[Expert consensus on clonal screening and monitoring of complement inhibitor therapy in paroxysmal nocturnal hemoglobinuria (2024)].

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease with abnormal hematopoietic stem cells that causes intravascular hemolytic anemia, thrombosis, and peripheral blood cytopenia. It has a chronic progressive course and can be fatal in severe cases if not treated aggressively. Complement inhibitors are the first-line recommended treatment for hemolysis-related symptoms of PNH. With the rapid development of new complement inhibitors, it is critical to quickly screen and confirm the diagnosis, identify patients with complement inhibitor indications, and monitor breakthrough hemolysis and extravascular hemolysis during complement inhibitor therapy. Drawing on the most recent guidelines, works of literature, and meta-reviews from around the world, as well as combining with experience from the experts, this consensus focused on PNH screening principles, the significance of PNH cloning detection, and post-treatment monitoring of terminal complement inhibitors, which may contribute to a better understanding of diagnosis and treatment monitoring in the era of complement inhibitors.

Impact of Lactate Dehydrogenase and Hemoglobin Levels on Clinical Outcomes in Patients With Paroxysmal Nocturnal Hemoglobinuria: Results From the National Korean PNH Registry.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder caused by uncontrolled terminal complement activation, which leads to intravascular hemolysis (IVH), thromboembolism (TE), renal failure, and premature mortality. METHODS: We performed a secondary analysis of data collected from patients enrolled in the Korean National PNH Registry to assess the relative importance of risk factors, specifically lactate dehydrogenase (LDH) and hemoglobin (Hb), in predicting the incidence of TE, impaired renal function, and death in complement inhibitor-naïve patients with PNH. RESULTS: Multivariate regression modeling indicated that LDH ≥ 1.5 × upper limit of normal (ULN), male sex, and pain were associated with increased risk of TE (P = 0.016, 0.045, and 0.033, respectively), hemoglobinuria and pain were associated with an increased risk of impaired renal function (P = 0.034 and 0.022, respectively), and TE was associated with an increased incidence of death (P < 0.001). Hb < 8 g/dL was not a predictor of TE, impaired renal function, or death in multivariate regression analyses. Standardized mortality ratio analysis indicated that LDH ≥ 1.5 × ULN (P < 0.001), Hb < 8 g/dL (P < 0.001), and Hb ≥ 8 g/dL (P = 0.004) were all risk factors for death; in contrast, patients with LDH < 1.5 × ULN had similar mortality to the general population. CONCLUSION: In complement inhibitor-naïve patients with PNH, LDH ≥ 1.5 × ULN was a significant predictor of TE, and TE was a significant predictor of death. Hb was not a significant predictor of TE, impaired renal function, or death. Therefore, controlling IVH will improve clinical outcomes for patients with PNH.

Classic paroxysmal nocturnal haemoglobinuria presenting with intestinal malabsorption syndrome, acute abdomen and acute kidney injury.

A male patient in his 30s presented with complaints of acute abdominal pain, black stools and red-coloured urine. CT revealed thrombi in the splenic and left renal veins, leading to infarctions. An endoscopy displayed scalloping of the duodenal folds, indicative of intestinal malabsorption syndrome (IMS). Histopathological examination confirmed IMS. Due to the presence of intravascular haemolysis, haemoglobinuria and thrombotic complications, paroxysmal nocturnal haemoglobinuria (PNH) was suspected and subsequently confirmed by flow cytometry. Thus, a diagnosis of classic PNH with IMS and thrombotic complications was established. This unique case highlights the coexistence of PNH and IMS, resembling the complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy disease, suggesting potential shared pathophysiology.

Treatment Patterns and Healthcare Resource Utilization of Patients With Paroxysmal Nocturnal Hemoglobinuria: A Retrospective Claims Data Analysis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder commonly treated with complement inhibitors such as eculizumab, ravulizumab, and pegcetacoplan. This study aims to describe treatment patterns, healthcare resource utilization, and cost for newly diagnosed PNH patients in 2 large, health insurance claims databases: MarketScan and Optum. Among the 271 patients meeting the inclusion criteria in MarketScan, 57.9% were female, and the average age was 46.6 years. Among these newly diagnosed patients, 25.1% (n = 68) of patients received a PNH-specific pharmacologic treatment, and the average time from diagnosis to treatment was 4.7 months. The medication possession ratio was 97.0%, but discontinuation was common (58.8%). The average per-patient-per-month costs were $18,978, driven by pharmacy and infusion ($11,182), outpatient ($4086), and inpatient ($3318) costs. Despite the availability of multiple treatments, 39.9% of patients had an inpatient stay, and 50.9% had an emergency department visit. Better care management and the introduction of new treatment options are needed to address delays between diagnosis and treatment, and high rates of hospitalization and emergency department use among patients with PNH.

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.

Uncovering the Genetic Etiology of Inherited Bone Marrow Failure Syndromes Using a Custom-Designed Next-Generation Sequencing Panel.

Inherited bone marrow failure syndromes (IBMFS) are a group of heterogeneous disorders that account for ∼30% of pediatric cases of bone marrow failure and are often associated with developmental abnormalities and cancer predisposition. This article reports the laboratory validation and clinical utility of a large-scale, custom-designed next-generation sequencing panel, Children's Hospital of Philadelphia (CHOP) IBMFS panel, for the diagnosis of IBMFS in a cohort of pediatric patients. This panel demonstrated excellent analytic accuracy, with 100% sensitivity, ≥99.99% specificity, and 100% reproducibility on validation samples. In 269 patients with suspected IBMFS, this next-generation sequencing panel was used for identifying single-nucleotide variants, small insertions/deletions, and copy number variations in mosaic or nonmosaic status. Sixty-one pathogenic/likely pathogenic variants (54 single-nucleotide variants/insertions/deletions and 7 copy number variations) and 24 hypomorphic variants were identified, resulting in the molecular diagnosis of IBMFS in 21 cases (7.8%) and exclusion of IBMFS with a diagnosis of a blood disorder in 10 cases (3.7%). Secondary findings, including evidence of early hematologic malignancies and other hereditary cancer-predisposition syndromes, were observed in 9 cases (3.3%). The CHOP IBMFS panel was highly sensitive and specific, with a significant increase in the diagnostic yield of IBMFS. These findings suggest that next-generation sequencing-based panel testing should be a part of routine diagnostics in patients with suspected IBMFS.

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.

Hemosiderin induced acute kidney injury requiring hemodialysis in patients with paroxysmal nocturnal hemoglobinuria: A case report.

RATIONALE: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disease with features of hemolytic anemia, thrombosis, and bone marrow failure. Due to intravascular hemolysis and hemoglobinuria, renal dysfunction is often accompanied in PNH patients. PATIENT CONCERNS: A 25-year old woman presenting gross hematuria after coronavirus disease 2019 infection was admitted to our medical center. She had mild nausea and headache. She was diagnosed with iron deficiency anemia few years ago and had no other underlying disease. Her laboratory findings showed acute kidney injury (AKI) and severe anemia, with evidences of hemolysis. DIAGNOSIS: Renal biopsy was done to determine the cause of renal failure and the result was acute tubular necrosis with deposition of golden pigments, hemosiderin. With pathologic result and laboratory finding of hemolysis, we did flow cytometry for PNH, and the patient was finally diagnosed with PNH. INTERVENTIONS: With AKI and oliguria, the patient started to take hemodialysis. OUTCOMES: After taking 5 sessions of hemodialysis, the patient's renal function was recovered from AKI. With diagnosis of PNH, the patient is now being treated with complement C5 inhibitor. LESSONS: This challenging case tells us that we should consider the first manifestation of PNH as a cause of severe AKI requiring hemodialysis in a patient with anemia and evidence of hemolysis.

Non-capsulated Neisseria meningitidis sepsis in a paroxysmal nocturnal hemoglobinuria patient treated with ravulizumab: case report and review of the literature.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired haematopoietic stem cell disease characterized by complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure. Eculizumab and ravulizumab are anti-C5 monoclonal antibodies that reduce hemolysis, anaemia and thrombotic risk, but are associated with increased risk of infection with encapsulated bacteria, including Neisseria meningitidis. We report a case of life-threatening infection by non-groupable Neisseria meningitidis in a young PNH patient treated with ravulizumab. Despite prompt admission to the intensive care unit, microbe isolation was delayed due to the negativity of capsular antigens, and the patient required intubation, dialysis, and transfusion support for pancytopenia. Notably, PNH disease activity remained controlled and no additional anti-C5 doses were administered. Increasing awareness regarding septic risk in PNH patients on complement inhibitors despite vaccinations is pivotal. A warning about serotypes generally not pathogenetic and not covered by vaccination, such as non-capsulated forms, is emerging.

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.

Severe Acute Kidney Injury in Children as a Rare Complication of Paroxysmal Cold Hemoglobinuria.

Paroxysmal cold hemoglobinuria (PCH) is a rare condition in childhood characterized by complement-mediated premature destruction of red blood cells. PCH is associated with intravascular hemolysis causing hemoglobinuria, which may result in acute kidney injury of various severity. We aimed to retrospectively analyze clinical and laboratory features of children with PCH-associated acute kidney injury received at tertiary Pediatric Hematology and Nephrology Center, University Motol Hospital, Prague, Czech Republic during the period 2016 to 2022. We present here 3 children with PCH-associated acute kidney failure requiring renal replacement therapy. We highlight the association of PCH with kidney disease. Renal parameters and urine examination should be regularly tested in all children with PCH.

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.

Epstein-Barr Virus-induced Paroxysmal Cold Hemoglobinuria in a 17-Year-old Male.

Paroxysmal cold hemoglobinuria is a rare autoimmune hemolytic anemia seen almost exclusively in children under 5 years of age after a viral illness. It is mediated by a biphasic polyclonal autoantibody against red blood cells, which causes severe hemolysis that typically self-resolves within 2 weeks without recurrence. While laboratory identification of the aforementioned antibody, the Donath Landsteiner antibody, would confirm this diagnosis, a negative test does not rule out this condition in the appropriate clinical context. We report on the rare occurrence of a severe presentation of paroxysmal cold hemoglobinuria in a 17-year-old male with Epstein-Barr virus infection.

Crovalimab treatment in patients with paroxysmal nocturnal haemoglobinuria: Long-term results from the phase I/II COMPOSER trial.

OBJECTIVES: This study reports long-term outcomes from the open-label extension (OLE) period of the Phase I/II COMPOSER trial (NCT03157635) that evaluated crovalimab in patients with paroxysmal nocturnal haemoglobinuria, who were treatment-naive or switched from eculizumab at enrolment. METHODS: COMPOSER consists of four sequential parts followed by the OLE. The primary OLE objective was to assess long-term crovalimab safety, with a secondary objective to assess crovalimab pharmacokinetics and pharmacodynamics. Exploratory efficacy endpoints included change in lactate dehydrogenase (LDH), transfusion avoidance, haemoglobin stabilisation and breakthrough haemolysis (BTH). RESULTS: A total 43 of 44 patients entered the OLE after completing the primary treatment period. Overall, 14 of 44 (32%) experienced treatment-related adverse events. Steady state exposure levels of crovalimab and terminal complement inhibition were maintained over the OLE. During the OLE, mean normalised LDH was generally maintained at ≤1.5× upper limit of normal, transfusion avoidance was achieved in 83%-92% of patients and haemoglobin stabilisation was reached in 79%-88% of patients across each 24-week interval. Five BTH events occurred with none leading to withdrawal. CONCLUSIONS: Over a 3-year median treatment duration, crovalimab was well tolerated and sustained C5 inhibition was achieved. Intravascular haemolysis control, haemoglobin stabilisation and transfusion avoidance were maintained, signifying long-term crovalimab efficacy.