Relationship of paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size to disease burden and risk of major vascular events in untreated patients: results from the International PNH Registry.

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by acquired gene mutations resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins on the surface of blood cells, leading to terminal complement-mediated intravascular hemolysis and increased risk of major adverse vascular events (MAVEs). Using data from the International PNH Registry, this study investigated the relationship between the proportion of GPI-deficient granulocytes at PNH onset and (1) the risk for MAVEs (including thrombotic events [TEs]) and (2) the following parameters at last follow-up: high disease activity (HDA); lactate dehydrogenase (LDH) ratio; fatigue; abdominal pain; and rates of overall MAVEs and TEs. A total of 2813 patients untreated at enrollment were included and stratified by clone size at PNH disease onset (baseline). At last follow-up, higher proportion of GPI-deficient granulocytes (≤ 5% vs. > 30% clone size) at baseline was associated with significantly increased HDA incidence (14% vs. 77%), mean LDH ratio (1.3 vs. 4.7 × upper limit of normal), and rates of MAVEs 1.5 vs. 2.9 per 100 person-years) and TEs (0.9 vs. 2.0 per 100 person-years). Fatigue was evident in 71 to 76% of patients regardless of clone size. Abdominal pain was more frequently reported with clone size > 30%. A larger clone size at baseline appears to indicate a greater disease burden and risk of TEs and MAVEs and may inform decision making among physicians managing PNH patients at risk of experiencing TEs or other MAVEs. ClinicalTrials.gov ID: NCT01374360.

Cost-effectiveness of eltrombopag vs intravenous immunoglobulin for the perioperative management of immune thrombocytopenia.

Eltrombopag has been shown to be noninferior to intravenous immunoglobulin (IVIG) for improving perioperative platelet counts in patients with immune thrombocytopenia (ITP) in a randomized trial; thus, cost is an important factor for treatment and policy decisions. We used patient-level data from the trial to conduct a cost-effectiveness analysis comparing perioperative eltrombopag 50 mg daily starting dose, with IVIG 1 or 2 g/kg (according to local practice) from a Canadian public health care payer's perspective over the observation period, from preoperative day 21 to postoperative day 28. Resource utilization data were obtained from the trial data (eltrombopag, n = 38; IVIG, n = 36), and unit costs were collected from the Ontario Schedule of Benefits, Ontario Drug Formulary, and secondary sources. All costs were adjusted to 2020 Canadian dollars. We calculated the incremental cost per patient for all patients randomized. Uncertainty was addressed using nonparametric bootstrapping. The use of perioperative eltrombopag for patients with ITP resulted in a cost-saving of $413 Canadian per patient. Compared with IVIG, the probability of eltrombopag being cost effective was 70% even with no willingness to pay. In a sensitivity analysis based on IVIG dose, we found that with the higher dose of IVIG (2 g/kg), eltrombopag saved $2,714 per patient, whereas with the lower dose of IVIG (1 g/kg), eltrombopag had a higher mean cost of $562 per patient. In summary, based on data from the randomized trial that demonstrated noninferiority, the use of eltrombopag for the management of ITP in the perioperative setting was less costly than IVIG.

Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry.

The International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry (NCT01374360) was initiated to optimize patient management by collecting data regarding disease burden, progression, and clinical outcomes. Herein, we report updated baseline demographics, clinical characteristics, disease burden data, and observed trends regarding clone size in the largest cohort of Registry patients. Patients with available data as of July 2017 were stratified by glycosylphosphatidylinositol (GPI)-deficient granulocyte clone size (< 10%, ≥ 10%-< 50%, and ≥ 50%). All patients were untreated with eculizumab at baseline, defined as date of eculizumab initiation or date of Registry enrollment (if never treated with eculizumab). Outcomes assessed in the current analysis included proportions of patients with high disease activity (HDA), history of major adverse vascular events (MAVEs; including thrombotic events [TEs]), bone marrow failure (BMF), red blood cell (RBC) transfusions, and PNH-related symptoms. A total of 4439 patients were included, of whom 2701 (60.8%) had available GPI-deficient granulocyte clone size data. Among these, median clone size was 31.8% (1002 had < 10%; 526 had ≥ 10%-< 50%; 1173 had ≥ 50%). There were high proportions of patients with HDA (51.6%), history of MAVEs (18.8%), BMF (62.6%), RBC transfusion (61.3%), and impaired renal function (42.8%). All measures except RBC transfusion history significantly correlated with GPI-deficient granulocyte clone size. A large proportion of patients with GPI-deficient granulocyte clone size < 10% had hemolysis (9.7%), MAVEs (10.2%), HDA (9.1%), and/or PNH-related symptoms. Although larger GPI-deficient granulocyte clone sizes were associated with higher disease burden, a substantial proportion of patients with smaller clone sizes had history of MAVEs/TEs.