The disease burden of paroxysmal nocturnal hemoglobinuria in Denmark: Epidemiology, survival, healthcare resource utilization, costs, treatment gaps, and labor market attachment.

OBJECTIVES: To establish epidemiology, healthcare costs, and labor market attachment in patients with paroxysmal nocturnal hemoglobinuria (Pt-PNH) in Denmark. METHODS: Data were from Statistics Denmark and the Danish Health Data Authority national population registers (2005-2021). Descriptive baseline statistics characterized the Pt-PNH analytic population; ordinary least squares and adjusted Cox proportional hazards regressions measured outcomes in the Pt-PNH versus Danish general population matched comparators. RESULTS: Overall PNH incidence in Denmark was n = 11 during 2007-2009, n = 25 during 2016-2018 and n = 7 during 2019-2020; prevalence increased from n = 13 in 2006 to n = 62 in 2021. Of the overall n = 85 Pt-PNH; n = 24 were treated with complement-5 inhibitors (Pt-C5i) and n = 61 not treated with C5i (Pt-nC5i). Versus respective comparators, all patients had significantly greater annual per-patient costs (from inpatient hospital admissions, outpatient contacts, PNH treatments; indirect costs from lost earnings + transfer payments; post-diagnosis for Pt-PNH and Pt-nC5i, post-treatment initiation for Pt-C5i). The Pt-C5i incurred the greatest healthcare and indirect cost differences (€709 119; €152 832, respectively) followed by the Pt-PNH (€189 323; €29 159, respectively) and Pt-nC5i (€95 548; €4713, respectively). The Pt-PNH versus comparators also had an increased hazard of death (2.71 [95% CI, 1.63 - 4.51]). CONCLUSION: Although a rare disease, PNH is associated with significant patient, healthcare system, and societal burdens in Denmark.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. METHODS: This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled. RESULTS: At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. CONCLUSION: These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: results from a US patient survey.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disease with symptoms of hemolysis and thrombosis. Current therapies for this complement-mediated disease rely predominantly on inhibition of the C5 complement protein. However, data on treatment responses and quality of life in C5-inhibitor (C5i)-treated PNH patients are scarce. The objective of this study was to determine C5i treatment effects on clinical parameters, PNH symptoms, quality of life, and resource use for PNH patients. This cross-sectional study surveyed 122 individuals in the USA receiving treatment for PNH with C5-targeted monoclonal antibodies, eculizumab (ECU) or ravulizumab (RAV). Despite most patients receiving C5i therapy for ≥ 3 months (ECU 100%, n = 35; RAV 95.4%, n = 83), many patients remained anemic with hemoglobin levels ≤ 12 g/dL in 87.5% (n = 28/32) and 82.9% (n = 68/82) of ECU and RAV recipients, respectively. A majority of patients on ECU (88.6%; n = 31/35) and RAV (74.7%; n = 65/87) reported fatigue symptoms. Among PNH patients receiving C5i therapy for ≥ 12 months, some still reported thrombotic events (ECU, 10.0%, n = 1/10; RAV, 23.5%, n = 4/17) and required transfusions within the past year (ECU, 52.2%, n = 12/23; RAV, 22.6%, n = 7/31). Other patient-reported PNH symptoms included breakthrough hemolysis, shortness of breath, and headaches. Patients reported scores below the average population norms on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scales. Overall, this study found that PNH patients receiving ECU or RAV therapy demonstrated a significant burden of illness, highlighting the need for improved PNH therapies.

Analysis of baseline characteristics, disease burden and long-term follow-up of 167 patients with Paroxysmal Nocturnal Hemoglobinuria at a single center in Brazil.

Paroxysmal nocturnal hemoglobinuria (PNH) can occur as a hemolytic form or small PNH clone found in a patient with bone marrow failure. METHODS: Describe Brazilian retrospective PNH cohort and identify the impact of disease burden on long-term follow-up. RESULTS: 167 patients, mean age at diagnosis 28.4 (7.1-71.2 years), four years mean interval between onset of cytopenia/aplasia diagnosis and PNH clone detection. Patients were divided into 15 Classic PNH, 55 Hemolytic PNH with bone marrow hypoplasia (PNH/AA), and 97 Subclinical PNH (sc-PNH). Hypocellular bone marrow was found in 89.2%; 55 had hemoglobinuria and 22 thrombosis during monitoring. WBC PNH clone correlated with RBC PNH clone, LDH and cytopenia. Subclinical patients had lower median lower RBC clone (2.0% vs 24.0% vs 57.8%) and WBC clone (11.7% vs 58.8% vs 81.2%) than PNH/AA and Classic PNH, respectively. PNH granulocyte clone was 89.1% in thrombotic patients. Ten-year overall survival 80.4% and mortality in transplanted patients 9.6%. Sepsis was mortality cause in subclinical PNH (16/18, 88.8%), and thrombosis in hemolytic PNH (11/13, 84.6%). CONCLUSION: Large PNH clones and LDH burden were associated with increased hemolysis and thrombosis risks, while young patients were associated with small PNH clones and subclinical form of the disease. Knowledge of the patient profile, the low risk associated with HSCT, and the use of long-term IST may be instrumental in the clinical management of PNH in restricted-resources countries.

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.

Establishing an autologous versus allogeneic hematopoietic cell transplant program in nations with emerging economies.

More than 70,000 hematopoietic cell transplants are currently performed each year, and these continue to increase every year. However, there is a significant variation in the number of absolute transplants and transplant rates between centers, countries, and global regions. The prospect for emerging countries to develop a hematopoietic cell transplantation (HCT) program, as well as to decide on whether autologous HCT (auto-HCT) or allogeneic HCT (allo-HCT) should be established to start with, relies heavily on factors that can explain differences between these two procedures. Major factors that will influence a decision about establishing the type of HCT program are macroeconomic factors such as organization of the healthcare network, available resources and infrastructure. Prevalence of specific diseases in the region as well genetic background of donors and recipients will also influence the mandate or priority of the HCT in the national healthcare plan to explain some of the country-specific differences. Furthermore, microeconomic factors play a role, such as center-specific experience in treating various disorders requiring hematopoietic stem cell transplantation, along with accreditation status and patient volume. The objective of the transplant procedure was to improve the survival and quality of life of patients. The regional difference that one notices in emerging countries about the higher number of allo-HCT compared with auto-HCT procedures performed is primarily based on suboptimal healthcare network in treating various malignant disorders that are the primary indication for auto-stem cell transplantation. In this context, nonmalignant disorders such as bone marrow failure syndromes, inherited genetic disorders and hemoglobinopathies have become the major indication for stem cell transplantation. Better understanding of these factors will assist in establishing new transplant centers in the emerging countries to achieve their specific objectives and positive outcome.