Clinical Characteristics of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): A Retrospective Chart Review Study

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease that manifests with complement-mediated chronic intravascular hemolysis resulting in hemolytic anemia, tendency to thrombosis, and peripheral blood cytopenias. Eculizumab is a recombinant humanized IgG2/4 chimeric monoclonal antibody that is approved for the treatment of PNH, generalized myasthenia gravis (gMG), atypical hemolytic uremic syndrome (aHUS), and neuromyelitis optica spectrum disorder (NMOSD). Eculizumab specifically binds to the human C5 complement protein (C5), thereby inhibiting the complement cascade. To obtain a better understanding of PNH biology and provide insight toward improving the clinical management of patients with this disease, a retrospective chart review was performed from pre-existing medical records of patients with PNH treated with eculizumab. This analysis is expected to inform eculizumab biosimilar development; data collected on clinical characteristics of this patient population are presented here.

Methods: This is a multicenter retrospective chart review study of pre-existing medical records of patients ≥18 years old with PNH who were treated with eculizumab between 01 January 2008 and 31 January 2016. Anonymized data from eligible patients were recorded by sites onto an electronic case report form (eCRF) and collected into an electronic data capture (EDC) system. The primary objective of the study was to assess the lactate dehydrogenase (LDH) concentration over time in eculizumab-treated patients with PNH, including during clinical events and after discontinuation of therapy. Secondary objectives included assessment of coexisting disease, vital signs, laboratory results, and clinical findings.

Subjects' LDH time profiles and mean change from baseline of LDH in the maintenance phase were assessed. Maintenance phase was defined as the time period from the first of every 2 weeks (Q2W) eculizumab dose to the data cutoff date, or from the first Q2W eculizumab dose date to the last Q2W dose date for patients who discontinued prior to data cutoff. Baseline of the maintenance phase was defined as the last non-missing assessment taken prior to or on the same day of the first Q2W eculizumab dose. The inter- and intra-subject coefficient of variation (CV) of the 12-week area under effective curve (AUEC) of LDH was based on patients who had at least 2 LDH measurements during the maintenance treatment phase within 12 weeks of each other.

Results: The medical records of 47 patients with PNH who were treated with eculizumab during the study period were reviewed; of these, 27 (57.4%) were female. At the time of the diagnosis, the mean age of all patients was 35.0 years and LDH values were reported for 5 of the 47 patients, 3 of which were ≥1.5 times the upper limit of normal.

LDH values for most subjects during the study were within the expected ranges for the PNH population with stabilized hemoglobin levels on eculizumab. The mean change from baseline of LDH in the maintenance phase showed a decrease or no change for most time points. For the 26 patients who had ≥2 LDH measurements that were ≤ 12 weeks of each other, inter- and intra-subject CVs for the 12-week AUEC of LDH were 74.70% (95% confidence interval [CI] of 58.23%, 88.15%) and 34.05% (95% CI of 30.65%, 38.34%), respectively.

The most commonly reported disease-related symptoms were hemoglobinuria (25 patients [53.2%]), abdominal pain (14 patients [29.8%]), thrombosis (11 patients [23.4%]), and infection (8 patients [17.0%]). Disease-related symptoms listed as 'Other' were reported in 14 (29.8%) patients and included dyspnea, fatigue, exertional dyspnea, aplastic anemia, kidney failure, and dysphagia.

All reported concurrent medical conditions and symptoms have been previously well-documented in PNH patients. Ninety-two transfusions were administered to 15 (31.91%) patients within 6 weeks of the first eculizumab dose. Vital signs data did not demonstrate any clinically significant findings.

Conclusions: The LDH levels for the majority of PNH patients with stabilized hemoglobin levels on eculizumab were well controlled and within the expected range; the inter- and intra-subject variability of 12-week AUEC of LDH were 74.70% and 34.05%, respectively. There were no unexpected or remarkable findings with respect to disease-related symptoms, vital signs, clinical findings, or laboratory data.