Management Of Paroxysmal Nocturnal Hemoglobinuria Research Articles

Management of paroxysmal nocturnal hemoglobinuria with low-level hemolysis in pregnancy- a report of two cases.

Pregnant women with paroxysmal nocturnal hemoglobinuria (PNH) are at high risk for life-threatening thromboembolism. Therapy with the complement inhibitor eculizumab is able to mitigate thrombotic risks in PNH and to improve pregnancy outcomes. However, whether PNH with low-level hemolysis in pregnancy can be safely managed without complement inhibition is unclear.Here, we describe two pregnant patients with PNH in the setting of bone marrow failure and low-level hemolysis with lactate dehydrogenase (LDH) < 1.5 x upper limit of normal [ULN]. In both patients, management consisted solely of prophylactic anticoagulation, without the use of complement inhibition. Both pregnancies ended successfully without thromboembolic complications.We conclude that in pregnant patients with PNH and low-level hemolysis (i.e. LDH < 1.5 x ULN), management with close monitoring and prophylactic anticoagulation only, without use of complement inhibition, might be a reasonable strategy. More data to guide optimal management of pregnant women with PNH are needed.

Epidemiological estimates of paroxysmal nocturnal hemoglobinuria in Bulgaria.

Paroxysmal nocturnal hemoglobinuria is a rare clonal hematopoietic stem cell disorder with debilitating health consequences if untreated. Although cases have been described globally, precise epidemiological distribution is difficult to assess due to geographical underrepresentation in disease reporting. Evaluation of the burden of paroxysmal nocturnal hemoglobinuria in Bulgaria is currently missing. To provide epidemiological estimates, a systematic literature search for publications in the Bulgarian language or by Bulgarian authors was performed for a ten-year period (2013-2022), and clinically relevant information on case presentation was collected. Additionally, data was retrieved from the National Health Insurance Fund and National Statistical Institute on the count of registered cases with ICD-10 code "D59.5" and census for the same period. The estimated prevalence of paroxysmal nocturnal hemoglobinuria is relatively lower in the Bulgarian population than in other countries, and it is estimated to be 2.77 cases per 1,000,000 patient years. The treatment pattern mainly shows conventional blood product support use and is consistent with the pre-complement inhibition era. Underdiagnosis, lack of a reliable disease reporting system, and, until recently, restricted access to complement inhibitor therapy are significant impediments to the management of paroxysmal nocturnal hemoglobinuria in Bulgaria.

Treatment of eculizumab refractory paroxysmal nocturnal hemoglobinuria: A systematic review about current treatment options and future direction.

C5 inhibitors such as eculizumab and ravulizumab are the first-line treatment in the management of paroxysmal nocturnal hemoglobinuria (PNH). However, some patients develop novel symptoms as part of their treatment with eculizumab, and the disease is termed as eculizumab refractory PNH. The aim of this study was to conduct a systematic review on the available treatment modalities for the management of eculizumab refractory PNH. Two authors independently searched two databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 70 studies were obtained: 4 out 70 studies were found to meet the inclusion criteria. Four studies were found to meet the inclusion criteria of our study. Two studies were published in 2021 and two studies were published in 2020. All four studies were multicenter clinical trials. Two studies were phase III clinical trials, one study was a phase II clinical trial, and one study was a phase I clinical trial. Two studies were about pegcetacoplan, one was about danicopan, and one was about iptacopan. Based upon the findings of our systematic review, we recommend an individualized treatment plan based on the mechanism of eculizumab refractoriness and the mechanism of PNH breakthrough. This recommendation is subject to the available resources and clinical expertise available at different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs should be performed to accurately assess the different medications and aid in designing guidelines of the management of eculizumab refractory PNH. Level I.

Real-World Eculizumab Dosing Patterns Among Patients with Paroxysmal Nocturnal Hemoglobinuria in a US Population.

PurposeCurrent pharmacologic management of paroxysmal nocturnal hemoglobinuria (PNH) consists of C5 inhibitors, eculizumab and ravulizumab; however, because patients experience incomplete symptom control, off-label doses may be utilized. We conducted a retrospective, longitudinal cohort study of provider-based claims data to assess the real-world eculizumab dosing patterns in PNH patients.Patients and MethodsPatients were ≥12 years, received ≥2 eculizumab infusions between January 1, 2015 and September 30, 2019, and had ≥3 months of continuous clinical activity prior to index. The index date was the first claim for eculizumab. Patients with ≥1 diagnosis of another indication for eculizumab were excluded. Treatment patterns including the proportion with high, label-recommended, and low dosages during induction (first 28 days) and maintenance (beginning day 29) phases were described. The proportion and time-to-first dose escalation, defined as an increase in dose or frequency of infusion, were assessed among a subset of patients (ie, escalation analysis cohort).ResultsA total of 707 patients were examined. Mean (standard deviation [SD]) starting dose was 862mg (412mg) and was higher than label-recommended 600mg for 64% of the patients. Mean (SD) dose per infusion was 859mg (391mg) during the induction phase; average dose was higher than label-recommended 600mg for 68%. Mean (SD) dose per infusion during the maintenance phase was 1005mg (335mg); average dose was higher than label-recommended 900mg for 43%. Dose escalation occurred in 40/121 escalation analysis cohort patients. Median time-to-first dose escalation was ~12 months.ConclusionResults suggest that deviations from label-recommended dosing patterns were common. Future budget impact assessments of eculizumab should account for real-world dosing patterns to comprehensively assess costs and benefits.

Intestinal ischemia in paroxysmal nocturnal hemoglobinuria with associated aplastic anemia: a rare and challenging association (case report)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder due to an acquired genetic mutation in phosphatidylinositol glycan anchor biosynthesis, class A (PIGA) gene. Paroxysmal nocturnal hemoglobinuria has different manifestations, the most common being hemolysis, thrombosis and aplastic anemia. For the latter, aplastic anemia can be both the cause and the consequence of PNH. Complement inhibitors, such as eculizumab and ravulizumab represents the cornerstone in the management of PNH as it is associated with fewer recurrence of hemolytic and thrombotic events. However, PNH associated aplastic anemia does not improve with complement inhibitor, and is managed either with allogeneic stem cell transplantation or immunosuppressive therapy. The major cause of death in PNH is thrombosis, which is often venous, and of unusual locations. Intestinal ischemia represents a rare location of thrombosis in PNH. There are a few cases reported, where the management was either surgical or conservative. Many of these reports showed a recurrence of thrombosis, and the outcome has been fatal in some. Severe aplastic anemia adds a level of difficulty to the therapeutic challenge as both resection surgery and efficient anticoagulation become infeasible or delicate. We report the case of a 24-year-old woman, who was diagnosed with severe aplastic anemia associated with PNH, for which she was put on triple immunosuppressive therapy. Eight months following the diagnosis, the patient complained of acute abdominal pain with vomiting. A contrast enhanced computed tomography scan showed a jejunal ischemia with signs of perforation. Due to the low platelet level, a conservative approach was taken consisting of oral feeding cessation, hydration, anticoagulation, and antibiotics therapy. This raises the question of whether a complement inhibitor therapy could have prevented this potentially fatal complication.

Pregnancy outcomes in women receiving eculizumab for the management of paroxysmal nocturnal haemoglobinuria.

To report pregnancy outcomes and complications in women receiving eculizumab for the management of paroxysmal nocturnal haemoglobinuria. A service evaluation of routinely collected medical records across 49 pregnancies in 21 women. Eculizumab was used in 37 pregnancies, 31 of which (83.8%) ended in live birth. Eight infants (25.8%) were born prematurely. Over half (54%) of women required increases in their dose of eculizumab to control their haemolysis. There were no reported cases of maternal thrombosis. Major ante/postpartum bleeding necessitating urgent intervention was reported in 10.8% of pregnancies. There were two cases of intrauterine death and three miscarriages. There were no maternal or neonatal deaths. Three newborns required prolonged hospital stays. Eculizumab appears to benefit pregnant women with paroxysmal nocturnal haemoglobinuria and pregnancy outcomes following its use are largely good.

Current global scenario of guidelines on the management of paroxysmal nocturnal hemoglobinuria: a systematic literature review

Objective: To report the outcomes of a systematic literature review of guidelines and consensus on the management of paroxysmal nocturnal hemoglobinuria (PNH) and describe the main therapeutic options available worldwide. Methods: A systematic literature review was conducted in April 2018 with no time limit and reported in line with the PRISMA statement. The AGREE II instrument was used to determine the quality of each guideline included in the systematic review. Results: Eight guidelines/consensus were eligible, one developed by an international group, two in Spain, and one each in Turkey, Germany, Argentina, Australia and the United Kingdom. Supportive treatment with erythrocyte transfusion, anticoagulants and steroids is indicated by all guidelines and consensus. The use of erythropoietin is suggested by three of them. Recommendations for the prescription of eculizumab were consistent in all but one guideline, published in 2005. Allogeneic hematopoietic stem cell transplantation is reported as the only potentially curative treatment for PNH, although its association with high mortality and morbidity rates is emphasized, being indicated for a selected group of patients. The AGREE II scores applied for each domain showed in general a low and heterogeneous methodological quality among guidelines. Conclusion: Despite the low and heterogeneous methodological quality, in general the comparison of guidelines and consensus for PNH management showed consistent recommendations regarding supportive care, eculizumab and hematopoietic stem cell transplantation.

Is Allogeneic Stem Cell Transplantation a Good Option for Paroxysmal Nocturnal Haemoglobinuria?

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, nonmalignant, haematopoietic clonal disorder that manifests with haemolytic anaemia, thrombosis, and peripheral blood cytopenias. The diagnosis is based on laboratory findings of intravascular haemolysis and flow cytometry. Clinical findings in PNH include haemolytic anaemia, thrombosis in atypical sites, or nonspecific symptoms attributable to the consequences of haemolysis. Thrombosis is the leading cause of death in PNH. Terminal complement pathway inhibition with eculizumab controls most of the symptoms of haemolysis and the life-threatening complications of PNH. However, there is still no consensus about haematopoietic stem cell transplantation (HSCT) in the management of PNH; it is the only potentially curative therapy for PNH. There are limited data and few case series about both the long-term outcomes of HSCT for PNH and the impacts of conditioning regimens on PNH clones. The authors have reviewed the findings of these studies which report on HSCT for the treatment of PNH.

Biotechnological products for the treatment of complement system disorders including paroxysmal nocturnal hemoglobinuria: currently available and in development

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal blood disorder caused by somatic mutations in phosphatidylinositol glycan, class A gene (PIG-A) in hematopoietic stem cells which manifests as haemolytic anemia, bone marrow failure, thromboses, impaired renal function, and other severe clinical symptoms. The management of PNH is a clinical challenge requiring a comprehensive approach. Over the past decade, target therapy with eculizumab, an antibody inhibitor of terminal complement activation, has played a key role in the treatment of PNH. Eculizumab is the first humanized anti-C5 monoclonal antibody that was proven effective in inhibiting the complement system and was approved as a standard treatment for PNH in many countries. Elizaria, the first biosimilar version of eculizumab, whose similarity to the original drug in terms of efficacy and safety was demonstrated in clinical trials, has been widely used in Russia since 2019. New complement inhibitors classified by their mechanism of action into inhibitors targeting complement component C5 (the terminal pathway) and those targeting early phases of complement activation cascade (the proximal pathway) are currently in development. These new drugs include monoclonal antibodies, small molecules, small peptide inhibitors, small interfering RNA, and recombinant proteins based on endogenous regulators of complement activation.

PF734 PATIENT PREFERENCES FOR THE TREATMENT OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA: RESULTS OF A PATIENT SURVEY OF RAVULIZUMAB (ALXN1210) AND ECULIZUMAB

Background:Since 2007, eculizumab has transformed the management of paroxysmal nocturnal hemoglobinuria (PNH). However, it has a treatment burden associated with q2w dosing. Recently, the FDA approved ravulizumab for PNH treatment. Ravulizumab administered q8w demonstrated noninferiority to eculizumab in two phase 3 trials on all primary and key secondary efficacy measures. In view of these two treatment options, it is important to consider patient preference in determining a treatment plan for these patients (pts).Aims:To assess patient preference for ravulizumab or eculizumab treatment, in clinical trial substudy ALXN1210‐PNH‐302 s.Methods:The substudy enrolled PNH pts who participated in the extension period of the phase 3 study (ALXN1210‐PNH‐302) and provided informed consent. In the phase 3 study, adult PNH pts stable on eculizumab for at least 6 months received ravulizumab or eculizumab in accordance with protocol for 26 wks (randomized period). All pts in the extension period received ravulizumab. In the substudy, patient treatment preference was evaluated at one time point using an 11‐item PNH‐specific Patient Preference Questionnaire (PNH‐PPQ©). Prior to the administration of the PNH‐PPQ, pts must have received at least two doses of ravulizumab during the extension period. Differences in preference between ravulizumab and eculizumab were examined with an exact binomial test (Q1), frequency distributions (Q2–3), and paired t‐tests (Q4–11), with P &lt; 0.05 considered statistically significant. Standardized effect sizes (d) were calculated for differences between evaluations of ravulizumab and eculizumab on Q4‐11.Results:Of 98 pts enrolled, 95 pts from 8 countries (European Union, North America, and Australia) completed PNH‐PPQs per protocol for analysis. The mean age of responders was 50 years (range: 22–78); 56% were male and 44% female. Mean time since diagnosis was 14 years (range: 2–48) and the mean number of days between the last randomized study treatment and completion of PNH‐PPQ was 306 (range: 196–457). Overall, 93% of pts (n = 88) preferred ravulizumab vs 7% (n = 7; P &lt; 0.001) who had no preference (n = 6) or preferred eculizumab (n = 1) (Table). With regard to specific aspects of treatment, ravulizumab was widely preferred on frequency of infusions (98%), ability to plan activities (98%), overall quality of life (88%), convenience of receiving treatment (85%), and effectiveness of medication until the next infusion (78%). Among pts who preferred eculizumab or had no preference, side effects of treatment (n = 52; 55%) and anxiety related to infusions (n = 49; 51%) were the leading factors in determining their choice. Frequency of infusions was selected by the most respondents (n = 41; 43%) as the most important factor determining treatment preference, followed by overall quality of life (n = 22; 23%). Moderate to large effect sizes were observed for factors favoring ravulizumab over eculizumab, including the frequency of infusions disrupting everyday life (d = –1.46, P &lt; 0.001), feeling fatigued after infusions (d = –0.56, P &lt; 0.001), and being able to enjoy life while receiving treatment (d = 0.88, P &lt; 0.001).Summary/Conclusion:In this clinical substudy of eculizumab‐experienced PNH pts, a vast majority preferred ravulizumab due to reduced infusion frequency (q8w vs q2w), ability to plan activities, overall quality of life, convenience of treatment, and effectiveness of medication compared to eculizumab. The study had a global outreach and imparts important patient perspective for treatment of PNH when there is more than one treatment option.image

Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria.

Once suspected, the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) is straightforward when flow cytometric analysis of the peripheral blood reveals a population of glycosyl phosphatidylinositol anchor protein-deficient cells. But PNH is clinically heterogeneous, with some patients having a disease process characterized by florid intravascular, complement-mediated hemolysis, whereas in others, bone marrow failure dominates the clinical picture with modest or even no evidence of hemolysis observed. The clinical heterogeneity is due to the close, though incompletely understood, relationship between PNH and immune-mediated bone marrow failure, and that PNH is an acquired, nonmalignant clonal disease of the hematopoietic stem cells. Bone marrow failure complicates management of PNH because compromised erythropoiesis contributes, to a greater or lesser degree, to the anemia; in addition, the extent to which the mutant stem cell clone expands in an individual patient determines the magnitude of the hemolytic component of the disease. An understanding of the unique pathobiology of PNH in relationship both to complement physiology and immune-mediated bone marrow failure provides the basis for a systematic approach to management.

Eculizumab in the management of paroxysmal nocturnal hemoglobinuria: patient selection and special considerations.

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disorder resulting from somatic mutation in the PIG-A gene leading to a deficiency of the membrane-anchoring molecule glycosylphosphatidylinositol. The lack of expression of two glycosylphosphatidylinositol-anchored proteins involved in the regulation of the complement system renders PNH erythrocytes susceptible to complement-mediated lysis. Clinical manifestations include thromboembolic disease, chronic kidney injury, pulmonary hypertension, smooth muscle dysfunction, and chronic hemolysis. Until recently, treatment was mainly supportive with most patients suffering from significant morbidity and shortened survival compared to age-matched controls. The development of eculizumab, a humanized monoclonal antibody directed against the terminal complement protein C5, has resulted in dramatic improvements of survival and reduction in complications. In this paper, we review some special considerations pertaining to the use of eculizumab for PNH.

New Insights in Bone Marrow Failure

Several rare haematological diseases are linked to bone marrow failure (BMF). This symposium provided the latest scientific insights into the different pathophysiological mechanisms and clinical advances in the management of these conditions, with a specific focus on the clinical management of patients with paroxysmal nocturnal haemoglobinuria (PNH) in the context of aplastic anaemia (AA), and the pathophysiology, consequences, and identification of PNH in the context of BMF. Prof Gérard Socié chaired the symposium and overviewed BMF. Dr Austin Kulasekararaj gave a presentation on new paradigms in BMF, followed by Prof Gérard Socié, who reviewed the diagnosis and management of AA. Dr Alexander Röth then discussed the diagnosis and management of PNH in the context of BMF. The symposium was concluded by a short question and answer session.

Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria

AbstractThe clinical management of paroxysmal nocturnal hemoglobinuria (PNH), a rare but life-threatening hematologic disease, has fundamentally improved with the introduction of a therapeutic that prevents complement-mediated intravascular hemolysis. However, a considerable fraction of PNH patients show insufficient treatment response and remain transfusion dependent. Because the current treatment only prevents C5-induced lysis but not upstream C3 activation, it has been speculated that ongoing opsonization with C3 fragments leads to recognition and phagocytosis of PNH erythrocytes by immune cells. Here, for the first time, we provide experimental evidence for such extravascular hemolysis and demonstrate that PNH erythrocytes from anti–C5-treated patients are phagocytosed by activated monocytes in vitro. Importantly, we show that this uptake can be mediated by the end-stage opsonin C3dg, which is not traditionally considered a phagocytic marker, via interaction with complement receptor 3 (CR3). Interaction studies confirmed that C3dg itself can act as a ligand for the binding domain of CR3. The degree of C3dg-mediated erythrophagocytosis in samples from different PNH patients correlated well with the individual level of C3dg opsonization. This finding may guide future treatment options for PNH but also has potential implications for the description and management of other complement-mediated diseases.

Advances of studies on pathogenesis and management of paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of hematopoiesis due to the inactivation of PIG-A gene. However, the presence of mutant PIG-A gene in a group of hematopoietic cells is not enough for the development of PNH, immunologic injury and apoptotic effects are considered to play an important role in clonal expansion. Knowledge of the molecular mechanisms leading to PNH has substantially increased in the past decades, which remarkably advances the diagnostic modalities and treatment approaches of patients with PNH. Though great progress has been made because of targeted therapy method, the challenges are still ahead. In this review the advances of studies on mechanism, laboratorial diagnosis and therapeutic protocols of PNH are summarized.

Diagnosis of Paroxysmal Nocturnal Hemoglobinuria in Peripheral Blood and Bone Marrow with Six-Color Flow Cytometry

Identification of paroxysmal nocturnal hemoglobinuria (PNH) by detecting a glycophosphatidylinositol-anchored defect by flow cytometry is presently the standard method of choice for diagnosing PNH. However, the selection of suitable markers will be critical and significantly affect the determination and quantification of PNH clones in various cell lineages. In this study, we investigated the performance of various immunophenotypic markers including CD59, GPHA (a clustered antigen, CD235a), CD33, CD15 and fluorescent aerolysin (FLAER) combined with CD16, CD24 and CD14 in a PNH panel using six-color flow cytometry. The results strongly indicate that these markers can collectively and effectively identify and quantify PNH clones in erythrocyte, granulocyte and monocyte populations derived from peripheral blood and bone marrow (BM). A sensitivity threshold as low as 0.01% in identifying PNH clones in erythrocyte and granulocyte populations from peripheral blood is achieved by this panel in a series dilution assay. In addition, a direct side-by-side comparison between BM and peripheral blood from the same patients suggests that the FLAER PNH test is capable of identifying to PNH clones in BM specimens. The data support the premise that a six-color flow cytometry PNH panel using the combination of CD59, CD235a, CD33, CD15, FLAER, CD16, CD24 and CD14 can enhance and improve the current methods used in diagnosis and management of PNH by specifically identifying PNH clones in the erythrocyte, granulocyte and monocyte population.

Pathophysiology and management of paroxysmal nocturnal hemoglobinuria

Pathophysiology and management of paroxysmal nocturnal hemoglobinuria

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Despite the availability of safe, effective targeted therapy that controls intravascular hemolysis, the management of paroxysmal nocturnal hemoglobinuria (PNH) remains complicated because of disease heterogeneity and close association with BM failure syndromes. The purpose of this review is to provide a framework for individualizing treatment based on disease classification. According to the recommendations of the International PNH Interest Group, patients can be placed into one of the following 3 categories: (1) classic PNH, (2) PNH in the setting of another BM failure syndrome, or (3) subclinical PNH. The PNH clone in patients with subclinical disease is insufficiently large to produce even biochemical evidence of hemolysis, and consequently, patients who fit into this category require no PNH-specific therapy. Patients with PNH in the setting of another BM failure syndrome (usually aplastic anemia or low-risk myelodysplastic syndrome) have at least biochemical evidence of hemolysis, but typically the PNH clone is small (< 10%) so that hemolysis does not contribute significantly to the underlying anemia. In these cases, the focus of treatment is on the BM failure component of the disease. Intravascular hemolysis is the dominant feature of classic PNH, and this process is blocked by the complement inhibitor eculizumab. The thrombophilia of PNH also appears to be ameliorated by eculizumab, but the drug has no effect on the BM failure component of the disease. Low-grade extravascular hemolysis due to complement C3 opsonization develops in most patients treated with eculizumab, and in some cases is a cause for suboptimal response to treatment. Allogeneic BM transplantation can cure classic PNH, but treatment-related toxicity suggests caution for this approach to management.

Strategy for bone marrow transplantation in eculizumab-treated paroxysmal nocturnal hemoglobinuria

Although the recent introduction of eculizumab has had a significant impact on the management of paroxysmal nocturnal hemoglobinuria (PNH), bone marrow transplantation (BMT) remains the only therapeutic option for patients who develop severe aplasia in the clinical course of PNH. However, information regarding BMT for eculizumab-treated PNH patients is scarce, and two major points-the optimal duration of eculizumab therapy, and the optimal BMT conditioning regimen-remain unclear. Here, we describe the clinical course of a PNH patient who was successfully treated with unrelated reduced-intensity BMT. Eculizumab was discontinued 2weeks prior to the initiation of the conditioning regimen, which consisted of fludarabine 180mg/m(2), cyclophosphamide 100mg/kg, rabbit anti-thymocyte globulin 2mg/kg, and TBI 3Gy. Complete donor chimerism was rapidly achieved in association with a rapid decrease in the proportion of PNH erythrocytes. The patient became transfusion-free immediately after BMT, and had no recurrence of hemolysis. The present case suggests that discontinuation of eculizumab before BMT and the use of a highly lymphoablative conditioning regimen may act as a successful treatment strategy in BMT for PNH. Further studies are warranted to evaluate the efficacy and safety of this treatment strategy.

Progress in the management of paroxysmal nocturnal hemoglobinuria by Eculizumab

Progress in the management of paroxysmal nocturnal hemoglobinuria by Eculizumab