Previous analyses of Registry data have demonstrated evidence of the clinical benefit of eculizumab (Soliris®, Alexion Pharmaceuticals, Inc., Boston, MA, USA) for patients who have hemolysis and clinical symptoms indicative of high disease activity (HDA). The International PNH Registry (NCT01374360) is the largest worldwide observational study of patients with PNH, designed to collect disease and treatment-related data that could be used to help optimize management of PNH. While larger GPI-deficient granulocyte clone size is associated with increased TE risk, all patients with PNH are at risk for a TE regardless of clone size. Although patients with larger GPI-deficient granulocyte clone size generally experience more debilitating symptoms and consequences of chronic complement-mediated intravascular hemolysis, limited data suggest that smaller GPI-deficient granulocyte clones may also confer significant disease burden. GPI-deficient granulocyte clone size, a measure of the relative proportion of GPI-deficient cells, varies widely among patients with PNH and may influence clinical characteristics and disease burden. This genetic mutation causes impaired glycosylphosphatidylinositol (GPI) biosynthesis and deficient GPI-anchored complement regulatory proteins on the surface of mature blood cells. PNH occurs as a consequence of a somatic mutation in the phosphatidylinositol glycan class A gene in bone marrow stem cells, followed by clonal expansion of the mutated cells. In a retrospective study, approximately 20% of patients with PNH treated only with supportive care died within 6 years of diagnosis. Thrombotic events (TEs) account for up to 67% of deaths with a known cause in patients with PNH. Other disease manifestations include fatigue, abdominal pain, esophageal spasms, male erectile dysfunction, pulmonary hypertension, and renal impairment. PNH is a clinically heterogeneous disease in addition to the primary clinical manifestation of chronic intravascular hemolysis, it is associated with bone marrow failure (BMF e.g., aplastic anemia, myelodysplastic syndrome) and thrombophilia. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, potentially life-threatening hematologic disorder characterized by chronic, intravascular hemolysis caused by uncontrolled activation of the terminal complement pathway. Although larger GPI-deficient granulocyte clone sizes were associated with higher disease burden, a substantial proportion of patients with smaller clone sizes had history of MAVEs/TEs. A large proportion of patients with GPI-deficient granulocyte clone size < 10% had hemolysis (9.7%), MAVEs (10.2%), HDA (9.1%), and/or PNH-related symptoms. All measures except RBC transfusion history significantly correlated with GPI-deficient granulocyte clone size. There were high proportions of patients with HDA (51.6%), history of MAVEs (18.8%), BMF (62.6%), RBC transfusion (61.3%), and impaired renal function (42.8%). A total of 4439 patients were included, of whom 2701 (60.8%) had available GPI-deficient granulocyte clone size data. Outcomes assessed in the current analysis included proportions of patients with high disease activity (HDA), history of major adverse vascular events (MAVEs including thrombotic events ), bone marrow failure (BMF), red blood cell (RBC) transfusions, and PNH-related symptoms. All patients were untreated with eculizumab at baseline, defined as date of eculizumab initiation or date of Registry enrollment (if never treated with eculizumab). Patients with available data as of July 2017 were stratified by glycosylphosphatidylinositol (GPI)-deficient granulocyte clone size (< 10%, ≥ 10%–< 50%, and ≥ 50%). Herein, we report updated baseline demographics, clinical characteristics, disease burden data, and observed trends regarding clone size in the largest cohort of Registry patients. The International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry (NCT01374360) was initiated to optimize patient management by collecting data regarding disease burden, progression, and clinical outcomes.
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