Clinical Impact of Unregulated Terminal Complement Activity in Never-Transfused Patients with Paroxysmal Nocturnal Hemoglobinuria.
Authors: Muus Petra , Risitano Antonio M. , Castro-Malaspina H.R. , Jones C. Michael , Fuller Stephen , Socie Gerard 
Published: October 2019

Abstract
Abstract 4029
Poster Board III-965
Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life-threatening hematopoietic stem cell disorder characterized by unregulated activation of the complement system leading to chronic intravascular hemolysis and an inflammatory prothrombotic state. PNH evolves from the clonal expansion of hematopoietic stem cells with complete or marked loss of terminal complement inhibitors CD55 and CD59 from the surface of hematopoietic cells, rendering red blood cells susceptible to terminal complement-mediated hemolysis, and white blood cells and platelets to terminal complement-mediated activation. Many of the clinical complications of PNH including severely impaired quality of life and life-threatening thromboembolism (TE), chronic kidney disease, pulmonary hypertension, end organ damage, fatigue, abdominal pain, dysphagia and dyspnea are a result of terminal complement-mediated activation. While many patients with PNH have anemia, hemoglobin and transfusion requirements may not adequately reflect the burden of disease due to hemolysis since these parameters are influenced by many factors unrelated to hemolysis or complement activation including bone marrow function, patient specific factors and physician clinical assessment. In order to understand the clinical burden of PNH in patients with no history of transfusions, we identified and evaluated 44 patients who had not received prior red cell transfusions and were considered a candidate for treatment with the terminal complement inhibitor eculizumab based on the physician's individual clinical assessment. This group of never-transfused patients included patients in France, Italy, the Netherlands, Australia, and the US. In this group, ages ranged from 16 to 84 years (median 41 yrs) and duration of diagnosis ranged from 1 month to 30 years (average 3.8 years). The median PNH granulocyte clone size was 72%, (n=36). Hemoglobin level ranged from 6.0 to 14.9 g.dL (median 9.8 g/dL, n=37). Almost one quarter (9/37) of these patients had hemoglobin ≥11.0 g/dL and 21/37 had Hgb ≤ 10.0 g/dL. The median LDH was 1,463 U/L (range from 180 to 5,950 U/L; n=39). Thrombosis was relatively common in this patient population – 28% (12/43). Interestingly, TE was similarly observed in patients with PNH granulocyte clones ≤ 50% (33%, n=9) and in patients with PNH granulocyte clone greater than 50% (30%, n=27), confirming that TE was not at all confined to patients with a large clone. Impaired quality of life was reported in 87% of patients (n=39) by the physician or patient, and only 5 patients (13%) reported normal or good quality of life. Impaired quality of life similarly affected patients with smaller and larger PNH granulocyte clones in this population. Impairment included the following assessments: mild impairment, disabling or moderate fatigue, disabling abdominal pain, shortness of breath with exertion, or poor quality of life. In conclusion, despite a history of no transfusions, patients presenting for treatment with the terminal complement inhibitor eculizumab demonstrated evidence of unregulated terminal complement activity, as measured by elevated levels of LDH. These never-transfused PNH patients had significant clinical evidence of TE and impaired quality of life. These findings underscore the central role of terminal complement activity, rather than anemia or transfusion requirements, in driving the significant disease burden and guiding the treatment of patients with PNH.
Parameter Median Range Age (n=44) 41 years 16 to 84 Time Since Diagnosis (n=38) 15 months 1 month to 30 years Hemoglobin (n=37) 9.8 g/dL 6.0 to 14.9 LDH (n=37) 1,463 U/L 180 to 5,950 % of PNH patients Evidence of TE (n=43) 28% Evidence of Impaired Quality of Life (n=39) 87%

Disclosures:
Muus: Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro-Malaspina:Alexion: Consultancy, Honoraria. Jones:Alexion: Speakers Bureau. Socie:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees.