Conference Coverage

Update in the Management of Sickle Cell Disease

In this episode, Nirmish Shah, MD, speaks about updates in the management of sickle cell disease (SCD), including the clinical utility, adverse effects, and appropriate monitoring of crizanlizumab, voxelotor, and L-glutamine for pediatric patients with SCD. Dr Shah also discusses the appropriate adjuvant agents for 3 pediatric patients in various clinical scenarios and reviews preliminary data from ongoing clinical trials in SCD.

Nirmish Shah, MD, is the director of the sickle cell transition program and the director of clinical research in benign hematology at Duke University School of Medicine in Durham, North Carolina.

For more information about ASPHO 2022, visit



Jessica Bard: Hello everyone and welcome to another installment of Podcast 360, your go-to resource for medical news and clinical updates. I'm your moderator, Jessica Bard, with Consultant360 Specialty Network. Sickle cell disease affects about 100,000 Americans, according to the Centers for Disease Control and Prevention. Dr. Nirmish Shah is here to speak with us today about his session at ASPO 2022, Update on Medical Management of Sickle Cell Disease. Dr. Shah is the Director of the Sickle Cell Transition Program and the Director of Clinical Research in Benign Hematology at Duke University School of Medicine in Durham, North Carolina. Thank you for joining us today, Dr. Shah. Can you please provide us with an overview of your session?

Dr Nirmish Shah: I think one of the nice things to see is that there is recognition that sickle cell disease has a lot of research going on and now, over the last couple years, we actually have a few new medications that are now approved. So the session was really focused on trying to understand how to now fit these new medications into our treatment paradigm. How do I figure out which patient should get which medication? And so, in addition to our standard of care hydroxyurea medication that's been around for a while, we now have these three new therapies, L-glutamine, voxelotor, and crizanlizumab as additional therapies. So really the objectives of this discussion was to lay out some cases of patients that we may see in our clinics, and then discuss each of those medications separately to look at, what is it that got the medications approved? What were the study and the data? What is the rationale behind it? And then finally, what are some treatment considerations?

Jessica Bard: Can you discuss the clinical utility side effects and appropriate monitoring of crizanlizumab, voxelotor, and L-glutamine for pediatric patients with sickle cell disease?

Dr Nirmish Shah: Yeah, sure. This is a big question because we really want to maybe take each of these medicines separately and kind of discuss each one in detail. So I'll start with one that was approved first, back in 2017, that's L-glutamine. L-glutamine is an antioxidant. It has the rationale behind the fact that patients with sickle cell disease have increased in oxidative damage within the sickle cells. That oxidative damage spills out into the bloodstream and can cause damage elsewhere as well. What was found is is that L-glutamine can actually have this antioxidant effect, which not only then decreases the oxidative damage and the oxidative stress, but then through the study that actually got it approved, showed that it improved pain. It actually improved pain from a median of four to three in a year, and it actually also decreased the rates of acute chest syndrome.

So for patients that we look at to try and discuss L-glutamine, we're really looking to patients who either are on hydroxyurea or not, again, hydroxyurea is our first line therapy, but they're having pain or they have a history of acute chest. And so it is a great conversation to have with patients because it's not really a medication per se so a lot of patients sometimes consider it as more naturopathic. It is an amino acid. And I think that's a great discussion to have with patients. The trade off is that there aren't major side effects. There are some GI side effects, but the issue that most patients have is it's twice a day. It's a powder packet they have to take twice a day. And so if compliance is great and the patient's a rockstar at taking their medications, it's a wonderful medication to add in that sense. Those are some of the considerations and pros and cons for L-glutamine.

The next medication to discuss would be the next one that was approved, what we'll start with is crizanlizumab. Crizanlizumab is an IV infusion to try and prevent pain crisis. It is at its essence a monoclonal antibody that's specifically focused at P-selectin. And as a reminder, P-selectin is an adhesion protein on the surface of cells, on the surface of sickle cells, on the damaged endothelium, on platelets, and the sticky protein then causes things to stick. So when things are stuck, blood doesn't flow, doesn't go where it needs to go and that can cause problems. And notably, we usually give the example, if blood doesn't get to your bones, it hurts. So having a medication that could potentially act almost like a lubricant, and that's how I describe it to patients, it acts like a lubricant, then hopefully the blood would flow and go where it needs to go.

The sustained study, which was performed a couple of years ago and again, led to the approval in 2019, just pre-pandemic. The sustained study showed 52 weeks of data that had a 45% decrease in pain crisis on those patients that were on treatment and had a delay in time to their first pain crisis from 3.1 months to 1.3 months. And actually a third of the patients didn't have pain crisis at all versus 11% in the placebo arm. So really very impactful in regards to pain crisis. The logistics is definitely something to consider, is an IV infusion. They have to come in once a month after the loading dose in the beginning, but it's once a month. You know they get it, so there's no worries about compliance. If they come in, you know they've gotten the medication, you know it's in their system. And then they continue on it monthly indefinitely.

The side effects are sometimes having an infusion reaction or having some body aches, myalgias, sometimes low-grade fevers. Usually are pretty manageable, not too significant. In the pediatrics I should say the indication as of right now is for 16 and older. I didn't mention that L-glutamine is approved for five and older, but crizanlizumab is for 16 and older. There are ongoing studies trying to get it approved for younger, 12 and older, and then younger even to that. Those are all underway right now. So that's crizanlizumab and definitely has a good place for that conversation with patients.

And the last medication that was approved also in 2019, right about the same time as crizanlizumab, is voxelotor. And so voxelotor is basically a new class of medication. It is a hemoglobin modifier. It binds to the hemoglobin to have it hold onto oxygen more tightly. And by holding onto oxygen, it actually prevents the sickling process. So the root cause of everything that's happening within sickle cell is because the cells sickle. So if you have a medication that prevents the sickling, then you have an opportunity to decrease the destruction of the cells, decrease hemolysis, and then the hemoglobin can rise after that. And that's what this study did. The Hope Study was having patients randomized to either the 1500 milligram arm, which is the approved dose, the 900-milligram dose, which is a lower dose, and then finally the placebo arm.

And if you compare 1500 approved dose to placebo, you see that a very significant increase in those patients on treatment. 51% of the patients had their hemoglobin go up by one gram as opposed to 6.5% in the placebo arm. And actually 27% went up by two grams in the treatment arm. So pretty robust improvement in hemoglobin. The discussion that comes up, and this is a great discussion at our session today, is there isn't any clinical data from that Hope Study. The Hope Study itself didn't show an improvement in pain. So the conversation always then, what rationale do I have to then using this, to use this in my patient? And for the most part right now, it's really anemia. I mean, if the patients are anemic, and the study included patients with a hemoglobin of 5.5 to 10.5, then you should consider this medication quite strongly.

And the tradeoff of course here for side effects is the balance of the discussion. I will say the package insert is very clear that 48% of the patients required dose modification through the 72 weeks due to side effects. So I have a conversation with every patient, make sure you let me know if you have any side effects, any concerns. If I need a dose reduce you, change your dosage, help you through that side effect, I really want to help that compliance. Because if they don't take the medication, then it's not going to work. So that's an overview. I know it was a lot to be said right there, because there are three very different medications, but I will say an exciting time to at least have three additional medications to talk about with our patients.

Jessica Bard: Absolutely. And in your session you spoke about three pediatric patients with sickle cell disease and varied clinical scenarios. Tell us about those patients and the appropriate agents for those patients.

Dr Nirmish Shah: First off, I just want to bring this up, every patient is different. Every patient has an individualized discussion. And I think one point that was brought up very well during the discussion is that one of the strategies that I take and that other panelists agreed with me is to have a conversation about all the medications with all your patients. Even if they don't need the medication now, at some point you may need to, and it's really about building trust with patients. So I do talk to all my patients about all the medications. But having said that, the cases that we outlined, the first patient was a patient with type SS sickle cell disease, was anemic, had some compliance issues with hydroxyurea, so wasn't always taking it every single day. Had some response to it, but was developing these allo-antibodies. So developing antibodies to blood for transfusions and had a history of acute chest and history of being in the intensive care unit.

The question was, well, which of these agents would I potentially add to the hydroxyurea, which as I said, this person was not taking very well? And it was a great conversation because the options are, should I add ENDARI? And ENDARI does help with acute chest, so I think that's a great conversation to have with the patient. But it's twice a day and it's a powder that they're going to mix in. So if you're already having issues with compliance, that may not be the perfect drug. The next discussion was, well, if they're anemic still, they have risk of being in the intensive care unit with acute chest, should I improve their hemoglobin? So I think there was some good conversation about potentially using voxelotor to do that.

And then the last option, which is what this case was actually based on, was adding crizanlizumab. And this patient actually was added crizanlizumab because there was pain issues and the concern about compliance led to the fact that by giving it IV, the patient got it. And we knew the patient got it. So as of right now, the patient case that it was based on, that patient was put on crizanlizumab and it was really based on making sure the patient got the medication.

The second case was a type SC patient. So an SC patient who was starting to have more pain crisis and had some anemia, but not as pronounced as someone who would have SS or S beta zero. And the conversation came up, well, what should we do? Patient was having some pain crisis and really came down to a discussion about hydroxyurea versus crizanlizumab versus ENDARI. Those are the three really indicated for pain. In the end, the majority of the audience, and we all agreed to this, it really fell on the end of either hydroxyurea or crizanlizumab. And I think it's a patient specific discussion. If a patient is willing to take hydroxyurea, there is a lot of retrospective data that hydroxyurea is helpful in type SC.

Crizanlizumab although, as I just mentioned, if you want to make sure this patient got it, just have them come in once a month. It is less of a burden per se for some patients because they just come in, they get their IV infusion, and they go home. In this scenario, based on this patient case, there was kind of a mixed answer that we could really do either one. And so I think it was just a good conversation about making it an individual discussion with our patient.

And then the last patient. And so the last patient, again, was a patient who had a history of significant anemia. It was pretty clear cut that is a rockstar with taking hydroxyurea, was doing everything they should, and compliance was great. But even on hydroxyurea, the hemoglobin was in the kind of six and a half, sevenish type range. And so what should we do for this patient? Has a sibling that had a history of stroke. And in this sense, I think voxelotor came more of the conversation. I will also add that our panelists all agreed that when they're on hydroxyurea, you want to titrate them to maximum tolerated dose. It's clear evidence that actually many providers, even in the sickle cell world, don't do as good a job as we hope to to get patients to maximum tolerated dose. So titrate them to the maximum tolerated dose and then consider adding voxelotor.

So those are three patient cases to kind of just get someone in our mind as to what scenarios we may need to consider. But I think it was a great exercise because we had great conversations that there's not necessarily a right answer, but it is really about having a conversation with the patients, their families, and with our colleagues to say, which is the best answer for this specific patient.

Jessica Bard: Yeah. That makes sense. My last question for you is, could you review preliminary safety and efficacy data from ongoing clinical trials from other disease-modifying therapies in the pipeline for SCD?

Dr Nirmish Shah: I actually started my talk today putting out a little bit of a shout-out to say that we're finally putting a lot more research into sickle cell disease. And it's been a journey to get to this point, but I'm really thankful to see that there are a lot of pharma companies finally putting a little bit of money behind trying to improve our efforts to have more options. And I can think of at least two companies in particular, Forum and Agios have been looking at pyruvate kinase receptor agonists, trying to see if another way of shifting the oxygen disassociation curve through the pyruvate kinase pathway. And also it increases ATP, which is helpful in red cell health. Those two agents and the mechanisms are the same but have some preliminary evidence that it does seem to not only improve hemoglobin, but also potentially improve pain. That's a great opportunity for our patients to both improve anemia and improve pain. Having that in the near future is likely something that we'll hear more about.

And then the only thing I'll end on is to say that gene therapy is kind of a hot topic. So gene therapy I think has amazing outcomes. I mean, really the patients who have undergone gene therapy based on what bluebird bio has shown, CRISPR Vertex has shown, their outcomes are great. The patients are normalizing their hemoglobin, fetal hemoglobin levels, or for bluebird bio, the T87Q product equivalent. They're really getting to great points. The issue that needs to be resolved is the conditioning regimen. Can they give it to patients safely? So I think we're going to hear a lot more about that over the next couple years. I'm really optimistic about where we're going.

Jessica Bard: Is there anything else that you'd like to add today?

Dr Nirmish Shah: Again, thank you for giving me this opportunity to talk about sickle cell and the new therapies that we have. I do want to continue to push all of us to try and do this as systematically as possible. We need to get more and more data about how to co-prescribe these medications, who are the right patients that we should prescribe to. And I think each of us is all thinking the same thing, we're just happy to have these options, and now how do we best get this into patient's care?

Jessica Bard: Well, thank you so much for your time today, Dr Shah. We really appreciate it and thank you for all of the work that you're doing on sickle cell disease.

Dr Nirmish Shah: Yeah. Thanks for the invitation. Appreciate the conversation

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