Effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) with or without aplastic anemia in the International PNH Registry

Although paroxysmal nocturnal hemoglobinuria (PNH) is a clinically heterogeneous disease, it often occurs in patients with underlying bone marrow failure (BMF), most commonly in those with aplastic anemia (AA),1, 2 and concurrent AA can be associated with poorer outcomes in patients with PNH.3 Furthermore, patients with high disease activity (HDA), defined as lactate dehydrogenase (LDH) ≥1.5 times upper limit of normal (ULN) and presence of 1 or more PNH signs/symptoms,4 typically have higher disease burden and an increased risk of thrombotic events (TEs) compared with patients without HDA.5 The presence of both PNH and AA presents a challenge to clinicians because the optimal management strategy for this patient population is often unclear.1, 6 More robust data are needed regarding treatment outcomes in patients with PNH with and without AA who are treated with eculizumab (Soliris, Alexion Pharmaceuticals, Inc., Boston, MA). We analyzed data from the International PNH Registry (NCT01374360)2 to evaluate whether treatment with eculizumab has clinical benefit and reduces complication risk in patients with PNH who have HDA, with or without AA. Our analysis included patients enrolled in the Registry as of July 17, 2017, who were treated with eculizumab; had nonmissing data on enrollment date, birth date, and sex; nonmissing data on AA status at baseline (defined as the date of eculizumab initiation); ≥6 months of follow-up after baseline; and presence of HDA at baseline. HDA was defined as elevated LDH ratio ≥1.5 times ULN and presence of 1 or more PNH-related symptoms, including fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia (hemoglobin <100 g/L), a major adverse vascular event (MAVE; including TE), dysphagia, or erectile dysfunction.4 Patients were stratified into three groups at baseline: (1) patients with PNH and ongoing AA; (2) patients with PNH and a history of AA, not ongoing; and (3) patients with PNH and no history of AA. Outcomes of interest included change in rate of MAVEs (including TEs) from the time period prior to treatment with eculizumab (ie, time from PNH disease start to baseline) to the time period during eculizumab treatment (ie, time from baseline to last follow-up); change in rate of red blood cell (RBC) units transfused from the 12 months prior to baseline to the period from baseline to last follow-up; changes from baseline to last follow-up in LDH ratio, hemoglobin levels, platelet counts, and neutrophil counts; and change in physician-reported PNH-related symptoms from baseline to last follow-up. As of July 17, 2017, 4948 patients were enrolled in the Registry; of these, 779 patients were included in the study population (ongoing AA, n = 214; history of AA, n = 74; no AA, n = 491). Mean standard deviation (SD) duration from baseline to last treated follow-up was 3.9 (2.33), 4.3 (2.75), and 4.4 (2.55) years in patients with ongoing AA, history of AA, and no AA, respectively. Overall, 54.0% of patients were female, mean (SD) age at baseline was 43.1 (16.67) years, mean (SD) duration of disease was 6.7 (7.60) years, and 89.3% of patients with available data on clone size had ≥50% glycosylphosphatidylinositol (GPI)-deficient granulocytes at baseline (ongoing-AA group, 80.5%; history-of-AA group, 87.0%; no-AA-group, 93.2%). The most common physician-reported PNH-related symptoms at baseline were fatigue (90.0% of patients) and hemoglobinuria (79.4% of patients). The proportion of patients with history of MAVEs, including TEs, was slightly higher in the no-AA group (30.8% [150/487]) than the AA groups (ongoing AA, 25.2% [53/210]; history of AA, 27.4% [20/73]); the proportion of patients with a history of RBC transfusions was highest in the ongoing-AA group (80.0% [120/150] vs 75.4% [46/61] for history of AA and 73.7% [263/357] for no AA). Patients in the AA groups were more likely to have a history of immunosuppressant therapy (64.6% [135/209] for ongoing AA and 63.9% [46/72] for history of AA) relative to patients in the no-AA group (5.6% [27/484]). Eculizumab treatment significantly decreased rates of MAVEs, TEs, and RBC transfusions in all groups. Rates of MAVEs decreased from ≥4.9 events per 100 patient-years prior to baseline to ≤1.5 events per 100 patient years after baseline in all 3 groups (Figure 1A). Rates of TEs decreased from ≥3.3 events per 100 patient-years prior to baseline to ≤1.3 events per 100 patient-years after baseline (Figure 1B), and rates of RBC transfusions decreased from ≥5.9 per 100 patient-years prior to baseline to ≤4.0 per 100 patient-years after baseline (Figure 1C). For most patients, there was no change in immunosuppressant therapy from baseline to last treated follow-up; 88.1% (118/134) of patients in the ongoing-AA group, 82.9% (34/41) in the history-of-AA group, and 87.3% (69/79) in the no-AA group had no change. Treatment with eculizumab was also associated with significant improvement from baseline to last follow-up in LDH ratio, mean hemoglobin levels, and absolute reticulocyte count regardless of AA status at treatment initiation (Table 1). Platelet count increased significantly after baseline in the group with ongoing AA, and absolute neutrophil count decreased significantly in the no-AA group; there were no significant changes in these parameters in the other study groups. Substantial improvement in PNH-related symptoms from baseline to last follow-up was observed for all symptoms regardless of AA status, with the exception of erectile dysfunction, which was not improved in the history-of-AA group in the nine patients with available data on erectile dysfunction (Supporting Information Table S1). Although there is a close association between PNH and AA, these conditions are distinguished based on their predominant clinical features and require different clinical management and treatment approaches. Our real-world analysis of a large group of patients from the International PNH Registry with and without comorbid AA, showed treatment with eculizumab to be associated with significant improvement in rates of MAVEs, TEs, and RBC transfusions as well as improvement in laboratory markers and most PNH-related symptoms regardless of the status of underlying AA. Rates of TEs and MAVEs (including TEs) prior to initiation of eculizumab were lowest in patients with ongoing AA and highest in patients without a history of AA. This is not surprising given that the patients without a history of AA had greater elevations in LDH and were more likely to have a PNH clone size ≥50% compared with patients who had ongoing AA or history of AA. Event rates decreased significantly after treatment with eculizumab in all groups. Rates of RBC units transfused were similar among the three groups prior to initiation of eculizumab and were reduced in all groups during eculizumab treatment. Interestingly, the greatest reduction in transfusion rate was seen in patients with no AA. It is possible that, while eculizumab addressed the hemolytic component of PNH in all groups, some patients with history of AA may have continued to require transfusions to address the underlying BMF, despite eculizumab treatment. In conclusion, this study of a very large population of patients in the International PNH Registry showed treatment with eculizumab was associated with significant improvement in rates of MAVEs, TEs, and RBC transfusions, LDH ratios, and hemoglobin levels as well as a substantial increase in proportions of patients with improvement in PNH-related symptoms, regardless of AA status. These findings suggest that patients with PNH who have HDA, including those with ongoing and resolved AA, may be managed effectively with eculizumab regardless of their AA status. The sponsor and investigators thank the patients and their families for their participation in and support for this clinical study. The authors would like to acknowledge Peloton Advantage, LLC, which provided editorial and medical writing support by Michael D. Morren, RPh, MBA, with funding from Alexion Pharmaceuticals, Inc. Jong Wook Lee: Has received honoraria, consulting fees, and research support (to Seoul St. Mary's Hospital) from Alexion Pharmaceuticals, Inc. Régis Peffault de Latour: Has received honoraria, consulting fees, and research support from Alexion Pharmaceuticals, Inc., Pfizer, and Novartis, and has received research support from Amgen. Robert A. Brodsky: Is a member of the scientific advisory board for and receives grant funding from Alexion Pharmaceuticals, Inc. Jun Ho Jang: Has nothing to disclose. Anita Hill: Has received honoraria and consulting fees from Alexion Pharmaceuticals, Inc. Alexander Röth: Has received honoraria, consulting fees, and research support from Alexion Pharmaceuticals, Inc. Hubert Schrezenmeier: Has received travel support, honoraria, and research support (to University of Ulm) from Alexion Pharmaceuticals, Inc. Amanda Wilson: Is an employee and stockholder of Alexion Pharmaceuticals, Inc. Jing L. Marantz: Is a former employee of Alexion Pharmaceuticals, Inc., and was employed during the study and preparation of the manuscript. Jaroslaw P. Maciejewski: Has received consulting fees from Alexion Pharmaceuticals, Inc., Apellis Pharmaceuticals, and Ra Pharma; has also received speaker fees from and is a member of the Executive Committee of the International PNH Registry for Alexion Pharmaceuticals, Inc. Qualified academic investigators may request participant-level, de-identified clinical data and supporting documents (statistical analysis plan and protocol) pertaining to this study. Further details regarding data availability, instructions for requesting information and our data disclosure policy will be available on the Alexion.com website (http://alexion.com/responsibility). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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