<p>As paroxysmal nocturnal hemoglobinuria (PNH) is a chronic condition that is increasingly managed through the use of C5 inhibitors, treatment focus is shifting toward improving patient quality of life (QOL), preventing breakthrough intravascular hemolysis, and reducing the risk of extravascular hemolysis. Several combination therapies have been US Food and Drug Administration (FDA) approved for persistent anemia, and work is ongoing to evaluate other combinations.</p>

PNH is a chronic disease, and many patients can have a more-or-less normal life expectancy. When that happens, priorities can change to include a focus on QOL. Not every patient who receives a C5 inhibitor has a normalization of hemoglobin. Many patients continue to have transfusion requirements and fatigue. Although these disease manifestations are not perfectly correlated, there is a relationship between them, and patients typically feel better with a higher hemoglobin level. The expectation is that if we improve the hemoglobin level, we help minimize or eliminate the need for transfusions and improve QOL.

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If a patient is on a C5 inhibitor and continues to have fatigue and significant anemia that requires continued transfusion in the absence of significant bone marrow failure, I think that one needs to try to understand why this is happening. Typically, I make sure that I am giving patients enough medication. If I find evidence of extravascular hemolysis, and 20% to 25% of patients have that, then I have a conversation with the patient, asking them, “Should we add a drug? Should we switch to something different?” Someone with persistent anemia despite adequate complement inhibition with a C5 inhibitor is the perfect patient with whom to discuss add-on therapy or a switch, depending on their wishes.

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One of the fears with PNH is that a breakthrough hemolytic event could result in a thrombotic event. At least in theory, combining a proximal and terminal complement inhibitor could help minimize the risk of breakthrough hemolytic events.

To date, we do not have data comparing the efficacy of the available proximal complement inhibitors such as pegcetacoplan, iptacopan, or danicopan in combination with ravulizumab or eculizumab. Therefore, practitioners are left to make decisions about the best next therapeutic option for treatment-experienced patients with PNH who are anemic or transfusion dependent despite C5 inhibitor therapy. I think that the next frontier in PNH treatment may be related to identifying a biological marker that would enhance our ability to understand which of the agents mentioned is likely to produce the best response in such patients.

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A particularly important consideration when it comes to choosing a therapy is how it may affect a patient’s QOL. People with PNH are living a lot longer than they previously did, and we want to make sure that we are utilizing treatments that enhance their QOL rather than worsen it.

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An area in which care for individuals with PNH can be improved upon is the recognition of extravascular hemolysis as an etiology for anemia in C5 inhibitor–treated patients. Proving that a patient has extravascular hemolysis can be achieved by using flow cytometry to identify C3 fragments on red blood cells, as was done in clinical trials, but this technology is more of a research tool and is not available to physicians in clinical practice. So, for a clinician to be able to say that their patient has extravascular hemolysis, they need to become familiar with how to make such a diagnosis. As such, a patient with extravascular hemolysis is likely going to have indirect hyperbilirubinemia and an elevated reticulocyte count with a normal or marginally elevated lactate dehydrogenase.

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In the setting of C5 inhibitor treatment, some patients develop extravascular hemolysis. This could lead to anemia and transfusion dependency, so it is important to identify and control this process. Technically speaking, adding a proximal complement inhibitor to a C5 inhibitor makes a lot of sense because it could both abrogate intravascular hemolysis and address the “iatrogenic” extravascular hemolysis related to the use of C5 inhibitors.

We have a data gap in terms of not really knowing which type of therapy switch or add-on therapy to select for each patient. At this point, it is a shared decision-making process with patients. Currently, the only FDA-approved combination therapy for PNH is danicopan added on to ravulizumab or eculizumab, based on the results of the ALPHA trial. Beyond that, other potential combination strategies, such as combining C3 and C5 inhibitors, have not been studied in the clinical trial setting.

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Theoretically, we think that the degree of breakthrough hemolysis may be less pronounced in patients who are receiving dual therapy with a C5 inhibitor and danicopan, and low rates of breakthrough hemolysis were seen in the long-term data from the ALPHA study evaluating this regimen. We continue to have concerns about the potential severity of breakthrough intravascular hemolytic events that may occur with iptacopan or pegcetacoplan monotherapy, and that is something that we have to continue to follow through evolving data. In addition to the risk of breakthrough intravascular hemolytic events, these patients have a larger PNH clone size, which, in theory, could also contribute to a more significant breakthrough event.