have a genetic polymorphism in C5 that prevents binding by the antibody. Paroxysmal nocturnal hemoglobinuria (PNH) arises as a consequence of clonal expansion of hematopoietic stem cells that have acquired a somatic mutation in the gene encoding phosphatidylinositol glycan anchor biosynthesis class A ( PIGA ). 1 – 3 The resulting hematopoietic cells are deficient in glycosylphosphatidylinositol-anchored proteins, including the complement regulatory proteins CD55 and CD59; this accounts for the intravascular hemolysis that is the primary clinical manifestation of PNH. 4 – 6 PNH frequently develops in association with disorders involving bone marrow failure, particularly aplastic anemia. Thrombosis is a major cause of PNH-associated morbidity and mortality, particularly among white patients. 7 – 9 Eculizumab (Soliris, Alexion Pharmaceuticals) . . .

Paroxysmal nocturnal hemoglobinuria (PNH) is associated with severe end-organ damage and a high risk of thrombosis. Budd- Chiari syndrome, which develops after thrombotic occlusion of major hepatic blood vessels, is relatively common in PNH and has been associated with increased mortality. We report the case of a 46-year-old male with PNH who presented with Budd-Chiari syndrome associated with portal cavernoma, portal hypertension and hypersplenism. In September 2010, the patient suffered gastrointestinal bleeding, hematuria, and elevated plasma lactate dehydrogenase; he started eculizumab therapy with a good response. In October 2012, he developed upper gastrointestinal variceal bleeding and a splenorenal shunt was placed. At the time of writing, the patient remains stable and eculizumab continues to be effective. There is limited data on the use of eculizumab for prevention of hemolysis and its consequences in PNH patients undergoing surgery. Our findings provide evidence for the efficacy and safety of eculizumab in this setting.