Melanie Cole, MS (Host): [00:00:00] Welcome to the podcast series from the specialists at Penn Medicine. I’m Melanie Cole. And today, we’re highlighting the Sickle Cell Program at Penn Medicine. Joining me is Dr. Nadia Dawn Ali, she’s the Director of the Sickle Cell Program at Penn Medicine; and Dr. Scott Peslak, he’s the Gene Therapy Lead and Adult Thalassemia Program Director at Penn Medicine.

Doctors, thank you so much for joining us today. Dr. Ali, I’d like to start with you. Speak briefly about the causes of sickle cell disease, who it affects. It’s not just a children’s disease, is it? Tell us a little bit about it.

Nadia Ali, MD: Absolutely. And first off, thank you so much for inviting us to be here today and to speak to our colleagues. So, sickle cell anemia or sickle cell disease is a congenital mutation in the hemoglobin gene and alters the production of adult hemoglobin in all individuals. So, what actually happens is that the mutation leads to hemoglobin forming rigid polymers in deoxygenated red blood cells. I like to say like the red blood cells are like the bags that carry oxygen throughout our body. And the hemoglobin is really important in delivering oxygen to our muscles and organs and allowing us to function.

In people who have sickle cell anemia or sickle cell disease, what ends up happening is that, when the red blood cell goes through the body and goes into areas where oxygen content is lower, the hemoglobin that is mutated ends up forming these long lines that make the red blood cells change in shape so they get stuck in places in our body. They often do not survive very long, and you end up with chronic breaking apart of the red blood cells. This leads to the overall hemoglobin or blood cell level being lower. And then, it also leads to periodic pain episodes and over time affects all parts of the body. So, it’s a congenital disorder that occurs in millions of people, and it causes lots and lots of morbidity and mortality.

Melanie Cole, MS: Well, thank you for that. So, Dr. Ali, sticking with you for just a second, how are the sickle cell programs at Penn Medicine reaching their respective patient populations for information and treatment? Tell us a little bit about the programs and the unique advantages that they hold.

Nadia Ali, MD: Well, I’m specifically working with the adult program here at Penn Medicine. And we have multiple ways that we reach out to individuals living with sickle cell disease as well as specific programs for our patients. For example, we have a social worker in our program who meets with all of our patients and also has individual sessions for peer support where patients can come together, allies of patients can come to learn more about sickle cell and just living with the disease and speak with one another.

I’ll also ask Dr. Peslak, who’s been with Penn Medicine longer than me, and he has participated in many of these programs.

Scott Peslak, MD: Thank you, Dr. Ali, and it’s a pleasure to be here as well, and really excited to be able to talk to the entire physician community about our sickle cell program here at Penn.

I have been here at Penn for about 10 years or so. I study sickle cell disease in the lab as well as thalassemia. But I’ve been really involved in trying to promote and educate our patients and connect them with the community. I will say our nursing team and our sickle cell coordinator team is really fantastic at the transitions from the pediatric to the adult phases of life. We have an excellent embedded psychologist in our program that provides much of the mental health coordination and care for patients, which is a major burden of health in many of our sickle cell patients. We have an excellent research team and we have several different research registries that we’re trying to understand how sickle cell disease affects patients throughout their lifespan, as well as developing new interventional and observational trials for sickle cell patients across the lifespan.

Melanie Cole, MS: Dr. Ali, tell us about the approved drug therapies for the treatment of sickle cell disease and describe how those medications work and when they are indicated.

Nadia Ali, MD: Unfortunately, we don’t have very many drugs in our toolbox. Currently, there are only three drug-modifying therapies that are FDA approved. The oldest and most well studied is hydroxyurea. So, hydroxyurea is a chemotherapy drug that was initially used for acute leukemias. But it has been studied very thoroughly and found to alter the production of hemoglobin in the bone marrow. And we can use this to our advantage in the induction of fetal hemoglobin, which is a type of hemoglobin that is made before birth and really in the first six months of life. So after the first six months of life, we start to make adult hemoglobin, and that’s where the sickle mutation causes problems, and you get sickled hemoglobin rather than adult hemoglobin.

So, hydroxyurea leads to the persistence and production of fetal hemoglobin. We now have evidence to show that it is helpful to give it as young as nine months of age.For patients who have traditional sickle cell anemia, this drug can help increase levels of fetal hemoglobin, which can help increase blood levels overall, it can help decrease ongoing hemolysis, and it’s really [00:06:00] been the longest studied medication that we have. It was originally approved back in 1995 after the multicenter MSH trial came out in New England Journal of Medicine. And we have a lot of good follow up data, particularly in adults. It helps with longevity and decrease of morbidity and mortality. And most importantly, it decreases the amount of vaso-occlusive events, including acute chest syndrome. So, hydroxyurea is really our number one tool that we have, and it has been well approved and well studied in children and adults.

There are two other drugs that I’ll briefly mention. The two others are L-glutamine and crizanlizumab. And so, both of those are a little newer, but we have pretty good data, but L-glutamine was actually approved first in [00:07:00] 2017. L-Glutamine is an amino acid and it helps decrease oxidative stress within the red blood cell. So, part of the pathology in sickle cell disease is that there is susceptibility to oxidative stresses. So, L-glutamine works by decreasing and fighting back against that oxidative stress that is ongoing in the red blood cells. But this medication’s a little more difficult to take. It’s a powder twice a day, but it can be mixed with a lot of things. And it has shown in original studies to decrease pain and how frequently there are pain episodes. This is something that is another tool that we can reach to, to see if it will help. And in my experience, it has been very beneficial.

The third one, which is completely different, is crizanlizumab, criz for short. And it is an IV infusion [00:08:00] and it targets P-selectin. So, it is not specific to the red blood cells. Rather, it works on decreasing stickiness inside the vessels. And this one is a little more mixed and nuanced. It is an infusion, and patients have to come to the infusion center. But in that sense, some people actually do prefer it because it’s not an everyday medication, but it is an infusion initially given once every two weeks, just for two doses and then monthly. I have found it to be very beneficial in some patients.

Scott Peslak, MD: And if I could just add two other points, one with hydroxyurea, this is a medication that has been shown to be safe really all through childhood as well as adulthood. One of the big questions was: do we use this only in patients who have severe pain? And we’ve found through several studies, including something called the Baby Hug Study, it was published in 2011, that hydroxyurea is safe and effective in children starting at the age of two, all throughout their lifespan. So really, [00:09:00] I think with this drug, we’re going to change a natural history of sickle cell disease in a very positive way. And we’re going to see patients with much fewer complications as they come into their adult life.

The other point I will say is that many patients who have certain kinds of complications, including a history of stroke, something called acute chest syndrome, which is an inflammatory disease of the lungs, or increased pressures in the heart, pulmonary hypertension, sometimes we start regular red blood cell transfusions, something called exchange transfusions in which we take the sickle cell blood out and transfuse in non-sickle cell blood. And this can really help to reduce the risk of recurrent stroke or other major complications or even severe pain longer term.

But I think the important point to make with all this is this can be very complex. And talking to a comprehensive program like the one here at HUP and Penn Medicine, it is really critical. You know, we have five physicians and we’re all excellent and a really excellent nurse practitioner as part of our practice, in addition to the entire team that we mentioned earlier, that [00:10:00] helps to understand which treatments are right for which patients, and being able to offer either established therapies, more advanced therapies and trials, or even gene therapy, which I know we’ll get to in just a few minutes.

Melanie Cole, MS: Thank you both of you, and such a comprehensive program with a multidisciplinary approach. And Dr. Peslak, your work in the laboratory and the clinic is focused on the development of new therapies in sickle cell disease. Give us a little update on new and ongoing developments in your lab and the sickle cell field in general, because I think it’s a pretty exciting time in your field.

Scott Peslak, MD: Absolutely. My laboratory here at Penn focuses on studying this fetal form of hemoglobin, as Dr. Ali mentioned before, the one that is changed and increased in the setting of hydroxyurea. We know that this works , many patients. But sometimes even with the maximal dose of Hydrea in many patients, we don’t achieve the effects that we want, which is really reducing as best we can and minimizing the amount of pain episodes that patients experience, minimizing [00:11:00] their time in the hospital, maximizing their productivity and, ensuring they live productive lives.

And so, to do that, we are pursuing many different therapies involving a phosphatase, which is a chemical that helps regulate the activity of certain cells, and we’re trying to understand the mechanism of this. This is something called PPP6C. The other is looking at repurposing other medications that are used for other blood disorders, something called IMiDs to try to understand how this works. We have a variety of high dimensional techniques, including looking at something called proteomics, all the proteins that are changed, all the different RNA that are changed and the messaging that’s changed to really be able to not only use these in a safe way, but also potentially to be able to develop new and better drugs through engineering in our lab and many others through the field and in collaboration with our industry partners to be able to move this forward.

Beyond fetal hemoglobin, which is what I focus on in my lab, many other researchers throughout the country are trying to understand other ways to change the [00:12:00] effectiveness of red blood cells in a way that these are more durable, less likely to break down. There’s a newer therapy that’s being studied, something called mitapivat, which helps increase energy levels in red blood cells and helps reduce the risk of these cells of sickling. That’s being studied in a large phase III trial that we have participated in here at Penn. And there’s many others that are trying to understand how do we change the individual risk of cells to reduce the amount of sickling and to improve the health of these red blood cells, again, to really allow our patients to have the best quality of life possible. ’

One of the things that we as a field are trying to figure out is how do we measure this, how do we understand what is best for patients to be able to design clinical trials that are effective, and then we can achieve appropriate endpoints. That’s something we’re really working on as a field to understand that better. But one of the things that we know is the most effective for achieving better outcomes in patients is fetal hemoglobin. And that’s why I study it in my lab. And we’re excited to be able to present much of this work at next year’s American Society of Hematology meeting as well as the work that’s been going on both [00:13:00] at the University of Pennsylvania and the Children’s Hospital of Philadelphia, where I collaborate with many other physicians including Dr. Gerd Blobel and Dr. Eugene Khandros, as well as Dr. Osheiza Abdulmalik and Stefano Rivella, all phenomenal scientists that are working on sickle cell disease and thalassemia in a really, I think, comprehensive and unique and creative way.

Melanie Cole, MS: That’s fascinating. And Dr. Peslak, along those lines, over the past several years, two new gene therapies have been approved for the treatment of sickle cell in adults. Describe a little bit about the clinical trials and research that led to these therapies and the link between this research and the sickle cell programs at the University of Pennsylvania.

Scott Peslak, MD: Absolutely. So, there has been a 25-year journey or more to try to bring gene therapy-based approaches to patients with sickle cell disease. These approaches essentially require us to what’s called mobilize or move stem cells out of the bone marrow into the blood, using a specific set of drugs. And this case a [00:14:00] sickle cell disease, we use something called plerixafor or Mozobil to be able to get these cells out of the bone marrow and to collect them using an apheresis procedure. We then can partner with one of several different industry partners to change these stem cells in a way that provides benefit to patients.

So, the two approved stem cell therapies are something called lovo‑cel, which is a gene addition therapy in which we add instructions to make a non-sickling hemoglobin to hematopoietic stem cells or something called exa-cel, which is a gene editing approach in which we change and decrease the amount of this repressor of fetal hemoglobin, something called BCL11A. BCL11A, when it’s there, prevents fetal hemoglobin from being expressed. If we take that break off, we can increase the levels of fetal hemoglobin. So either of these, either increasing fetal hemoglobin or expressing a non-sickling hemoglobin can significantly reduce in 90-95% of patients that receive this therapy the risk of acute pain episodes. And so, they’re [00:15:00] equivalent in terms of their effectiveness. It is a very long process. Once we collect these cells, they have to be sent to the company. It takes about three to four months to manufacture in addition to the five to six months before that when we had to collect these cells. And then, patients have to be admitted to the hospital for what is essentially an autologous transplant. We’re giving them chemotherapy and infusing in these edited or gene addition cells, and allowing them to engraft and make new non-sickling hemoglobin.

I think it’s transformative therapy. So, we’re really excited about offering this at Penn. We are discussing our first sickle cell patient right now who will be collecting stem cells and doing gene therapy in 2026. And we’re excited about offering this broadly to the community. But the caveats to this is that it is a very long process, we need to make sure patients are ready from a social perspective, from a psychological perspective, from a medical perspective, make sure their iron levels are good, make sure they understand the process.

It does require fertility preservation as patients getting busulfan chemotherapy need to preserve their fertility, either their eggs or their sperm [00:16:00] prior to the chemotherapy being administered. And there is a small but significant risk of cancers related to busulfan. And we know that the risk is higher in sickle cell patients. And this is just recent data at ASH that suggests that the risk of cancer in general is higher in sickle cell patients. So, it’s further augmented by these therapies. We’re trying to reduce that by getting better ways to condition the bone marrow to remove the stem cells that make sickled hemoglobin. And eventually, we’re going to have the approach, we call in vivo gene therapy, where we can essentially give an infusion with the instructions to change the stem cell to make non-sickling hemoglobin without the need for mobilization and chemotherapy and everything else. But we are a few years away from that. We’re excited for that as a field. But again, I think it’s early days. It’s a great option for a subset of patients. But it is one in which requires a significant discussion and comprehensive evaluation for patients that might be interested in these cellular therapies.

Melanie Cole, MS: Do you have some final thoughts on how someone would contact the sickle cell program at Penn Medicine?

Scott Peslak, MD: It’s 215-615-6555, is our main [00:17:00] number. So, that is the contact number for anybody that is interested in referral to the sickle cell program, either for a one-time consult visit, for a comprehensive visit, for advanced therapy discussion.

Nadia Ali, MD: If you call the clinic line, that will be redirected to our nurse navigator who will assess all the information given, give the person, patient, referring provider, anyone a call back to clarify.

Melanie Cole, MS: Thank you both so much for joining us today and telling us about such a comprehensive approach at Penn Medicine and for sharing your expertise. Thank you again for joining us. And to refer your patient to Dr. Ali or Dr. Peslak at Penn Medicine, please call our 24/7 provider-only line at 877-937-PENN, or you could submit your referral via our secure online referral form by visiting our website at pennmedicine.org/refer. That concludes this episode from the specialists at Penn Medicine. I’m Melanie [00:18:00] Cole.