Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).

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.

HLA-haploidentical stem cell transplantation in children with inherited bone marrow failure syndromes: A retrospective analysis on behalf of EBMT severe aplastic Anemia and pediatric diseases working parties.

Haploidentical stem cell transplantation (haplo-SCT) represents the main alternative for children with inherited bone marrow failure syndrome (I-BMF) lacking a matched donor. This retrospective study, conducted on behalf of the EBMT SAAWP and PDWP, aims to report the current outcomes of haplo-SCT in I-BMFs, comparing the different in vivo and ex vivo T-cell depletion approaches. One hundred and sixty-two I-BMF patients who underwent haplo-SCT (median age 7.4 years) have been registered. Fanconi Anemia was the most represented diagnosis (70.1%). Based on different T-cell depletion (TCD) approaches, four categories were identified: (1) TCRαß+/CD19+-depletion (43.8%); (2) T-repleted with post-transplant Cyclophosphamide (PTCy, 34.0%); (3) In-vivo T-depletion with ATG/alemtuzumab (14.8%); (4) CD34+ positive selection (7.4%). The cumulative incidences (CI) of neutrophil and platelet engraftment were 84% and 76% respectively, while that of primary and secondary graft failure was 10% and 8% respectively. The 100-day CI of acute GvHD grade III-IV(95% CI) was 13%, while the 24-month CI of extensive chronic GvHD was 4%. After a median follow-up of 43.4 months, the 2-year overall survival(OS) and GvHD/Rejection-free Survival (GRFS) probabilities are 67% and 53%, respectively. The TCR CD3+αß+/CD19+ depletion group showed a significantly lower incidence of both acute and chronic GvHD and higher OS (79%; p0.013) and GRFS (71%; p < .001), while no significant differences in outcomes have been observed by different diagnosis and conditioning regimens. This large retrospective study supports the safety and feasibility of haplo-SCT in I-BMF patients. TCRαß+/CD19+ depletion offers higher chances of patients' survival, with a significantly lower risk of severe a- and c-GvHD in I-BMFs compared to other platforms.

Feasibility of electronic patient-reported outcome monitoring and self-management program in aplastic anemia and paroxysmal nocturnal hemoglobinuria-a pilot study (ePRO-AA-PNH).

INTRODUCTION: Electronic patient-reported outcomes (ePRO) are increasingly recognized in health care, as they have been demonstrated to improve patient outcomes in cancer, but have been less studied in rare hematological diseases. The aim of this study was to develop and test the feasibility of an ePRO system specifically customized for aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). METHODS: After performing a user-centered design evaluation an ePRO system for AA and PNH patients could be customized and the application was tested by patients and their medical teams for 6 months. Symptom-reporting triggered self-management advice for patients and prompts them to contact clinicians in case of severe symptoms, while the medical team received alerts of severe symptoms for patient care. RESULTS: All nine included patients showed a high adherence rate to the weekly symptom-reporting (72%) and reported high satisfaction. The system was rated high for usage, comprehensibility, and integration into daily life. Most patients (78%) would continue and all would recommend the application to other AA/PNH patients. Technical performance was rarely a barrier and healthcare providers saw ePRO-AA-PNH as a useful supplement, but the lacking integration into the hospital information system was identified as a major barrier to usage. CONCLUSION: An ePRO system customized for AA and PNH was feasible in terms of adherence, satisfaction, and performance, showing a high potential for these rare conditions in terms of data collection and patient guidance. However, the integration into clinical workflows is crucial for further routine use. TRIAL REGISTRATION: ClinicalTrials.gov NCT04128943.

Inherited bone marrow failure syndromes: a review of current practices and potential future research directions.

PURPOSE OF REVIEW: Recent advances in diagnosis and treatment of inherited bone marrow failure syndromes (IBMFS) have significantly improved disease understanding and patient outcomes. Still, IBMFS present clinical challenges that require further progress. This review aims to provide an overview of the current state of diagnosis and treatment modalities of the major IBMFS seen in paediatrics and present areas of prioritization for future research. RECENT FINDINGS: Haematopoietic cell transplantation (HCT) for IBMFS has greatly improved in recent years, shifting the research and clinical focus towards cancer predispositions and adverse effects of treatment. Each year, additional novel genes and pathogenic variants are described, and genotype-phenotype mapping becomes more sophisticated. Moreover, novel therapeutics exploring disease-specific mechanisms show promise to complement HCT and treat patients who cannot undergo current treatment options. SUMMARY: Research on IBMFS should have short-term and long-term goals. Immediate challenges include solidifying diagnostic and treatment guidelines, cancer detection and treatment, and continued optimization of HCT. Long-term goals should emphasize genotype-phenotype mapping, genetic screening tools and gene-targeted therapy.

Complement Inhibitors in the Management of Complement-Mediated Hemolytic Uremic Syndrome and Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Complement-mediated HUS (CM-HUS) and paroxysmal nocturnal hemoglobinuria (PNH) are rare hematologic disorders that cause dysregulation and hyperactivation of the complement system. Historically, treatment of CM-HUS involved plasma exchange (PLEX), often with limited benefit and variable tolerance. Conversely, PNH was treated with supportive care or hemopoietic stem cell transplant. Within the last decade, monoclonal antibody therapies that block terminal complement pathway activation, have emerged as less invasive and more efficacious options for management of both disorders. This manuscript seeks to discuss a relevant clinical case of CM-HUS and the evolving landscape of complement inhibitor therapies for CM-HUS and PNH. AREAS OF UNCERTAINTY: Eculizumab, the first humanized anti-C5 monoclonal antibody, has been the standard of care in treating CM-HUS and PNH for over a decade. Although eculizumab has remained an effective agent, the variability in ease and frequency of administration has remained an obstacle for patients. The development of novel complement inhibitor therapies with longer half-lives, has allowed for changes in frequency and route of administration, thus improving patient QOL. However, there are limited prospective clinical trial data given disease rarity, and limited information on variable infusion frequency and length of treatment. THERAPEUTIC ADVANCES: Recently, there has been a push to formulate complement inhibitors that improve QOL while maintaining efficacy. Ravulizumab, a derivative of eculizumab, was developed to allow for less frequent administration, while remaining efficacious. In addition, the novel oral and subcutaneous therapies, danicopan and crovalimab, respectively, along with pegcetacoplan are currently undergoing active clinical trials, and poised to further reduce treatment burden. CONCLUSION: Complement inhibitor therapies have changed the treatment landscape for CM-HUS and PNH. With a significant emphasis on patient QOL, novel therapies continue to emerge and require an in-depth review of their appropriate use and efficacy in these rare disorders. CLINICAL CASE: A 47-year-old woman with hypertension and hyperlipidemia presented with shortness of breath and was found to have hypertensive emergency in the setting of acute renal failure. Her serum creatinine was 13.9 mg/dL; elevated from 1.43 mg/dL 2 years before. The differential diagnosis for her acute kidney injury (AKI) included infectious, autoimmune, and hematologic processes. Infectious work-up was negative. ADAMTS13 activity level was not low at 72.9%, ruling out thrombotic thrombocytopenic purpura (TTP). Patient underwent a renal biopsy, which revealed acute on chronic thrombotic microangiopathy (TMA). A trial of eculizumab was initiated with concurrent hemodialysis. The diagnosis of CM-HUS was later confirmed by a heterozygous mutation in complement factor I (CFI), resulting in increased membrane attack complex (MAC) cascade activation. The patient was maintained on biweekly eculizumab and was eventually transitioned to ravulizumab infusions as an outpatient. Her renal failure did not recover, and the patient remains on hemodialysis while awaiting kidney transplantation.

Paroxysmal cold hemoglobinuria: A diagnostic dilemma in a paediatric patient.

BACKGROUND: Autoimmune hemolytic anaemia is rare in the paediatric population. Differentiation of the underlying aetiology is complicated by heterogeneity in diagnostic criteria and testing strategies. Paroxysmal cold hemoglobinuria (PCH) is an uncommon form of paediatric autoimmune hemolytic anaemia. Identification of the causative biphasic hemolysin requires clinical recognition and access to the Donath-Landsteiner (DL) test. CASE PRESENTATION: We report a young paediatric patient with no significant past medical history who presented with severe anaemia, jaundice, and dark urine following a respiratory illness. Initial laboratory evaluation showed a haemoglobin of 3.6 g/dL with plasma free haemoglobin 170 mg/dL (reference range <5 mg/dL), 3+ hemoglobinuria (reference range = 0), and direct antiglobulin testing (DAT) positive for complement component 3 (C3) only. Haemoglobin continued to decline following RBC transfusions using a blood warmer for presumed cold agglutinin syndrome. Subsequent testing at the reference laboratory revealed a DAT positive for C3 and immunoglobulin isotype G (IgG) and an eluate pan-agglutinin most consistent with a warm autoantibody, but the patient's anaemia was non-responsive to glucocorticoids and blood warmer cessation. However, a maximum cold agglutinin titre of 4 and absent thermal amplitude substantially weakened the evidence for the clinical significance of the cold autoantibodies. Consultation with the institutional transfusion medicine specialist prompted collection for the DL test, which demonstrated a definitive biphasic hemolysin consistent with PCH. DISCUSSION: Conflicting clinical and immunohematologic evidence can obscure the aetiology of autoimmune hemolysis, including concurrent warm and/or cold autoantibodies. Clinical correlation, consultation with the institutional transfusion service, and access to specialised testing are essential to establish the correct diagnosis.

[COVID-19 development during the treatment of paroxysmal nocturnal hemoglobinuria].

Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder in which an activated complement causes intravascular hemolysis of erythrocytes that do not have complement regulators. It is critical to monitor the rapid progression of hemolysis caused by infection and thrombosis. As far as we can tell, this is the first report of 5 COVID-19 patients with PNH in Japan. Three patients were being treated with ravulizumab, one with eculizumab, and one with crovalimab. All five cases had received two or more COVID-19 vaccinations. COVID-19 was classified as mild in four cases and moderate in one. None of the cases required the use of oxygen, and none became severe. All of them experienced breakthrough hemolysis, and two required red blood cell transfusions. In any case, no thrombotic complications were observed.

How we('ll) treat paroxysmal nocturnal haemoglobinuria: diving into the future.

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by complement-mediated intravascular haemolysis, severe thrombophilia and bone marrow failure. While for patients with bone marrow failure the treatment follows that of immune-mediated aplastic anaemia, that of classic, haemolytic PNH is based on anti-complement medication. The anti-C5 monoclonal antibody eculizumab has revolutionized treatment, resulting in control of intravascular haemolysis and thromboembolic risk, with improved long-term survival. Novel strategies of complement inhibition are emerging. New anti-C5 agents reproduce the safety and efficacy of eculizumab, with improved patient convenience. Proximal complement inhibitors have been developed to address C3-mediated extra-vascular haemolysis and seem to improve haematological response.

Subacute stent thrombosis with spontaneously resolved secondary thrombi in paroxysmal nocturnal hemoglobinuria: a case report.

BACKGROUND: Stent thrombosis (ST) is a serious complication; however, a method to prevent ST in patients with thrombophilic diseases has not been established. CASE PRESENTATION: We report a case of subacute ST in a patient with paroxysmal nocturnal hemoglobinuria (PNH) who was receiving continuous heparin treatment in addition to the usual dual antiplatelet therapy for contrast defects at the proximal site of the occluded right coronary artery and the proximal site of the left circumflex artery. Despite the resolution of thrombi in secondary lesions, subacute ST occurred. After percutaneous coronary intervention for ST, triple therapy, including oral anticoagulation for PNH-related thrombosis, was initiated. The patient subsequently underwent craniotomy hematoma removal for hemorrhagic cerebral infarction. CONCLUSIONS: Reported cases of ST in patients with PNH are very few, and this case adds evidence with respect to antithrombotic therapy in patients with thrombotic tendencies. Both thrombosis and bleeding should be considered when administering antithrombotic therapy to patients with thrombotic diseases. If there are specific treatments for thrombophilic diseases, they should be initiated early.

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.

The Hematopoietic Cell Transplant Comorbidity Index predicts survival after allogeneic transplant for nonmalignant diseases.

Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases.

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.

PNH Clones for Aplastic Anemia with Immunosuppressive Therapy: A Systematic Review and Meta-Analysis.

OBJECTIVES: PNH clones, also aptly called "escape clones," are evidence of acquired immune-mediated bone marrow failure and have a high prevalence in patients with aplastic anemia (AA). Several studies have reported contradictory results regarding the impact of PNH clones on AA patients with immunosuppression treatment, and PNH clones have not been confirmed as positive predictors of response in the AA guidelines of the British Society for Standards in Haematology. METHODS: We performed a meta-analysis to address this issue by searching for articles in PubMed, EMBASE, The Coch-rane Library, Web of Science, and ClinicalTrials.gov, and for abstracts from the annual meetings of the American Society of Hematology and the European Hematology Association. We included 1,236 participants from 11 cohort-controlled studies. Our primary outcome was the 6-month hematologic response with a secondary outcome of the mortality rate within 3 months. RESULTS: A better response rate was observed in the PNH+ group than in the PNH- group (odds ratio [OR] 2.85; 95% confidence interval [CI] 2.17-3.75; p < 0.00001), and further subgroup analysis strengthened the outcome, with minor heterogeneity in non-Asian countries. In contrast, the early mortality was not significantly different between the PNH+ and PNH- groups (OR 0.54; 95% CI 0.26-1.10; p = 0.09). CONCLUSIONS: The meta-analysis suggested an evidence-based role for PNH clones in predicting a better response in AA patients with immunosuppression.

Allogeneic Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria: Multicenter Analysis by the Polish Adult Leukemia Group.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole potential cure for paroxysmal nocturnal hemoglobinuria (PNH); however, the data on its utility in PNH are limited. This retrospective analysis of patients with PNH who underwent allo-HSCT in 11 Polish centers between 2002 and 2016 comprised 78 patients with PHN, including 27 with classic PNH (cPNH) and 51 with bone marrow failure-associated PNH (BMF/PNH). The cohort was 59% male, with a median age of 29 years (range, 12 to 65 years). There was a history of thrombosis in 12% and a history of hemolysis in 81%, and 92% required erythrocyte transfusions before undergoing allo-HSCT. No patient received eculizumab, and 26% received immunosuppressive treatment. The median time from diagnosis to allo-HSCT was 12 months (range, 1 to 127 months). Almost all patients (94%) received reduced-toxicity conditioning, 66% with treosulfan. The stem cell source was peripheral blood in 72% and an identical sibling donor in 24%. Engraftment occurred in 96% of the patients. With a median follow-up of 5.1 years in patients with cPNH and 3.2 years in patients with BMF/PNH, 3-year overall survival (OS) was 88.9% in the former and 85.1% in the latter (P = not significant [NS]). The 3-year OS for patients with/without thrombosis was 50%/92% (P = NS) in the cPNH group and 83.3%/85.3% (P = NS) in the BMF/PNH group. The 3-year OS for in the BMF/PNH patients with/without hemolysis was 93.9%/62.9% (hazard ratio, .13; P = .016). No other factors impacted OS. After allo-HSCT, the frequency of the PNH clone was reduced to 0%, <1%, and <2.4% in 48%, 48%, and 4% of cPNH patients and in 84%, 11%, and 5% of BMF/PNH patients, respectively. The frequency of acute graft-versus-host disease (GVHD) grade II-IV was 23%, and the cumulative 1-year incidence of extensive chronic GVHD was 10.8% in the BMF/PNH group and 3.7% in the cPNH group. Allo-HSCT is a valid option for PNH patients, effectively eliminating the PNH clone with satisfactory overall survival and acceptable toxicity. Reduced-toxicity conditioning with treosulfan is effective and safe in patients with cPNH and BMF/PNH.

Paroxysmal nocturnal haemoglobinuria (PNH): novel therapies for an ancient disease.

In the UK, early work on paroxysmal nocturnal haemoglobinuria (PNH) was conducted by John Dacie who, at the Hammersmith Hospital, first hypothesised that the PNH abnormality might arise through a somatic mutation; and who outlined with S.M. Lewis the relationship between PNH and aplastic anaemia. When the phosphatidylinositol glycan anchor biosynthesis Class A (PIGA) gene was identified by Taroh Kinoshita's group, jointly with him the Hammersmith group proved that PNH is caused in most patients by a single somatic mutation in the PIGA gene. At the same time, after Bruno Rotoli had spent a sabbatical at the Hammersmith, the 'immune escape model' for the pathogenesis of PNH was developed. Early this century, Peter Hillmen, formerly at the Hammersmith and now in Leeds, spearheaded the use of the complement-blocking (anti-C5) antibody eculizumab. This new medicine radically changed the management and the clinical course of patients with PNH. Recently a derivative of eculizumab with more favourable pharmacokinetics has been introduced. In view of the fact that these agents are associated with C3-dependent extravascular haemolysis, it is important that a number of inhibitors of the proximal complement pathway are now in the offing and may further improve the life of patients with PNH.

Macrophage TNF-α licenses donor T cells in murine bone marrow failure and can be implicated in human aplastic anemia.

Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-γ produced by donor T cells and the IFN-γ receptor in the host in murine immune-mediated BM failure models. TNF-α has been assumed to function similarly to IFN-γ. We used our murine models and mice genetically deficient in TNF-α or TNF-α receptors (TNF-αRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-α-/- donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-αR-/- recipients both induced BM failure, with concurrent marked increases in plasma IFN-γ and TNF-α levels. Surprisingly, in TNF-α-/- recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, whereas injection of recombinant TNF-α into FVB-LN cell-infused TNF-α-/- recipients increased T-cell IFN-γ expression and accelerated BM damage. Furthermore, infusion of TNF-αR-/- donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction. Thus, TNF-α from host macrophages and TNF-αR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-γ secretion. In AA patients, TNF-α-producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease.

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.

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.