Extravascular Hemolysis and Residual Anemia in Paroxysmal Nocturnal Hemoglobinuria
Researchers at the 64th ASH Annual Meeting and Exposition presented data from several studies evaluating the treatment of paroxysmal nocturnal hemoglobinuria (PNH). Proximal pathway inhibition appears to address the problem of extravascular hemolysis in PNH.
Following these presentations, featured expert Carlos M. de Castro III, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr de Castro’s clinical perspectives on these findings are presented here.
Carlos M. de Castro III, MD
Professor of Medicine
“The observation that a significant percentage of patients who are taking C5 inhibitors may experience extravascular hemolysis and ongoing anemia has spurred the development of newer complement inhibitors that target proximal complement pathways.”
While C5 inhibitors address intravascular hemolysis and thrombosis in PNH, extravascular hemolysis is an additional hemolytic mechanism that may develop and become clinically significant in patients who are on anti-C5 therapy. When you block C5 with intravenous eculizumab or ravulizumab, you prevent the lysis of PNH erythrocytes by inhibiting the formation of the membrane attack complex. This is a distal, or terminal, step in the complement pathway. The proximal part of the complement pathway, which involves C3 and many other complement-regulating proteins, is still intact.
The site of complement pathway inhibition is relevant because the affected erythrocytes in PNH do not have an efficient means of removing C3 (or C3 fragments) from the cell surface. Normally, the glycosylphosphatidylinositol-anchored surface protein CD55 would affect the formation and the decay of the C3 convertase, thus disabling the upstream activation of the complement cascade; however, PIGA-mutated hematopoietic stem cells in PNH give rise to erythrocytes that lack CD55. Thus, in patients receiving anti-C5 therapy, the PNH erythrocytes develop a coating of C3 and its degradation products, especially C3d. These products, or fragments, serve as opsonins for receptors on immune cells, which sets the stage for extravascular hemolysis by macrophages within the reticuloendothelial system.
There is currently no way to predict which patients will exhibit extravascular hemolysis. The triggers and mechanisms that govern extravascular hemolysis are not completely understood. Consider, for instance, that only approximately 15% to 20% of people who are on C5 inhibitors have problems with extravascular hemolysis, whereas a much larger percentage have C3-coated erythrocytes.
The observation that a significant percentage of patients who are taking C5 inhibitors may experience extravascular hemolysis and ongoing anemia has spurred the development of newer complement inhibitors that target proximal complement pathways. We have had 1 such approval by the US Food and Drug Administration for the anti-C3 agent pegcetacoplan, which is delivered via subcutaneous infusion using an infusion pump.
Pegcetacoplan can be used in all adult patients with PNH, regardless of whether they were suboptimal responders to C5 blockers, and it appears to address the problem of extravascular hemolysis. We do see breakthrough intravascular hemolysis in patients receiving pegcetacoplan, however. At the ASH conference, Griffin and colleagues shared their work looking into potential interventions for the immediate treatment of such acute hemolytic episodes (abstract 1255). This type of investigation is important because we need to know how to optimally manage these events.
Many other novel proximal complement inhibitors are under consideration, including oral iptacopan and oral danicopan, which are probably the furthest along in their clinical development. Danicopan blocks factor D, while iptacopan blocks factor B.
In a late-breaking abstract at the ASH conference, Peffault de Latour presented the primary efficacy and safety data from the 24-week randomized treatment period of the phase 3 APPLY-PNH study (NCT04558918) with oral iptacopan in patients with PNH and residual anemia on intravenous anti‑C5 therapy (abstract LBA-2). Iptacopan met both primary end points in this study, showing superiority over the standard-of-care (SOC) therapies. A total of 51 of 60 patients who were treated with iptacopan increased their hemoglobin by 2 g/dL or more in the absence of red blood cell transfusions, and 42 of 60 patients who were treated with iptacopan achieved a hemoglobin of 12 g/dL or higher without transfusions. None of the 35 patients who received SOC therapies achieved these results. Red blood cell transfusion independence was observed in almost all patients who were treated with iptacopan (60/62), while only 14 of 35 patients avoided transfusions with SOC treatment. The side-effect profile was also favorable for iptacopan, with researchers reporting a low risk of infections.
These results truly speak for themselves. I think that it would be wonderful to have iptacopan available, partly because the oral formulation makes it very convenient for patients to take and partly because these results look very good right now. We hope that it will be approved in the near future. The ongoing APPOINT-PNH trial (NCT04820530) is exploring the use of iptacopan in treatment-naive adult patients with PNH.
Returning to the problem of extravascular hemolysis and persisting anemia, I think that the issue of C3 coating the PNH erythrocytes is likely one of the biggest reasons for inadequate hemoglobin responses in patients who are on C5 inhibitor therapy. Of course, we always investigate other potential causes of anemia, and this includes the evaluation for bone marrow failure and other conditions. We are also mindful that another possible reason for anemia and an inadequate hemoglobin response to C5 inhibitors may be related to dosing. A patient on eculizumab may need to have their dose increased, while a patient on ravulizumab might need to have their schedule modified to receive it more frequently (eg, every 12 days). However, my sense is that extravascular hemolysis is the biggest reason for a poor hemoglobin response and persisting anemia in this setting.
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ClinicalTrials.gov. Study of efficacy and safety of twice daily oral iptacopan (LNP023) in adult PNH patients who are naive to complement inhibitor therapy (APPOINT-PNH). Updated November 25, 2022. Accessed December 19, 2022. https://clinicaltrials.gov/ct2/show/NCT04820530
ClinicalTrials.gov. Study of efficacy and safety of twice daily oral LNP023 in adult PNH patients with residual anemia despite anti-C5 antibody treatment (APPLY-PNH). Updated November 25, 2022. Accessed December 19, 2022. https://clinicaltrials.gov/ct2/show/NCT04558918
Griffin M, Kelly R, Deeren D, et al. Intensive pegcetacoplan dosing in the management of acute hemolysis as part of the 307 open-label extension study [abstract 1255]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
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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.
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