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I'm Doctor Norma Shah. I'm at Duke University. I'm the Director of the Sickle Cell Transition Program and also the Director of Clinical Research and benign hematology with an interest in sickle cell disease. And what I'm going to talk to the, to you about today is the evolving treatment paradigm for sickle cell disease. We've had an amazing journey with sickle cell disease in the last 5 to 10 years. And we're actually finally getting to the point that we're having multiple medications that are being evaluated. And so it's really important for us to really think about what is right for our patients. What is a uh what are the steps that we need to go through to try to understand how can we best help our patients? So we're gonna talk about is how to integrate these emerging therapies and and really consider the fact that we probably need to uh have the important aspect of a multimodal approach with each of our patients. So these are my disclosures that are listed here and we're gonna go ahead and just dive in with our learning objectives. The first is in, in regards to, again, looking at the emergent therapies and multi modal approaches, evaluate the patient eligibility for current and emerging therapies. And that includes novel ph uh pharmacologic agents, hematic, uh HS CT or uh stem cell transplant and bodily gene therapy. We'll also look into incorporating multimodal pain management strategies and balancing this um really uh constant issue that we get into is balancing this opioid stewardship with non pharmacologic therapies as well as targeted approaches and finally go into the uh treatment strategies and how to adjust them for older patients. And, and that I think is an important aspect as our patients are getting older in our communities with sickle cell disease. So I'm gonna start with a case. Uh II think it really, I think roots us in the fact that we're always trying to take uh advantage of the fact that we have a lot of uh considerations for each of our patients. Uh And we wanna have that as an upfront discussion with each, with each patient that uh and understand the fact that every patient is different. So we have a 48 year old patient with severe sickle cell disease phenotype uh has frequent vocs uh despite uh pharmacologic therapy and trying to get to the optimal dosing for each of those, he has a matched sibling donor and is interested in discussing curative options when counseling the patient, which of the following is the most accurate statement. And you can see here the first a is gene therapy as the preferred option as it offers a 90% reduction in VOC S and avoids GVHD B matched sibling donor uh transplant. So that's a well-established option for him. His age is within the typical range considered and this procedure has a 95% survival C is not a suitable cater for either therapy because uh he's, he's in his mid forties in his age range. Uh And finally, the, the last uh D is both options are equivalent. Gene therapy, has longer term term follow up. Uh and and is designed to increase fetal hemoglobin to 40 to 45%. So keep that in the back of your mind. It's just a case as a a as we're thinking through all these uh uh treatment options that we have for our patients because II want you to potentially think about how circling back to this case and answering this uh case uh would be important for us to think about framing our discussion today. So we've made a lot of progress with uh the landscape of sickle cell therapy, the historical approach uh in the past and this is up until about the 19 nineties or so, was really supportive. It really didn't have any disease modifying options for our patients. And so we use analgesics for pain. We had blood transfusions for anemia and we had antibiotics for infection. We really didn't have much else beyond that. The disease modifying era began in 1998 following the Multicenter Sickle cell hydroxyurea trial, uh which led to the approval of 98 of, of hydroxyurea. And, and this was our first specific therapy for sickle cell disease. And of course, the, the goal here is to increase fetal hemoglobin. Uh And this induction, it was, was very critical and to it's helping uh patients, it also is myelosuppressive and increasing nitric oxide. So it did uh uh a nu a number of things that were helpful for a patient. But then we uh follow that uh for after a period of time uh to have LGT approved in 2017, Crisi I in 2019. Um And, and then uh I'm gonna pivot to the curative front and the curative front uh stem cell transplant has been established quite well. Actually, gene therapies are emerging. Now, uh allotransplant has been around since the eighties. It was interesting that the, the first patient with uh AML and leukemia uh was treated for that leukemia with the transplant and then was cured of sickle cell at the same, the same time. And so, uh more and more uh through the mid nineties. And, and um subsequently, we've had a number of transplants with uh mat sibling haploidentical uh uh mass unrelated that we and, and also uh now moving to, to the new era of gene therapy and most recently in uh 2023 we now have Lova and A L both approved as well. Now, uh I think it's really important again to try and think about well, for each of those three medications that are focused on sickle cell. Ho how do we determine who, who is indicated for? What are the uh outcomes reach of those? Which then allows me to think about who this may be a, a treatment option for and then what are other considerations? And so I have that listed here. If you look at that first tile uh with hydroxyurea, thi this is the standard of care for patients. We have the the greatest amount of data and literature supporting it. It was classically approved for sickle cell anemia. So the SSS beta zero, it's moved into SS be uh beta. Um I'm sorry, uh I see patients as well. Um And then, and quickly also uh we want want to mention that it's not only standard of care but it's started in pediatrics. So it's a one medication that's, it's really aimed to try to prevent issues and not being responsive but really uh a a medication to try and prevent patients from having issues in the first place. So we start at age nine months of age on the adult side of it. And this is really based on the MS H trial. It was approved for patients who had at least three pain crises uh per year. Now, the monitoring for hydroxyurea is blood counts. We want to make sure we not only monitor them but titrate it to maximum tolerated dose. We show a a significant decrease in pain uh as well as acute chest and transfusions. And, and in fact, there's actually multiple studies that can be referenced of, of all the good that hydroxyurea does. The consideration is is compliance, of course, with any medication, we want to make sure patients are compliant. But also the fact that it's a progressive disease and inevitably a patient is not going to respond the same way when they start on it, as let's say, 1020 years later, and the patient has progressive disease and patients need to understand that that it is still doing benefit but probably more. So in the background, L glutamine, which is the middle tile here uh is an antioxidant. Uh It again also uh addressed for patients who have recurrent vo CS and, and those that may have been on hydroxyurea but are continuing to have issues or patients who are intolerant for whatever reason with hydroxyurea uh indication is for five years of age and older. Also a significant reduction in pain and uh and acute chest. And the considerations here is, is really the fact that um yes, it does cause gi side effects, but it's twice a day and it's a power. So we have to really work with patients to get them to be compliant and, and take it as directed. And finally, Crizanlizumab. So Crissum is a monoclonal antibody to P selectin, it's indicated for patients with at least two pain crises in the past year, 16 years of age and older. Again, pretty spot on with reduction in pain crises. Uh The, the consideration for this is it's an IV medication. So they have to come in once a month to try and get those uh infusions and because it's a humanized antibody, they can have uh infusion reactions as well. Now, in regards to selecting patients uh for each of these therapies, the first thing is, you know, do they match the criteria to make them eligible? Of course, uh with uh criteria uh included in, in prior authorization forms and getting approval through insurance, you wanna make sure that patients are fitting uh the criteria. You do wanna look at organ damage assessment, you wanna make sure that the renal function is doing well. They're not uh endstage renal on dialysis. For example, it's an extreme example of why a patient may not be eligible for uh for some of these medications the age. Uh again, typically the the transplant patients are less than 50 gene therapy. Uh I should mention the oldest patient uh in the trial in the mid forties, although one trial was 50 younger, one was 35 and younger. But, but we really have limited data for older patients. And then really thinking about uh psychosocial, do we have some stability, a support system for our patients? I I'll move to the bottom left here where, where counseling I think is really important, start your discussions early. II really think it's very important for all patients to know all their options and make sure you're having this uh back and forth discussion and not having over one visit. So you wanna have these considerations uh about the risk benefit uh for each of these therapies. And then there's fertility preservation discussion. Whenever you get chemotherapy, there is this concern that uh you, you're gonna be infertile from the chemotherapy. And how can we uh discuss uh the the potential for having patients either bank their sperm or having egg harvesting postprocedure. There, there are uh requirements, there's logistics of having uh patients move through this over a month. And so we need to make sure that we're sending realistic expectations. Now on the right here, gene therapy and