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.

How the United States syphilis epidemic may portend a resurgence of an unusual hematologic condition: The connection between syphilis and paroxysmal cold hemoglobinuria.

The connection between syphilis and paroxysmal cold hemoglobinuria.

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.

Long-term effectiveness of eculizumab: Data from the International PNH Registry.

OBJECTIVES: Data from the International PNH Registry (NCT01374360) were used to estimate the overall survival and first occurrence of thromboembolic events/major adverse vascular events (TEs/MAVEs) for eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) compared with a contemporaneous untreated cohort. METHODS: Patients enrolled in the Registry from March 16, 2007, to February 14, 2022, were included. Treated patients received eculizumab for >35 days; untreated patients did not receive eculizumab at any time. Univariable and multivariable analyses were performed using a Cox proportional hazards regression model comparing eculizumab treatment periods to untreated periods and were adjusted for baseline covariates (e.g., high disease activity [HDA], transfusion dependency, and eculizumab treatment status). RESULTS: The analysis included 4118 patients. The univariable hazard ratio (HR) (95% CI) for mortality in eculizumab-treated time versus untreated time was 0.51 (0.41-0.64; p < 0.0001). Significant baseline covariates included age, sex, history of bone marrow failure, ≥4 erythrocyte transfusions within 12 months before baseline, and an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 (all p < 0.0001). In the adjusted analysis, patients with baseline HDA had the greatest reduction in mortality risk (HR [95% CI], 0.51 [0.36-0.72]). Treated patients had approximately 60% reduction in TE/MAVE risk during treated versus untreated time (HR [95% CI]: TE: 0.40 [0.26-0.62], MAVE: 0.37 [0.26-0.54]; p < 0.0001). CONCLUSION: Using data from the largest Registry of patients with PNH, with ≥14 years of overall follow-up, we demonstrate that treatment with eculizumab conferred a 49% relative benefit in survival and an approximately 60% reduction in TE/MAVE risk.

Characteristics of paroxysmal nocturnal hemoglobinuria patients in Brazil: A retrospective administrative claims database analysis of PNH patients in Brazilian public healthcare system.

INTRODUCTION: Few studies have reported the profile of patients with paroxysmal nocturnal hemoglobinuria (PNH) and their care in the Brazilian health system. OBJECTIVE: To describe clinical and epidemiological characteristics of patients with PNH in the Brazilian public health system including procedures performed, associated comorbidities and visits to health care professionals. METHODS: In a real-world observational, retrospective, population-based cohort study, anonymized secondary data provided by the Department of Informatics of the Brazilian Unified Health System (DATASUS) were analyzed. Patients were considered eligible if they had at least one procedure coded with the ICD-10 code D59.5 from January 1, 2008 to December 30, 2018. RESULTS: In total, 675 individual PNH patients were identified (52.4% female; prevalence of 1:237,000 people). Around 15.8% of the patients included had myelodysplastic syndrome and about half of the sample had other aplastic anemias and/or other bone marrow failure syndromes. Portal vein thrombosis (I82 ICD code) was reported in 4.3% of patients. Regarding hospitalizations, 263 individual PNH patients had 416 inpatient admissions with the ICD code for PNH (D59.5) on admission. Twelve deaths occurred during the study period, of which two had the PNH ICD code related with the cause of death, while another three deaths were associated with acquired hemolytic anemia (D59.9), unspecified aplastic anemia (D61.9) and acute respiratory failure (J96.0), respectively. CONCLUSION: Despite its limitations, this statistical analysis of data extracted from DATASUS reasonably describes PNH patients in Brazil and its variations across different regions of the country. Comorbidities frequently associated with PNH such as portal vein thrombosis were not as common in our study, but it is assumed that several thrombotic events at specific sites were coded under the broader I82 ICD code. The frequency of visits to different health professionals, including hematologists, increased after the diagnosis of PNH. Among hospitalized PNH patients, the mortality rate was 4.5%.

Nationwide study of eculizumab in paroxysmal nocturnal hemoglobinuria: Evaluation of treatment indications and outcomes.

Eculizumab is an effective treatment for paroxysmal nocturnal hemoglobinuria (PNH). However, considering the risk of life-threatening meningococcal disease, life-long duration and costs, there are strict criteria for initiation of therapy. To evaluate the application and real-world effectiveness of eculizumab in the Netherlands, a multicenter retrospective cohort study was conducted: indications and treatment outcomes were collected for 105 Dutch PNH patients. In all patients, eculizumab was initiated conforming to indications as formulated in the Dutch PNH guideline. According to recently published response criteria, 23.4% of the patients had reached a complete hematological response, 53.2% a good or partial response, and 23.4% a minor response after 12 months of therapy. In the majority of patients the response remained stable during long-term follow-up. The degree and relevance of extravascular hemolysis significantly differed between response groups (p = 0.002). Improvements of EORTC-QLQc30 and FACIT-fatigue scores were observed, however patients reported lower scores than the general population. A detailed evaluation of 18 pregnancies during eculizumab showed no maternal or fetal deaths, and no thromboembolic events during pregnancy. This study demonstrates that the majority of patients benefit from eculizumab when adhering to the indications as formulated in the Dutch PNH guideline. However, novel therapies are needed to further improve real-world outcomes, such as hematological responses and quality of life.

Clinical and epidemiological features of paroxysmal cold hemoglobinuria: a systematic review.

Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia often overlooked as a potential etiology of hemolysis and is challenging to diagnose because of the complicated testing methods required. We performed a systematic review of all reported cases to better assess the clinical, immunohematologic, and therapeutic characteristics of PCH. We systematically analyzed PubMed, Medline, and EMBASE to identify all cases of PCH confirmed by Donath-Landsteiner (DL) testing. Three authors independently screened articles for inclusion, and systematically extracted epidemiologic, clinical, laboratory, treatment, and outcomes data. Discrepancies were adjudicated by a fourth author. We identified 230 cases, with median presentation hemoglobin of 6.5 g/dL and nadir of 5.5 g/dL. The most common direct antiglobulin test (DAT) result was the presence of complement and absence of immunoglobulin G (IgG) bound to red blood cells, although other findings were observed in one-third of cases. DL antibody class and specificity were reported for 71 patients, of which 83.1% were IgG anti-P. The use of corticosteroids is common, although we found no significant difference in the length of hospitalization for patients with and without steroid therapy. Recent reports have highlighted the use of complement inhibitors. Among patients with follow-up, 99% (213 of 216) were alive at the time of reporting. To our knowledge, this represents the largest compilation of PCH cases to date. We discovered that contemporary PCH most commonly occurs in children with a preceding viral infection, corticosteroid use is frequent (but potentially ineffective), and DAT results are more disparate than traditionally reported.

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.

Clinical characteristics of 512 eculizumab-naive paroxysmal nocturnal hemoglobinuria patients in China: a single-center observational study.

OBJECTIVES: With large patient population and complement inhibitors naïve background, the characteristics patients with paroxysmal nocturnal hemoglobinuria (PNH) in China have not been well studied, especially for different subtypes. METHODS: We retrospectively reviewed patients with complete data who visited Peking Union Medical College Hospital (PUMCH) from 2009 to 2019 and had been followed up for more than 2 years. RESULTS: Five hundred and twelve patients were enrolled including 56.3% males and 43.7% females. The median age at disease onset was 33 (9∼80) years. Most were aged 21∼40 years (50.6%). 52.1%, 46.3% and 1.6% of the patients had classic PNH, bone marrow failure (BMF)/PNH and subclinical PNH, respectively. Symptoms of classic PNH were associated with hemolysis, whereas bleeding was more common in BMF/PNH patients. Classic PNH had higher survival rate, larger PNH clone size, higher lactate dehydrogenase (LDH) level and lower ferritin level than BMF/PNH. Although the rate of thrombosis was similar in the classic PNH and BMF/PNH (P = 0.66), those with BMF/PNH had higher chance of renal impairment (P < 0.05). Immunosuppressive agents was more common use in BMF/PNH (P < 0.05), but glucocorticoids, iron supplements and anticoagulants were more common used in classic PNH (P < 0.05) patients. Less evolution to myeloid malignancies was observed in classic PNH than in BMF/PNH (P = 0.02). The major causes of deaths were thrombosis (29.6%), hemorrhage (18.5%) and infections (18.5%). CONCLUSION: Patients with classic PNH and BMF/PNH have different clinical profiles, and we described a more hemolytic features of PNH in China which might be improved with complement inhibitors.

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.

Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and lifethreatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.

The incidence and prevalence of patients with paroxysmal nocturnal haemoglobinuria and aplastic anaemia PNH syndrome: A retrospective analysis of the UK's population-based haematological malignancy research network 2004-2018.

OBJECTIVES: A retrospective population-based study to determine the incidence and prevalence of patients with the rare blood disease paroxysmal nocturnal haemoglobinuria (PNH). METHODS: All patients were identified by flow cytometric detection of blood cells deficient in glycosylphosphatidylinositol (GPI) linked proteins at a single diagnostic reference laboratory that serves the Yorkshire based, Haematological Malignancy Research Network (HMRN) with a population of 3.8 million. RESULTS: One hundred and ninety-seven patients with detectable PNH clones at a level of >0.01% in at least two lineages of cells (neutrophils, monocytes and/or red cells) were identified over a 15-year period (2004-2018). Of these, 88% had aplastic anaemia (AA), 8% classical PNH and 3% myelodysplastic syndrome. The overall incidence rate was estimated at 0.35 cases per 100 000 people per year. This equates to 220 cases newly diagnosed in the United Kingdom each year. The overall prevalence rate was 3.81 per 100 000, this equates to an estimated 2400 prevalent cases in the UK. The overall and relative 5-year survival rates were 72% and 82.7%, respectively. CONCLUSIONS: This study showed that classical haemolytic PNH is a rare disease and represents only a small proportion overall of patients with detectable PNH cells, the majority of which have aplastic anaemia.

Clinical characteristics and therapeutic outcomes of paroxysmal nocturnal hemoglobinuria patients in Turkey: a multicenter experience.

The aim of this study is to collect paroxysmal nocturnal hemoglobinuria (PNH) patient data from hematology centers all over Turkey in order to identify clinical features and management of PNH patients. Patients with PNH were evaluated by a retrospective review of medical records from 19 different institutions around Turkey. Patient demographics, medical history, laboratory findings, and PNH-specific information, including symptoms at the diagnosis, complications, erythrocyte, and granulocyte clone size, treatment, and causes of death were recorded. Sixty patients (28 males, 32 females) were identified. The median age was 33 (range; 17-77) years. Forty-six patients were diagnosed as classic PNH and 14 as secondary PNH. Fatigue and abdominal pain were the most frequent presenting symptoms. After eculizumab became available in Turkey, most of the patients (n = 31/46, 67.4%) were switched to eculizumab. Three patients with classic PNH underwent stem cell transplantation. The median survival time was 42 (range; 7-183 months) months. This study is the first and most comprehensive review of PNH cases in Turkey. It provided us useful information to find out the differences between our patients and literature, which may help us understand the disease.

Prognostic factors and follow-up parameters in patients with paroxysmal nocturnal hemoglobinuria (PNH): experience of the Austrian PNH network.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by a deregulated complement system, chronic Coombs-negative, intravascular hemolysis, and a variable clinical course with substantial risk to develop thromboembolic events. We analyzed diagnostic and prognostic parameters as well as clinical endpoints in 59 adult patients suffering from PNH in 5 hematology centers in Austria (observation period: 1978-2015). Median follow-up time was 5.6 years. The median clone size at diagnosis amounted to 55% and was higher in patients with classical PNH (81%) compared to patients with PNH associated with aplastic anemia (AA) or myelodysplastic syndromes (MDS) (50%). The clone size also correlated with lactate dehydrogenase (LDH) levels. In one patient, anemia improved spontaneously and disappeared with complete normalization of LDH after 16 years. Seventeen patients received therapy with eculizumab. The rate of thromboembolic events was higher in the pre-eculizumab era compared with eculizumab-treated patients but did not correlate with the presence of age-related clonal hematopoiesis or any other clinical or laboratory parameters. Peripheral blood colony-forming progenitor cell counts were lower in PNH patients compared with healthy controls. Only two patients with classical PNH developed MDS. Overall, 7/59 patients died after 0.5-32 years. Causes of death were acute pulmonary hypertension, Budd-Chiari syndrome, and septicemia. Overall survival (OS) was mainly influenced by age and was similar to OS measured in an age-matched healthy Austrian control cohort. Together, compared with previous times, the clinical course and OS in PNH are favorable, which may be due to better diagnosis, early recognition, and eculizumab therapy.

Beneficial effects of eculizumab regardless of prior transfusions or bone marrow disease: Results of the International Paroxysmal Nocturnal Hemoglobinuria Registry.

OBJECTIVES: To evaluate the effects of eculizumab on transfusions and thrombotic events (TEs) in patients with and without prior history of transfusion in the International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry. METHODS: Registry patients enrolled on or before January 1, 2018, initiated on eculizumab no more than 12 months prior to enrollment, having known transfusion status for the 12 months before eculizumab initiation, and ≥12 months of Registry follow-up after eculizumab initiation, were included. RESULTS: Eculizumab treatment was associated with a 50% reduction in transfusions in patients with a transfusion history (10.6 units/patient-year before eculizumab vs 5.4 after; P < .0001), with greater reduction observed in those with no history of bone marrow disease vs those with bone marrow disease. Mean lactate dehydrogenase levels decreased from a mean of 6.7 to 1.4 times the upper limit of normal (ULN) in patients with transfusion history and from 5.1 to 1.2 times ULN in those with no transfusion history. TE and major adverse vascular event rates also decreased by 70% in patients with and without history of transfusion. CONCLUSIONS: The benefit of eculizumab therapy does not appear to be limited to any group defined by transfusion history or bone marrow disease history.

Small Paroxysmal Nocturnal Hemoglobinuria Clones in Autoimmune Hemolytic Anemia: Clinical Implications and Different Cytokine Patterns in Positive and Negative Patients.

Autoimmune hemolytic anemia (AIHA) is characterized by immune mediated erythrocytes destruction by autoantibodies with or without complement activation. Additional pathologic mechanisms include cellular cytotoxicity, cytokline dysregulation, and inadequate bone marrow compensation with fibrosis/dyserythropoiesis. The latter resembles that of bone marrow failures, namely aplastic anemia and myelodysplastic syndromes. Paroxysmal nocturnal hemoglobinuria (PNH) clones are increasingly recognized in bone marrow failure syndromes, and their selection and expansion are thought to be mediated by immune mechanisms. In this study, we aimed to evaluate the prevalence of PNH clones in 99 patients with primary AIHA, and their correlations with disease features and outcomes. Moreover, in the attempt to disclose the physiopathology of PNH positivity in AIHA, serum levels of several immunomodulatory cytokines were tested. A PNH clone was found in 37 AIHA patients (37,4%), with a median size of 0.2% on granulocytes (range 0.03-85). Two patients showed a large clone (16 and 85%) and were therefore considered as AIHA/PNH association and not included in further analysis. Compared to PNH negative, PNH positive cases displayed a higher hemolytic pattern with adequate bone marrow compensation. AIHA type, response to therapy, complications and outcome were comparable between the two groups. Regarding cytokine levels, IFN-γ and IL-17 were lower in PNH positive vs. PNH negative AIHAs (0.3 ± 0.2 vs. 1.33 ± 2.5; 0.15 ± 0.3 vs. 3,7 ± 9.1, respectively, p = 0.07 for both). In PNH positive AIHAs, IFN-γ positively correlated with reticulocytes (r = 0.52, p = 0.01) and with the bone marrow responsiveness index (r = 0.69, p = 0.002). Conversely, IL-6 and IL-10 showed the same pattern in PNH positive and PNH negative AIHAs. IL-6 levels and TGF-ß positively correlated with clone size (r = 0.35, p = 0.007, and r = 0.38, p = 0.05, respectively), as well as with LDH values (r = 0.69, p = 0.0003, and r = 0.34, p = 0.07, respectively). These data suggest testing PNH clones in AIHA since their prevalence is not negligible, and may correlate with a prominent hemolytic pattern, a higher thrombotic risk, and a different therapy indication. PNH testing is particularly advisable in complex cases with inadequate response to AIHA-specific therapy. Cytokine patterns of PNH positive and negative AIHAs may give hints about the pathogenesis of highly hemolytic AIHA.

Nationwide study of paroxysmal nocturnal hemoglobinuria in South Korea: paradox of eculizumab.

Eculizumab is effective in managing patients with paroxysmal nocturnal hemoglobinuria (PNH). In South Korea, the financial support for eculizumab therapy is extended by the National Health Insurance Services (NHIS) only to patients with high-risk PNH for approximately 10 years. In this study, we performed a nationwide analysis of the real-world efficacy of eculizumab therapy in patients diagnosed with PNH between January 1, 2002, and December 31, 2016, by using the NHIS database. Patients treated with eculizumab (the eculizumab-treated group) exhibited a significantly higher survival rate than patients not treated with eculizumab (the eculizumab-untreated group), with 4-year survival rates after propensity score matching of 98.31% and 79.67%, respectively (p = 0.0489). The mean red blood cell (RBC) transfusion units per 12 months after eculizumab therapy were significantly lower than that before eculizumab therapy (5.75 units vs. 12.28 units, p < 0.0001). The median time for the first transfusion in the eculizumab-treated group was significantly longer than that in the eculizumab-untreated group. The 4-year transfusion-independence rate for the eculizumab-treated group was significantly higher than that for the eculizumab-untreated group (20.81% vs. 10.24%, p = 0.078). There was no significant difference between the two groups in the incidence of new documented complications related to PNH. In conclusion, eculizumab therapy for patients with high-risk PNH may effectively improve the survival rate and reduce the transfusion requirement. Paradoxically, eculizumab-treated patients with severe PNH exhibit a higher survival rate than eculizumab-untreated patients with less severe PNH.

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.

Prevalence of Paroxysmal Nocturnal Hemoglobinuria Clones in Myeloproliferative Neoplasm Patients: A Cross-Sectional Study.

INTRODUCTION: The myeloproliferative neoplasms (MPN) are clonal diseases that confer an increased risk of thrombohemorrhagic complications. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease associated with an increased thrombotic risk. Small PNH clones are prevalent in aplastic anemia and myelodysplastic syndrome patients, but their prevalence in MPN patients is unknown. PATIENTS AND METHODS: Consecutive patients with MPN followed up at a single center were recruited. PNH clones were analyzed in erythrocytes and white blood cells by flow cytometry. RESULTS: PNH clones were detected in 2% of patients and were more common in JAK2 V617F positive patients. We could not detect any differences in clinical manifestations or complications in patients either with or without PNH clones because of the small patient numbers. CONCLUSION: The prevalence of PNH clones in MPN is similar to that described in myelodysplastic syndromes. Whether PNH clones influence MPN phenotype and complications should be studied prospectively in larger patient cohorts and over long-term follow-up.