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.

Progress in the Management of Pregnancy with Paroxysmal Nocturnal Hemoglobinuria: A Review.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired complement-mediated hemolytic disease characterized by intravascular hemolysis, thrombosis, smooth muscle dystonia, and so on. Thrombosis is the principal cause of death in PNH patients. During the perinatal period, pregnant PNH patients have increased morbidity and mortality with a heightened risk of complications, including significant preterm birth. The management of pregnancy complicated by PNH is difficult. Therefore, early diagnosis, standardized treatment protocols, and improving perinatal outcomes are crucial. However, there is a lack of consensus on treating patients with PNH during pregnancy. This article reviews 32 studies of pregnancy affected by PNH, focusing on the clinical presentation, diagnosis, and treatment strategies of PNH, to provide guidance for obstetricians on how to handle pregnant patients with PNH, and to offer academic support for the management of PNH patients. We found that Eculizumab has become the primary choice for treating PNH, effectively controlling intravascular hemolysis and reducing the frequency of blood transfusions necessary to stabilize the condition, with no severe threat to the safety of the mother and fetus.

Posttransplant complications in patients with marrow failure syndromes: are we improving long-term outcomes?

Inherited bone marrow failure syndromes (IBMFS) encompass a group of rare genetic disorders characterized by bone marrow failure, non-hematologic multisystemic comorbidities, disease defining congenital anomalies, and a susceptibility to myelodysplastic syndrome, acute myeloid leukemia, and in some instances solid tumors. The most common IBMFS include Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and telomere biology disorders/ dyskeratosis congenita. Allogeneic hematopoietic stem cell transplant (HCT) is a well-established curative treatment to correct the hematological manifestations but does not halt or reverse the nonhematological complications and may hasten them. With advances in HCT and in our ability to care for patients with IBMFS, an increasing number of survivors are making it imperative to not only diagnose but also treat late effects from the pre-, peri-, and post-HCT course and complications relating to the natural history of the syndrome. As the field of HCT evolves to allow for the incorporation of alternate graft sources, for expansion of donor options to include unrelated and mismatched donors, and for use of reduced-intensity conditioning or reduced toxicity myeloablative regimens, we have yet to determine if these advances modify the disease-specific course. While long-term outcomes of these patients are often included under one umbrella, this article seeks to address disease-specific post-HCT outcomes within IBMFS.

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.

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.

[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.

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.

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.

Recent advances in hematopoietic cell transplantation for inherited bone marrow failure syndromes.

Inherited bone marrow failure syndromes (IBMFSs) are a group of rare genetic disorders characterized by bone marrow failure with unique phenotypes and predisposition to cancer. Classical IBMFSs primarily include Fanconi anemia with impaired DNA damage repair, dyskeratosis congenita with telomere maintenance dysfunction, and Diamond-Blackfan anemia with aberrant ribosomal protein biosynthesis. Recently, comprehensive genetic analyses have been implemented for the definitive diagnosis of classic IBMFSs, and advances in molecular genetics have led to the identification of novel disorders such as AMeD and MIRAGE syndromes. Allogeneic hematopoietic cell transplantation (HCT), a promising option to overcome impaired hematopoiesis in patients with IBMFSs, does not correct nonhematological defects and may enhance the risk of secondary malignancies. Disease-specific management is necessary because IBMFSs differ in underlying defects and are associated with varying degrees of risk for clonal evolution and early or late complications after HCT. In addition, long-term follow-up is essential to detect complications related to the IBMFS or HCT. This review provides a summary of current clinical practices along with the latest data on HCT in IBMFSs.

SUZ12 participates in the proliferation of PNH clones by regulating histone H3K27me3 levels.

Paroxysmal nocturnal hemoglobinuria (PNH) is a disease involving hematopoietic stem cell membrane defects caused by acquired phosphatidylinositol glycan anchor biosynthesis class A (PIGA) mutations. In this study, 97 target genes were selected as a target gene panel and screened in 23 PNH patients via the sequencing of specific DNA target regions. Through functional analysis, we identified that suppressor-of-Zeste 12 (SUZ12) may be involved in the proliferation of PNH clones. mRNA and protein expression levels of SUZ12 and the trimethylation level of histone H3 at lysine 27 (H3K27) in CD59- peripheral blood leukocytes from PNH patients were higher than those in CD59+ cells from PNH patients and peripheral blood leukocytes from healthy controls. In addition, the relative expression of SUZ12 in PNH patients was positively correlated with Ret% and the proportion of PNH clones. When we knocked down SUZ12 expression in a PIGA knockdown THP-1 cell line (THP-1 KD cells), the trimethylation of histone H3K27(H3K27me3) and cell proliferation decreased, apoptosis increased, and cell cycle arrest occurred in G0/G1 phase. In conclusion, SUZ12 participates in the proliferation of PNH clones by regulating histone H3K27me3 levels. Our results may provide new therapeutic targets and possibilities for PNH patients.

Unmanipulated haploidentical donor and matched unrelated donor hematopoietic stem cell transplantation in patients with paroxysmal nocturnal hemoglobinuria: a single-center study.

We analyzed the outcomes of 32 patients with paroxysmal nocturnal hemoglobinuria (PNH) who underwent either a haploidentical donor (HID) or a matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT). Seventeen patients received an HSCT from an HID and 15 patients received an HSCT from an MUD. The median follow-up time of the surviving patients was 36 months (range: 12-96 months). No significant differences were observed in the 3-year overall survival (OS) between the HID and MUD cohorts (74.1%±11.4% vs. 93.3%±6.4%, respectively, p=.222) or in the 3-year failure-free survival (68.8%±11.8% vs. 86.7%±8.8%, respectively, p=.307). Treatment-related mortality occurred in five patients. A univariate analysis of risk factors revealed platelet engraftment failure negatively impacted OS and FFS. We conclude that HID and MUD-HSCT are feasible and can be effective options for those PNH patients with concomitant bone marrow failure, recurrent life-threatening thrombosis, and uncontrollable hemolysis.