As outcomes continue to improve for patients with paroxysmal nocturnal hemoglobinuria (PNH), the focus of clinical management has expanded beyond controlling hemolysis to addressing potential treatment-related complications, including preventing infection, monitoring for complement-activating events, and managing treatment interruptions.

We have a lot to think about as we watch these patients and monitor them closely in clinic. The first thing we always do is make sure our patients with PNH are vaccinated against encapsulated organisms, which is a requirement for all therapies that are currently available to our patients. There are US Food and Drug Administration Risk Evaluation and Mitigation Strategy (FDA REMS) programs that strictly monitor this, which is how we also get reminders that these individuals are due for their vaccines. Although vaccines may occasionally trigger hemolytic exacerbations in some patients, resulting in transient declines in hemoglobin, I tell my patients, “While this is a possibility, I really need you vaccinated, and I will watch you very closely postvaccination. We need these vaccinations completed to keep you safe and to be able to continue therapy.” I definitely hear my patients when they express these concerns, but I strongly encourage them to receive their vaccines.

Recognizing complement-activating events such as an upcoming surgery or procedure, a pregnancy, or an unexpected infection is important because these events warrant closer monitoring and patient counseling. Other aspects to consider include things that we are still learning about, such as iron overload, which is a possible complication of long-term C5 inhibition with ongoing C3b deposition.

Another issue that can come up is travel. My patients often ask me something like, “What do I do about my ravulizumab while I am on my trip this summer?” And I usually ask about their specific travel dates and when their medication is due. If it is due during the time of their travel, I will often give it early, prior to their travel, rather than delay it. If they are taking an oral medication, my biggest fear is that they will forget their oral factor B inhibitor at home or the suitcase with the medication will get lost. These would be very difficult scenarios to manage and could result in patients having breakthrough hemolysis. So, I usually ask them where they are going and determine whether there is a physician experienced in managing PNH nearby in case one is needed.

One potential complication of PNH that we need to monitor for is breakthrough hemolytic events that happen spontaneously as a result of triggering events or a patient not taking their medication. Fortunately, I see very few breakthrough events each year. So, the good news is that breakthrough events are fairly uncommon, as long as patients are taking their medication correctly. The patients I am most worried about are those who have bone marrow failure or other hematologic disorders, in whom it is not just the hemolysis that impacts their outcomes. You have to separate typical patients from those for whom this is a component of a larger process.

The other group that I monitor for potential complications is women of childbearing age who become pregnant. The key question is: What drugs do you use during pregnancy? I think that eculizumab or ravulizumab can be used in this situation. Oral agents are still of uncertain teratogenicity and would likely be avoided. I have patients who are on oral agents right now who may decide that they want to have a child. We will end up switching them to eculizumab or ravulizumab as soon as they become pregnant.

I think one of the challenges is that a lot of patients with PNH are underdiagnosed, and those who live in underserved medical areas often have trouble accessing pills or infusions for treatment. We have a lot of patients who are put on steroids who actually have PNH. I think that the diagnosis, although easy to make with the appropriate testing, is often not considered until the disease becomes very advanced. As a result, many patients may spend months or even years before a PNH diagnosis is appropriately made.

Another problem community hematologists and oncologists may face is the lack of readily available backup resources to treat a patient with PNH who is receiving an oral agent. That can become a drawback; in some situations, you may want to keep the patient on an intravenous agent, just to provide more latitude than that provided by the oral agents.

I have to say that the drugs used for the treatment of PNH are overall very safe. Severe infectious complications are actually quite rare, in my experience. I cannot remember any patients in recent years having serious infectious complications. Except for during the first couple of weeks after starting therapy and vaccinating the patient, I do not keep them on indefinite prophylactic antibiotics.

I also want to point out that many of these trials in PNH have international participation, so some of the trial guidelines and requirements regarding vaccinations and antibiotics may vary by region. I think that this is important to keep in mind when interpreting some of the recommendations.

Another challenge is that there are reports of PNH occurring without hemolysis. Sometimes it is just neutropenia or thrombocytopenia, and it is not affecting the red blood cells at all. These cases are obviously very difficult to diagnose—or even to suspect—because we do not have the equivalent of a haptoglobin test for neutropenia, neutrophil destruction, or platelet destruction. We also do not have reticulocyte counts or other markers that are as helpful in identifying these situations. So, it can be particularly challenging to recognize and diagnose PNH in these patients.

For somebody who is already on an anticoagulant for prior clots and is then later diagnosed with PNH, the other challenge is deciding whether we should stop anticoagulation after a certain number of months of complement suppression. I think that, in theory, perhaps after 6 or 12 months of coverage with anticomplement therapy and if the clot was not recent, it is probably safe to try to get patients off anticoagulation.