Advances in Treating PNH (Paroxysmal Nocturnal Hemoglobinuria) with Dr. Allyson Pishko - 2022 | Aplastic Anemia and MDS International Foundation (AAMDSIF) Return to top.

Advances in Treating PNH (Paroxysmal Nocturnal Hemoglobinuria) with Dr. Allyson Pishko - 2022

Dr. Allyson Pishko shares the latest advances in the treatment of PNH, or Paroxysmal Nocturnal Hemoglobinuria.


Leigh Clark:    00:00    Hi, everyone. This is Podcast for Patients with the Aplastic Anemia and MDS International Foundation. I'm Leigh Clark, director of patient programs, and I'll be moderating the podcast today. Our podcast series is brought to you, and I'd like to give special thanks to our corporate sponsors and our patients' families and caregivers for supporting the podcast series.
Leigh Clark:    00:26    Today, we're talking about advances in treating PNH with Dr. Allyson Pishko, who is an assistant professor in hematology oncology at the University of Pennsylvania. Welcome, Dr. Pishko.
Allyson Pishko,...:    00:41    Thank you. It's so great to be here.
Leigh Clark:    00:46    Thank you for joining us. Let's start out. What is PNH?
Allyson Pishko,...:    00:51    So PNH is a rare disorder, with two hallmark features being the breakdown of red cells, or lysis, and tendency to clot in atypical places. The name paroxysmal nocturnal hemoglobinuria comes from the fact that the onset of symptoms are paroxysmal, or sudden; nocturnal, as the symptoms often increase at night, and hemoglobinuria, which is the presence of free hemoglobin, which is usually found inside intact red cells, being present in the urine, leading to a dark color.
Allyson Pishko,...:    01:29    In PNH, what causes the red cells to lyse is really a loss of two markers on the red cell surface, um, that's CD55 and CD59, and these markers on the red cell surface usually are there to signal the body's immune system not to attack the cell. When these markers are not on the red cell surface, the immune system is missing this do not attack signal, and thus will destroy the red cells, specifically by comp-, by complement depositing on the red cell membrane.
Allyson Pishko,...:    02:03    What causes this loss of this important cell surface markers are acquired mutations, which occur in the stem cells in the bone marrow where the red cells are produced and mature. Uh, we generally say acquired as it's not something that's inherited from your mother or father, but rather develops after birth. This mutation in the stem cells is specifically in the PIGA gene, and it's unclear why some patients develop this mutation. Um, we don't have clear risk factors for developing it, although we do know that patients with other bone marrow disorders, conditions like aplastic anemia, are more likely to have this and to have PNH.
Leigh Clark:    02:47    Thank you so much. Uh, what are the current treatments available for PNH?
Allyson Pishko,...:    02:53    Yeah, so fortunately, we have expanded, uh, treatments for PNH. Um, like we talked about, PNH is the loss of these cell surface markers on the red cells, which leads to too much of complement activation by the immune system. So the approach to treatment is really turning off this complement system.
Allyson Pishko,...:    03:16    In the complement system, it's a cascade where one thing activates another, activates another to form this attack complex which ultimately can lead to lysis of what's supposed to lyse, which is bacteria. But in this case, it can lead to lysis, or breakdown, of the red cell. So complement inhibitors were developed to treat this and other disorders which involve overactivation of the complement system.
Allyson Pishko,...:    03:45    Eculizumab was the first complement inhibitor FDA approved in this space and inhibits the complement protein C5. This medication is intravenous and dosed every two weeks. The second complement inhibitor to be developed was ravulizumab, which has a similar mechanism which also inhibits C5, and this is dosed every eight weeks.
Allyson Pishko,...:    04:11    And now, we have the newest complement inhibitor on, on the block, which is pegcetacoplan, which is a subcutaneously-infused medication via an infusion pump. This medication also targets the complement system, but a little bit higher up, or proximal, in the complement cascade. It inhibits something called C3. Thus, this medication has been shown to inhibit the red cell lysis that not only occurs in the blood vessel, which we call intravascular, but also extravascular hemolysis, that red cell breakdown that can occur in the liver and the spleen.
Allyson Pishko,...:    04:51    Additionally, patients may not just need complement inhibitors, because another component of this disorder can be thrombosis, or clotting. Uh, the clotting can occur in the leg, where we call it deep vein thrombosis. It can be in the abdomen or near the liver like a portal vein thrombosis. And those patients with, with clots may also need anticoagulation, or blood thinners. This is, uh, typically been with, uh, either warfarin or enoxaparin, but newer medications, um, called the direct oral anticoagulants like apixaban, uh, rivaroxaban are now also being used for the clotting component of this disorder.
Leigh Clark:    05:38    Thank you so much for that answer. What should patients consider when selecting a treatment for PNH?
Allyson Pishko,...:    05:46    A, a great question. Um, first, I, I just wanna start off by mentioning that the good news is that medications for PNH are generally very effective at, at halting the, the red cell breakdown and are, are pretty well tolerated. Um, the medications that we generally used in the, the first line are the eculizumab or the ravulizumab, which were those, uh, C5 inhibitors. The major risk of these medications that patients and providers need to be aware of is this increased risk of meningitis, 'cause you really need your complement system to fight off, uh, that type of infection. So it's very important that patients are vaccinated against meningitis before or, or after, shortly after starting therapy and really keep up with these, with these vaccinations.
Allyson Pishko,...:    06:39    As far as, um, the choice between, the two medications, um, the ravulizumab does have a longer half-life, so it can be dosed every eight weeks versus every two weeks for the eculizumab. And so that is a, a major advantage for some, for some patients,  it is IV, so they don't have to infuse it as, as frequently. So that may affect the decision of which medication to use.
Allyson Pishko,...:    07:09    As far as the newer medication, the one that is subcutaneous, or, you know, given under the skin, that's pegcetacoplan, um, that may be advantageous, advantageous to patients who are still having significant red cell breakdown despite ravulizumab or eculizumab. So patients may be switched to that medication if we're still seeing that they're having a lot of red cell turnover, perhaps still needing, um, red blood cell transfusions, because that medication not only targets the intravascular hemolysis, or that red cell breakdown that's happening in the blood vessel, but it also targets the, the hemolysis that is happening in the liver and the spleen. So that is generally some- something, at this time, that patients would be switched to if they weren't having, uh, as good of a response to the... those other two agents.
Leigh Clark:    08:06    What's on the horizon for treating PNH?
Allyson Pishko,...:    08:10    Another really... a really good question. So I'm happy to say that there are, um, lots of, different agents in development. Um, there are oral, um, inhibitors of complement that are under investigation. So even though, um, we can decrease the frequency of infusion, um, with the ravulizumab, it can be burdensome to, to have to infuse, um, this medication via, via IV. So an oral medication, I think, would be a, a big, uh, advance, uh, potentially, and there are some under development.
Allyson Pishko,...:    08:45    There are also other approaches to blocking, um, complement activation, um, ongoing with some other monoclonal antibodies, which means, um, things that can kind of block or inhibit the complement from depositing on, on the red cells. And so there, there is, more to be done in PNH and, and trials, uh, ongoing, so hopefully the, the list of medications that patients are offered in the future will be much longer. We're also learning more about how, uh, best to manage patients, um, which therapies should be used, you know, first and second line, and learning about which anticoagulation strategy is best as well.
Leigh Clark:    09:34    Thank you. And last question, Dr. Pishko. You mentioned about clinical trials. If somebody was interested in looking for clinical trials, where would someone find, uh, listings for clinical trials?
Allyson Pishko,...:    09:48    Well, um, they can always, uh, speak to, to their provider. Uh, they also can go on, um, If you type in, paroxysmal nocturnal hemoglobinuria, uh, it should, it should list any ongoing trials if you click those that are, are currently enrolling.
Allyson Pishko,...:    10:08    And Leigh, I should've asked you. Is there anything on the, um, aplastic anemia website about clinical trials?
Leigh Clark:    10:15    Absolutely.
Leigh Clark:    12:53    Thanks, Dr. Pishko. How would someone go about finding a clinical trial for PNH?
Allyson Pishko,...:    12:59    That's a really important question, and we always encourage our patients to enroll in clinical trials so that we can improve therapies for patients with PNH. I suggest, you know, they start off by talking to, to their clinician about, uh, trials they may be aware of, and then they can also search the website. If  you click on Clinical Trials, you can actually type in some of your criteria that, um, you, that you have and look and find out watch... which clinical trials you would be eligible for. Another resource, which is a, which i- is available to patients, the website, which also can be, um, searched directly by typing in, PNH.
Leigh Clark:    13:56    Well, thank you so much, Dr. Pishko, for sharing your time and your expertise with all of us today. And you can find out more about PNH and other bone marrow failure diseases on our website at You can also follow us on Facebook, Instagram and Twitter, or give us a call at our helpline, which is 800-747-2820. This concludes our podcast.