Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by chronic complement-mediated hemolysis, leading to life-threatening events, such as thromboembolism (TE) and chronic kidney disease (CKD), and devastated quality of life (QOL). The terminal complement inhibitor eculizumab (ECU) was approved in Japan in 2010 under the indication to suppress hemolysis in PNH. We comprehensively report as post marketing surveillance (PMS) on the efficacy and safety of ECU administered from June 2010 to March 2013 in Japanese patients with PNH. In spite of complete blocking hemolysis, the degree of improvement of anemia by ECU treatment varies patient by patient. Analyzing the data of PMS, we investigated if patient characteristics, such as LDH, bone marrow function and renal function, can affect anemia in PNH patients treated with ECU.

Methods: The PMS data of 242 patients were used for demographics and safety assessment. Of 242, 144 patients with ECU treatment at least for 1 year were analyzed for efficacy evaluation. We used platelet (PLT) count as a marker of bone marrow function and divided it into three groups, <88 (Low), 88-155 (Mid) and ≧155 x109/L (High). We also utilized CKD stage calculated by estimated GFR (eGFR) which is widely accepted as a renal function classification, eGFR <60 (CKD stage 3-5), 60-90 (CKD stage 2) and ≧90 mL/min/1.73m2 (CKD stage 0/1), according to Japanese CKD guideline.

Results: In Japan LDH>1000 IU/L is commonly considered as ECU applicable severe PNH patients, but this was not correlated with other markers related to PNH severity. 41.2% of patients who started ECU had eGFR <60 mL/min/1.73m2, CKD stage 3-5. The prevalence of CKD stage 3-5 in PNH population was much higher than that of the normal Japanese population, especially in PNH patients over 65 years old. ECU treatment dramatically and quickly reduced the serum level of LDH, and 18-month (median)-teatment with ECU increased hemoglobin level by 1.9 g/dL, reduced annual transfusion units by half, made 55.3% of transfusion-dependent patients transfusion-independent, improved one CKD stage in 29% of the patients with CKD stage 3-5 and made 14% returned to CKD stage 2. Side effects of all grades associated with ECU were reported in 36.8% of patients and severe ones were observed in 8.3%, which include 10 infectious events in 8 patients. 18-month-treatment with ECU increased hemoglobin (Hb) level by 1.2 g/dL in the Low-PLT, 1.5 g/dL (p<0.001) in the Mid-PLT and 2.9 g/dL (p<0.001) in the High-PLT group and reduced annual RBC transfusion (TF) unit 21.6→11.3 (p=0.002), 11.0→7.0 and 10.0→1.1 (p<0.001), respectively. ECU augmented Hb level by 2.4 g/dL (p<0.001) in CKD stage 0/1, 2.3 g/dL (p<0.001) in CKD stage 2 and 1.1 g/dL (p=0.022) in CKD stage 3-5 and decreased annual TF units 13.4→2.9 (p<0.001), 11.5→3.3 (p=0001) and 16.5→10.4 (p=0.036), respectively.

Conclusion: ECU treatment for 18 months reduced hemolysis and improved anemia, renal function and QOL. It is concluded that ECU is safe and well tolerated.

Anemia in PNH would be caused not only by hemolysis but also modified by bone marrow as well as renal function.


Obara:Alexion Pharma: Research Funding. Ninomiya:Alexion Pharma: Honoraria, Research Funding. Chiba:Alexion Pharma: Research Funding. Usuki:Alexion Pharma: Speakers Bureau. Shichishima:Alexion Pharma: Honoraria, Research Funding. Nishimura:Alexion Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ohyashiki:Alexion Pharma: Honoraria, Research Funding. Nakao:Alexion Pharma: Honoraria, Research Funding. Ando:Alexion Pharma: Research Funding. Kawaguchi:Alexion Pharma: Honoraria, Research Funding. Nakakuma:Alexion Pharma: Honoraria. Hamada:Alexion Pharma: Employment. Shimono:Alexion Pharma: Employment. Kinoshita:Alexion Pharma: Honoraria. Ozawa:Alexion Pharma: Honoraria. Omine:Alexion Pharma: Honoraria. Kanakura:Alexion Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Author notes


Asterisk with author names denotes non-ASH members.

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