Nirmish Ramesh Shah, MD, Duke University

 What I’m hearing from you guys is that it’s important to educate your patients, to provide informed tools for them to make an informed decision based on their specific scenario. For our last question, I’m going to ask all of you: sickle cell disease has been around for over 100 years, and we’re still dealing with organ damage, acute exacerbations, quality-of-life issues, fatigue, difficulty finding a mate, difficulty finding work. What are your concerns around health equity and access to care that are persistent? What would be the 1 thing that if you could fix about sickle cell disease if you had a magic wand or a genie bottle? I’m going to have Dr Desai start, then Dr Shah and Dr Smith.

 I’m going to make the first wish. It’s to get every patient connected to some care—having somebody who will care and talk about these things, to say “I don’t know” sometimes and walk through life with them. We’ve talked about how complicated it is; they can’t do it by themselves. Everybody needs that advocate, they need the person that understands the disease. Even if they don’t understand, they’re willing to take that extra step. I wish everybody had a place that they could be connected to care.

 Excellent. Dr Shah, what’s your 1 wish from the genie bottle or magic wand?

 For wish No. 2, I have a 2A and 2B; they’re connected. The 2A is a big shift in mindset about therapies, from being reactive to prophylactic. We have drugs that are reactive because they’re anemic or because they have pain. But why do they have to be anemic or in pain? Why can’t we move more toward prophylactic? But because therapies are expensive, there’s so much out there, and not all patients are in centers that can give you those therapies, when we get to those therapies being prophylactic, they must be accessible, easy to take, and cost-effective. Not a drug that’s so expensive that a payer isn’t going to want to support that across the country. We have patients who aren’t plugged in to care, don’t have access to health care, and don’t have insurance. Why aren’t they getting the same therapy as another patient in an area that has a comprehensive sickle cell center? So there are 2 arms: better prophylactic medications with access to as many patients as possible.

 Public health. We don’t know how many patients have sickle cell disease in the United States, but Brazil does. Brazil is supposed to be an emerging nation. That’s a travesty. If we knew how many patients had sickle cell disease in every state in the United States, then we could more appropriately advocate for resources to do everything you just heard. We can know just by having somebody snap their finger and make each state share their newborn screening registry with each other; we could do that. Eleven states are already doing it, according to the CDC [Centers for Disease Control and Prevention]. My 1 wish is to get all 50 states to do that so we can talk intelligently about how many patients have the disease. We can then make health care allocation decisions for not just doctors but community health workers, hospitals with drugs, and community-based organizations and resources to help these patients.

 Thank you so much. My 1 wish is that all 3 of your wishes—or 3½ to 4 wishes—come true. If we get there, then each individual with sickle cell disease should be able to live to be 99 years old, get to lose all their teeth, and use a walker. Having a quality of life and a quantity of life that equals that of their peers is the ultimate goal.

I want to thank you, Dr Desai, Dr Shah, and Dr Smith. Thank you for this very informative session, for all your knowledge, and for sharing your experiences. This is a transformational period in sickle cell disease care. I look forward to more drugs being approved, I look forward to a lot more research, and I look forward to the 50 states being connected and for every patient to have access to the right type of care. Thank you very much, everyone.

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Concluding their discussion on sickle cell disease management, expert panelists share key unmet needs and hopes for the future.

Sickle Cell Disease: Unmet Needs and Future Directions in Care

 Dr Smith, what are the common misconceptions and misunderstandings that you’ve seen or heard in discussing gene therapy with your patients? What should this dialogue be? There are issues about traveling to a center. How do they get access to this? Is it efficacious? Are they going to transform into a mutant? Are they going to grow 5 different heads and 6 tails? What exactly do you hear at the community level?

 Let me start with my top observed misconceptions. Misconception No. 1: it’s a procedure. Yes and no. The procedure of the gene therapy is a simple injection, and it’s an infusion, or you extract and inject. Before and after, there’s a year’s worth of medical care, which we just got through talking about. Chemotherapy, a lot of blood testing, cleaning out the bone marrow, and then observing. You need to take a year out of your life, and you need a significant other to take a year out of their life if you want to go through with these procedures and these therapies. You’re going to be at the doctor a lot. So it’s not a procedure; it’s a process. It’s a yearlong journey, so you have to tell that to patients. When you tell that to patients, a lot of people turn around and walk out, because they got misinformed that there was this quick, painless infusion that would cure their sickle cell disease. I’m using the exact words that people say.

No. 2, “I still need a donor.” No, you don’t need a donor. What you need is someone to come and get the cells out of you. So you have to be in the right medical center to even be in 1 of these trials. It’s not the same. That gets misinterpreted as, “Oh, I need a donor.” No, you just have to be in the right center that’s enrolling people in these trials. No. 3, and you just talked about it, Dr Desai, it causes cancer. Is it that the chemotherapy causes cancer, or is sickle cell disease predisposing some patients to cancer? That’s where all the hot research is. We’ve pretty much absolved the gene-adding vehicle of causing cancer. There’s been enough work done that we say it’s not that. That leaves the chemotherapy itself and the disease, and we have a little evidence, though it may be evidence, that sickle cell by itself may predispose people to leukemia and myeloid dysplasia. We need to do a lot of work, and we need to reassure patients that we’re going to try to keep things safe for them.

I have all those conversations with people. This takes time. This isn’t a 1-visit conversation. This is a multivisit conversation, during which I’m encouraging people to think, “Is the risk now worth it given the complications you’ve undergone?”

 Just a quick 2 words from each of you on gene therapy for sickle cell disease: yea, nay, cautiously optimistic, need more time to tell, what would that be?

 Yea if the right person wants it. They have to be very sick. For most people it’s nay, but for a few it’s yea. They have to be pretty sick and willing to take the risks.

 Yes, I’m not a Nervous Nellie. I’m not nervous about things in general, so I’m usually on the end of being optimistic. But in this situation, 2 words: cautious but optimistic.

 I’m also cautiously optimistic despite all my caution. I want people to go into it informed. That’s why I say all the other parts, because I want them to understand those risks. If they understand the risk, for the right patient, it’s a yea.

Shared insight on patient education surrounding gene therapy in sickle cell disease and common misconceptions about this approach.

Educating Patients on Gene Therapy in Sickle Cell Disease

 That’s a great segue into the next section: the role of curative therapy, including gene therapy, in the management of sickle cell disease. One treatment option we didn’t get to is transfusion therapy, which is an amazing intervention to take care of acute complications—chest, stroke, sequestration episodes, preoperatively multiorgan failure. But it’s also given chronically to prevent recurrent strokes or when you have your first stroke. However, there are curative therapy options for sickle cell disease, and it’s important that people are aware. As Dr Shah said, we notify people that these are the options we have. Multimodal therapy, as Dr Smith and Dr Desai mentioned, is going to be the way to go. Some of that will play out based on your insurance coverage and access, but 1 drug isn’t going to fix it all for sickle cell disease. Is there an option for some intervention to completely fix it all? 

Let’s talk about gene therapy. Starting with Dr Shah, what’s the role of gene therapy? I want to hear your perspective on gene therapy. Who should get it? Who has gotten it? How does it play out in terms of your clinical practice? Once that’s done, I want to go to Dr Desai about the risk-benefit ratio of gene therapy. Dr Shah, let’s start with you. Gene therapy, yea or nay?

 It’s too early for me to say yea. I can’t say yes for sure. What I can say is I’m optimistic. I’m glad Dr Desai will go through all the risks and things to consider because there are a lot, and we must put it in perspective. Let me start with the gene therapy. Why is it different from standard bone marrow transplant? The interesting part and the reason there’s optimism is that this is an autologous transplant; we’re taking the patient’s own stem cells from their marrow. We’re manipulating it. We’re changing the gene so they don’t have sickle cell. What they’re doing is inserting genes, or changing the genes, so they make more fetal hemoglobin targeting that 40% range, and then patients don’t have symptoms or complications from sickle cell. The cells aren’t sickling, and the results are pretty good. 

Across the board, if you look at what’s out there, patients are not having pain. Their hemoglobin is pretty much normalizing. Their fetal hemoglobin is on the 40% to 45% range. I don’t think we’re arguing that it’s an issue, and the patients are not rejecting it because it’s their own marrow. They don’t have graft-vs-host disease because it’s their own marrow, so they don’t need immunosuppressive, which makes me very optimistic about what this can do. I prefer the doctor to give specifics, but how comfortable am I with the potential risk of doing this? I have to give busulfan-based conditioning, which is the chemotherapy. I have to clean out the marrow to make room for the new and improved marrow, and cleaning out the marrow with chemotherapy has risks.

That brings me to this moment. I only consider the most severe patients, who don’t have a match sibling donor. If I was to give you a type of patient, a patient who’s had recurrent strokes, has iron overload, I would rather them not get ongoing transfusions if possible. They have a lot of alloy antibodies, so I can’t even do exchange transfusions. The most severe may be candidates for gene therapy. If we can work out some of the considerations of what the risk is—I don’t know that number. Is it 2%, 3%, 5%? What’s the risk? Once I know that, I could probably give you a better idea of exactly what patients will be right and how many of my patients I would give this to.

 Dr Desai, what are those risks? What would you counsel your gene therapy candidate who is gung-ho and wants to get this done? They heard about CRISPR-Cas9, and they want them to fix their sickle cell disease.

 Not all gene therapy is equivalent, and there are several ways we do gene therapy. All of them carry their own adverse effects. We’re all shying away from calling it a potential cure because we don’t know. Let me be the Eeyore. Let me bring you down and talk about all the adverse effects, all the potential issues. I will preface this by saying that for that really complex patient, even in the adult world, they don’t have an option. The risks may be worth not knowing if you think that next acute chest episode might be it. They’ve had 10 episodes, and they’ve had more complications. Despite everything, they keep getting more complications. Even with the potential risk, this might be the right thing for them, and it’s not up to me to say how bad those risks should be. This should be their choice to make an informed decision.

What’s an informed decision? Dr Shah talked about this. There are potential adverse effects up front that, because sickle cell is a complex disease that might affect the marrow in ways we don’t know, particularly as patients get older. Is it because of the chemotherapy itself and the potential impact of long-term adverse effects? Some patients after gene therapy could go on to develop acute leukemia or myelodysplastic syndrome. For those 2 things, we’re trading out the sickle cell. People can live an event-free life with sickle cell, but for how long? Which patients are prone to this very serious life-ending complication? We need to identify those patients.

The other part has to be, is it the therapy itself? In terms of the fetal hemoglobin expression with the vectors they’ve used, that’s the 1 that has the most data, the vector site itself. Where it’s going in to fix the sickle cell has not been shown to be problematic. But when we look at the data from the American Society of Hematology [Annual Meeting], and we talk about CRISPR-Cas9—you snip and insert—there are sometimes chunks of DNA missing. What are the implications of that? What does that mean? Are the libraries appropriate for sickle cell in African Americans, who have seen most of this therapy? There are a lot of unknowns about how this is happening.

It’s promising if you look at that data. We all sat in the audience—I sat with some of you when they presented at the American Society of Hematology [Annual Meeting] a couple of years ago—when there were 30,000 people in the audience and we all used to sit together before COVID-19. All of us had this wash over us when we saw the cure data from gene therapy in sickle cell disease. We want it to be true, we want it to work, and we want it to be successful. But I’m the Nervous Nellie. I’m a little scared. What does that mean? Is it really a cure? How long does the cure last? What happens if there’s a complication? Do they have another infusion they do? Can they fix the problem if it causes MDS [myelodysplastic syndrome] or acute leukemia? Those are the unknowns.

I’m still very hopeful despite saying all this. We should go into it with open eyes and pick the patient who’s best suited for this therapy. Those risks are worth it, and I can’t quantitate what that looks like. To wake up without pain 1 day might be worth the risk for that patient. I can’t tell you where that inflection point is for that individual patient, and it’s their choice to make. But they should go into it knowing that it might impact their reproductive health. They may not be able to have babies after, and it might impact their potential marrow for long-term complications.

An overview of gene therapy in sickle cell disease with a focus on the risk-benefit ratio observed in clinical trials and practice.

Understanding the Risk-Benefit Ratio of Gene Therapy in SCD

 Who would be the right candidate for voxelotor vs crizanlizumab vs Endari? We probably should get hydroxyurea. Starting with Dr Smith, who would be the best person for voxelotor?

 I’m a huge fan of drug cocktails. Each of these 3 drugs was used along with hydroxyurea in their formative trials. They showed additive effects to hydroxyurea. I have people on 3 drugs that their insurance will pay for. I have a person who’s on Endari, hydroxyurea, and voxelotor. You could have somebody on crizanlizumab, Endari, and hydroxyurea, or crizanlizumab, voxelotor, and hydroxyurea, if their insurance companies will pay for it. Of course, they won’t, but that’s my belief. I don’t know how well I do this, but I try to present all these therapies to patients and let them tell me what they want—not select for them, but let them tell me what they want.

To make the selection, they’ll usually ask me to explain 1 or 2 of the drugs that sound interesting to them. They’ll ask me to confirm adverse effects, how you take it, how often you have to take it, or the mechanism of action. I don’t necessarily buy into “If you’re anemic, take voxelotor. If you hurt a lot, take Endari, hydroxyurea, and crizanlizumab.” You can back yourself up into some corners. I’d rather start with, “You have sickle cell disease. You want everything you can do to make your life better. We have 3, 4 possibilities. Which of these appeals to you, and how much can we get paid for it?”

 I’m going to let Dr Desai and Dr Smith affirm or rebut what Dr Smith has said. Do you have a different opinion?

 I agree. I present the patients with all the data. Having said that, genotype matters, but not in terms of hydroxyurea. I offer hydroxyurea to anyone having pain episodes. Because we know a little less, I’m a little more cautious, and maybe more scared, about the higher hemoglobin because I’ve seen a couple of complications. I’ve had patients have improvement in their pain with voxelotor,so I don’t think the boxes fit necessarily for just hemoglobin or pain. I don’t think there’s just 1 thing, and I’m hopeful that over time we’ll discover that they do multiple things. But if people have a higher hemoglobin—over 8 g/dL is usually my cutoff—I don’t always think about voxelotor. If I offer it to them if that’s what they decide, I start slower and give only 1 to 2 pills, and I closely monitor their hemoglobin.

In terms of crizanlizumab, it affects the platelets, so if patients are on full-dose blood thinners, none of those patients was included in the pivotal trial. I’m still a little hesitant. I want more data in terms of patients on anticoagulants and a P selectin inhibitor. In terms of Endari, sometimes those are patients who haven’t even tried hydroxyurea. Sometimes they have a little milder disease and accept those therapies. They are willing to because they want to do the amino acid, the thing that feels like it’s more of a supplement. That’s not saying it works better or worse, but the commitment to take a supplement 2 times a day every day indefinitely requires a patient who wants to be on board with that type of commitment. Those are some of the other nuances on top of what everybody has already mentioned in terms of drug therapy selection.

 I completely agree that we should be discussing these therapies with everyone, even if you don’t feel this patient needs crizanlizumab or voxelotor. We should offer all this and have patients be aware. As Dr Desai brought up, we don’t have guidelines. We have guidelines for pain, but they’re not all agreeing with one another. We don’t have guidelines at all for this yet. We’re thankful that we have these options. Without a doubt, just like hypertension and congestive heart failure, for a complex disease like sickle cell, we’re going to need multiple medications to control it. Inevitably, hydroxyurea will not be enough, and we’re going to consider what else we can do. If I want to talk about a cutoff, I use somewhere around 9 to 9.5 g/dL; the study was up to 10.5 g/dL. You can draw the line in the sand anywhere. But it comes down to making sure that the patient is onboard and part of the decision about what this drug can do for them.

It’s also important to say that patients don’t know until they know, meaning not just about the drugs. I’ve had patients start voxelotor and say, “Dr Shah, I can do so much that I didn’t think I could do.” I ask them, “How are you doing?” “I’m doing great.” “Are you short of breath?” “No.” “Can you do what you need to do?” “Yes, I can do everything.” They start voxelotor, and they’re like, “My gosh. I clean the garage and my room—my wife is so happy I’m cleaning.” All these conversations that patients don’t know until they know, and the same thing holds true with crizanlizumab. “Dr Shah, I didn’t realize I was having pain and I was dealing with it, but I feel better. I have less pain.” It’s on us to offer everything we can. Patients have gotten used to where they are, and they don’t need to. Patients need to understand there are options, and they may be a good option once they start.

Panelists take a step back to consider when they might use certain disease-modifying therapy in the setting of sickle cell disease.

Nirmish Ramesh Shah, MD, Duke University

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