Paroxysmal Nocturnal Hemoglobinuria: Initial Presentation, Diagnosis, and Management
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired blood disorder resulting in complement-mediated hemolytic anemia. As seen at the 64th ASH Annual Meeting and Exposition, researchers are exploring novel anticomplement therapies in an effort to optimize outcomes for patients with PNH.
Following these presentations, featured expert Ronald S. Go, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Go’s clinical perspectives on these findings are presented here.
Ronald S. Go, MD
Professor of Medicine
“ . . . in my 13 years of community practice, I have only encountered a single case of PNH. However, when a patient with hemolytic anemia is Coombs negative or DAT negative, PNH is a diagnosis that we consider; when there is pancytopenia in addition to DAT-negative hemolytic anemia at presentation, the index of suspicion for PNH rises even further.”
PNH is not commonly seen in routine clinical practice. In fact, in my 13 years of community practice, I had only encountered a single case of PNH. However, when a patient with hemolytic anemia is Coombs negative or direct antiglobulin test (DAT) negative, PNH is a diagnosis that we consider; when there is pancytopenia in addition to DAT-negative hemolytic anemia at presentation, the index of suspicion for PNH rises even further.
PNH presents in different ways. Some patients have thrombosis, especially in unusual sites such as the splanchnic venous system, hepatic veins, portal veins, and other abdominal or cerebral veins. Others have signs and symptoms that reflect cytopenias, with anemia being the most common (eg, fatigue, dyspnea on exertion, and even chest pain). Red-tinged urine, which is most pronounced during the first morning void, is a commonly listed symptom of PNH. In my experience, however, it is not an exceptionally common symptom—it might apply to approximately 15% to 20% of patients. Additionally, individuals may experience a variety of muscular dystonia symptoms, such as abdominal pain, esophageal spasms, dysphagia, and, in men, erectile dysfunction. These manifestations are thought to be due to the free hemoglobin in the blood, which depletes nitric oxide and results in changes in the smooth muscle tone.
Flow cytometry is a key part of the evaluation and workup to confirm that a patient has PNH. The PNH clone size by flow cytometry is relatively large in classical PNH, often 50% or more, and clone size correlates with thrombotic risk; thus, those with classical PNH often have a history of thrombosis at presentation. Additionally, the workup includes a bone marrow biopsy to ensure that there is no bone marrow failure, myelodysplastic syndrome, or aplastic anemia.
At this year's ASH meeting, abstracts relevant to the clinical presentation and natural history of PNH largely reflect what we have observed in our own practices. Going back decades, Kelly et al reported data from the United Kingdom on patients who were treated with intravenous anti-C5 monoclonal antibodies (abstract 2566). C5 inhibition acts downstream in the complement cascade, so agents in this class (eg, eculizumab and ravulizumab) are known as terminal complement inhibitors. These agents represent a major advance in the treatment of PNH and address the thrombotic risk nicely. Notably, however, a subset of patients on C5 inhibition in this analysis had ongoing hemolysis and clinically significant anemia. Researchers showed that, in the most recent 12 months on C5 inhibition, 27.6% of patients required transfusions, of which 76.4% needed 3 or more transfusions. Further, among the 474 patients who were treated with eculizumab, 16.2% required doses that were higher than the recommended dosing due to pharmacokinetic breakthrough hemolysis. Finally, Neisseria meningitidis septicemia has been reported in 10 patients, albeit over this very long period of observation. Taken together, these data suggest that, while C5 inhibitors are a significant advance in therapy, an important subgroup of patients on C5 inhibitors are being inadequately treated, and there are still unmet needs.
When you target C5, many erythrocytes will still have C3 fragments on their surface, leading to opsonization and extravascular hemolysis within the reticuloendothelial system. Pegcetacoplan and iptacopan are examples of newer drugs that target the complement pathway, and, because they act more proximally, they have the potential to address the extravascular hemolysis that is seen in many patients on C5 inhibitors.
Pegcetacoplan was approved by the US Food and Drug Administration for PNH in 2021. Here at ASH 2022, Patriquin and colleagues presented 48-week data from their ongoing extension study with pegcetacoplan evaluating adults with PNH who completed previous pegcetacoplan phase 1, 2, and 3 trials (abstract 1248). Their findings suggest that the normalization of hematologic parameters is achievable with pegcetacoplan treatment. Specifically, researchers reported robust improvements in hemoglobin, lactate dehydrogenase, and fatigue, as well as a reduced need for transfusions, in individuals with PNH on pegcetacoplan. Approximately 16% of the adverse events that were reported were determined by investigators to be related to pegcetacoplan, with the most common treatment-related adverse event being hemolysis, which was reported in 16.8% of patients in this analysis.
Iptacopan is a first-in-class oral selective complement factor B inhibitor. In a late-breaking abstract, Peffault de Latour et al reported primary efficacy and safety data for iptacopan from the 24-week, phase 3 APPLY-PNH study (abstract LBA-2). In this trial, adult patients with PNH and a mean hemoglobin of less than 10 g/dL who were stable on standard-of-care therapy (ie, eculizumab or ravulizumab) for 6 months or longer were randomized to receive iptacopan monotherapy or to continue their standard-of-care regimen for 24 weeks. Oral iptacopan treatment was associated with clinically meaningful hemoglobin increases in almost all patients, with 70% achieving a hemoglobin of 12 g/dL or higher via the resolution of extravascular hemolysis and maintenance of intravascular hemolysis control. Transfusion independence was also observed in almost all patients. This more proximal inhibitor actually takes care of C5, in addition to the problem of extravascular hemolysis. As a result, there is less hemolytic anemia reported among patients with PNH on iptacopan therapy, as reflected in this abstract.
Babushok DV. When does a PNH clone have clinical significance? Hematology Am Soc Hematol Educ Program. 2021;2021(1):143-152. doi:10.1182/hematology.2021000245
Elias NS, Riedl J, Stouten K, et al. Abdominal pain in combination with an unexplained hemolytic anemia are crucial signs to test for paroxysmal nocturnal hemoglobinuria: a case report. Clin Case Rep. 2019;7(1):175-179. doi:10.1002/ccr3.1771
Keeney M, Illingworth A, Sutherland DR. Paroxysmal nocturnal hemoglobinuria assessment by flow cytometric analysis. Clin Lab Med. 2017;37(4):855-867. doi:10.1016/j.cll.2017.07.007
Kelly R, Holt M, Vidler J, et al. Treatment outcomes of complement protein C5 inhibition in 509 patients with paroxysmal nocturnal hemoglobinuria in the United Kingdom [abstract 2566]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005;106(12):3699-3709. doi:10.1182/blood-2005-04-1717
Patriquin CJ, Bogdanovic A, Griffin M, et al. Long-term safety and efficacy of pegcetacoplan treatment in adults with paroxysmal nocturnal hemoglobinuria [abstract 1248]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
Peffault de Latour R, Roeth A, Kulasekararaj A, et al. Oral monotherapy with iptacopan, a proximal complement inhibitor of factor B, has superior efficacy to intravenous terminal complement inhibition with standard of care eculizumab or ravulizumab and favorable safety in patients with paroxysmal nocturnal hemoglobinuria and residual anemia: results from the randomized, active-comparator-controlled, open-label, multicenter, phase III APPLY-PNH study [abstract LBA-2]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
Risitano AM, Marotta S, Ricci P, et al. Anti-complement treatment for paroxysmal nocturnal hemoglobinuria: time for proximal complement inhibition? A position paper from the SAAWP of the EBMT. Front Immunol. 2019;10:1157. doi:10.3389/fimmu.2019.01157
Schrezenmeier H, Muus P, Socié G, et al. Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica. 2014;99(5):922-929. doi:10.3324/haematol.2013.093161
Schrezenmeier H, Röth A, Araten DJ, et al. Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry. Ann Hematol. 2020;99(7):1505-1514. doi:10.1007/s00277-020-04052-z
Wong RSM, Pullon HWH, Amine I, et al. Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria. Ann Hematol. 2022;101(9):1971-1986. doi:10.1007/s00277-022-04903-x
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