Terminal Complement Inhibition Exhibiting Higher Response in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Multicentric Real-World Evidence in Brazil
Authors: Justino Caio Cesar , Yamakawa Patricia Eiko , Azambuja Ana Paula , Marchesini Rafael , Fonseca Ana Rita , Gomes Iara Baldim Rabelo , Arruda Martha Mariana Almeida Santos , Dias Cruz Lafayette Cavalcanti Bezerra , Ribeiro Ferdinando Cesar Batista , Vasconcelos Yuri , de Molla Vinicius Campos , Figueiredo Maria Stella , Arrais-Rodrigues Celso 
Published: December 2024

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by acquired abnormalities in the PIG-A gene, leading to hemolytic anemia, a hypercoagulable state, and cytopenias. Complement inhibitors targeting C5 have transformed PNH management improving survival and quality of life. Patients and Methods: Multiparametric flow cytometry identified 338 PNH patients in five Brazilian centers, categorized as classic PNH, PNH with another hematologic disease, or subclinical PNH. Clinical and laboratory data were collected pre- and post-treatment using standardized forms based on information obtained from medical records. Descriptive statistics summarized the baseline patient and disease characteristics. The probability of overall survival (OS) was demonstrated by Kaplan-Meier. Results: Of the 338 patients (53% male; median age at diagnosis: 32 years) diagnosed between 1988 and 2024 in five Brazilian centers, the hemolytic group (N=176, 52%) exhibited common symptoms: fatigue (90%), hemoglobinuria (61%), abdominal pain (46%), headaches (26%), and dysphagia (15%). Venous thromboembolism occurred in 42 cases (24%), abdominal thrombosis in 25 cases (14%), and arterial thrombosis in 14 patients (8%). Acute renal injury requiring dialysis affected five hemolytic patients (3%), with eventual recovery. The subclinical PNH cohort (n=162, 48%) had a median clone size of 1.7% in granulocytes and 2.7% in monocytes, with aplastic anemia as the most common hematological condition (n=153, 95%). The majority of hemolytic patients (n=93, 53%) was treated with terminal complement inhibitor, with 87 patients receiving eculizumab and 6 patients receiving crovalimab after a median time of 24 months, and the median duration of the treatment was 86 months. It significantly reduced intravascular hemolysis, improved anemia, and alleviated symptoms. Within six months, 83% achieved transfusion independence. Sixteen patients (17%) received transfusion after the beginning of anti-complement treatment, with nine of them experiencing persistent cytopenias due to bone marrow failure, five experiencing significant extravascular hemolysis and two for irregular use. The anti-complement treated group had a significantly higher transfusion-avoidance rate at one year (83% vs. 73%, p=0.02). A normal hemoglobin (&gt;12g/dL) was achieved in 48 patients (52%). According to the response rate proposed by the Severe Aplastic Anemia Working Party (SAAWP), 26 (30%) patients achieved complete response, followed by major (22%), good (36%), partial (9%) and minor (3%) responses. Overall survival (OS) at six years was 90% for classical PNH, 75% for PNH with another hematologic disease, and 65% for subclinical PNH. Notably, treated patients had significantly higher OS compared to untreated individuals (100% vs. 44%, p&lt;0.0001). Anti-complement treatment was withdrawn in eight patients (9%) due to hematopoietic stem cell transplantation (HSCT) in five, PNH clone remission in two, and the other one progressing to myelodysplastic syndrome. None of the patients experienced severe infections. Conclusions: This study corroborates clinical characteristics and PNH subtype distributions found in previous publications. Lower thrombosis and chronic kidney disease rates were reported in this cohort and require further investigation. Terminal complement inhibition was safe and effectively controlled hemolysis, improved symptoms, and reduced complications, with normalization of hemoglobin and transfusion- avoidance rate slowly higher than previously reported.