Comparable Outcomes with Eculizumab in Paroxysmal Nocturnal Hemoglobinuria Patients with or without Aplastic Anemia in a Prospective Korean PNH Registry
Authors: Jang Jun Ho , Kim Jin Seok , Jo Deog-Yeon , Lee Je-Hwan , Choi Chul Won , Kim Hyeoung Joon , Won Jong-Ho , Chung Joo Seop , Kim Hawk , Lee Jae-Hoon , Sohn Sang Kyun , Kim Jeong A , Lee Jong Wook 
Published: October 2019

Abstract
Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disease characterized by the intravascular lysis of red blood cells. The three major pathophysiological features of the disease-hemolysis, bone marrow failure (BMF) and thrombosis-historically have been managed with blood transfusions, steroids and anticoagulation. For optimum management, the relative contribution of both hemolysis and BMF to the complex anemia of PNH should be determined. Aplastic anemia (AA) is the most frequently associated BMF syndrome in PNH. In recent years, eculizumab, a humanized monoclonal antibody that binds specifically to human complement protein C5 and inhibits the formation of the terminal complement complex, has been used to prevent the hemolysis associated with PNH. The aim of this study is to evaluate clinical outcomes with eculizumab in patients with PNH concomitant with AA (PNH-AA) and without AA (classic PNH) in a Korean PNH population.
Methods
Thirty-five patients >18 years of age with PNH diagnosed by flow cytometry and treated with eculizumab for ≥6 months were analyzed in the prospective PNH registry study. Patients were categorized into two groups: PNH-AA and classic PNH. Patients with severe AA were excluded from eculizumab treatment. Biochemical indicators of intravascular hemolysis and hematological laboratory values were assessed at least every 6 months after initiation of eculizumab treatment.
Results
The median age of the study population was 35 years (range, 21-76 years) at eculizumab initiation and the median duration of eculizumab treatment was 28 months (range, 6-31 months). The treatment effect for reducing hemolysis remained consistent after 6 months of follow up. All patients showed a reduction in LDH levels, which was sustained over the course of treatment (median LDH level, 6.7-fold at baseline to 1.0-fold at 6 months), reflecting inhibition of chronic hemolysis. Fourteen patients (40%) had been diagnosed with aplastic anemia in PNH, and 5 of these patients had received immunosuppressive therapy (IST) for AA management. Of these, 2 achieved complete remission (CR) with hematological recovery before eculizumab initiation, whereas 3 had partial response. Of 35 total patients, 12 were classified as having PNH-AA and 23 with classic PNH, including the 2 patients with CR from IST for management of AA. The mean PNH clone did not change significantly after 6 months of follow up in PNH-AA or classic PNH patients (p=0.575 and 0.965, respectively). Patients receiving eculizumab in both groups had significant changes in mean hemoglobin level after 6 months (p=0.028 and p= 0.035, respectively). The mean number of packed RBC units transfused in patients with PNH-AA was significantly reduced, from 7 units during the previous 6 months to 2 units during the first 6 months of eculizumab use (p=0.009). Thereafter, 1.0, 0.8, and 1.6 units per every 6 months were required from month 6‒12, 12‒18, and 18‒24, respectively. In classic PNH patients, transfusion independence was achieved by 57% (13 of 23) within the first 6 months of treatment and 89% by the last 24 months. Eculizumab also resulted in sustained hematological improvement for patients. There were no significant differences in clinical outcomes (ie, LDH and hemoglobin levels, transfusion requirements) with eculizumab between the two groups.
Conclusions
Clinical outcomes with eculizumab were significantly improved compared with baseline in patients with both PNH-AA and classic PNH. All patients have been followed up without any recurrence of hemolytic events; overall, the population achieved improvement in hemoglobin levels and a significant reduction in frequency of blood transfusions required. Some PNH-AA patients still required transfusion, reflecting in part a production defect of the bone marrow, whereas classic PNH patients became transfusion-independent over time. These results demonstrate that eculizumab has a role in in the management of patients with PNH-AA, similar to that of classic PNH, to inhibit hemolysis and reduce transfusion requirements.

Disclosures
Jang: Alexion Pharmaceuticals: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Jo:Alexion Pharmaceuticals: Research Funding. Lee:Alexion Pharmaceuticals: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Won:Alexion Pharmaceuticals: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding. Kim:Celgene: Research Funding; Il-Yang: Research Funding; Alexion Pharmaceuticals: Research Funding; Novartis: Research Funding. Lee:Alexion Pharmaceuticals: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Lee:Alexion Pharmaceuticals: Research Funding.