Toward a cure for sickle cell disease

Transformative therapies for sickle cell disease are redefining what is possible for patients, offering the potential for cure alongside substantial risks. In CMAJ, the article Transformative therapies for sickle cell disease outlines how stem cell transplant and emerging gene therapies are changing the trajectory of a condition long defined by recurrent crises, shortened life expectancy, and inequities in care.

Dr. Kareem Jamani, a haematologist and clinical associate professor at the University of Calgary, explains how stem cell transplant replaces a patient’s blood-forming system to eliminate sickling haemoglobin, offering what can reasonably be considered a cure. Outcomes are generally favourable, particularly with matched sibling donors, but risks remain, including graft-versus-host disease, infertility, rejection, and mortality that can reach 5–7% with less well-matched donors. He also outlines the role of gene therapy, which modifies a patient’s own stem cells to increase fetal haemoglobin production, resulting in a functional cure with similar improvements in quality of life.

The episode is grounded in the experience of Ufuoma Muwhen, who underwent a stem cell transplant as a teenager after years of frequent hospitalizations and functional limitations. She describes the toll of both the disease and the treatment process, as well as the shift in her daily life following transplant, including her ability to travel, exercise, and live without recurrent crises. Her account highlights the importance of wraparound supports and trust in the healthcare system.

For physicians, these therapies require balancing meaningful benefit against real risk, often early in life and under uncertainty. The discussion also underscores persistent inequities, including delayed acute care, limited access to fertility preservation, and the challenges of delivering advanced therapies within systems designed around oncology rather than chronic genetic disease.

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Transcript

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Dr. Blair Bigham I'm Blair Bigham. Dr. Mojola Omole I'm Mojola Omole. This is the CMAJ podcast. Dr. Blair Bigham Jola, we have talked about sickle cell disease before. Dr. Mojola Omole Yeah. Dr. Blair Bigham And mostly around the challenges people get just getting treated for their crisis, getting adequate narcotic. Dr. Mojola Omole But also not just treatment with adequate narcotic, but some of the biases they face when they present to emergency in a crisis. Dr. Blair Bigham Totally. And that leads to undertreatment. But we're going to talk about some cool stuff today. But it's grounded in not just sort of those inequities around the acute management, but really about the impact that sickle cell has every day of somebody's life. Dr. Mojola Omole Yeah. And we're looking at an article titled, Transformative therapies for sickle cell disease, looking at some of the relative new treatment that offer a promise, what seems like a cure for sickle cell. Dr. Blair Bigham Yeah, this can be absolutely life changing. But as with anything in medicine, it's not without risk. So first, we're going to start by speaking to a patient who has actually gone through a stem cell transplant for sickle cell disease. Dr. Mojola Omole So in the article, Dr. Jamani lays out these two modes of now therapy to cure those with sickle cell. One of those is stem cell transplant, which has been around for some time, especially in the U.S. But depending on patient selection, might be the right form of treatment for some patients with sickle cell. And the other one is gene therapy, which is much newer. Dr. Blair Bigham And of course, the trouble with stem cell transplant is that you have to have a match, and not a lot of people do. And so then you're kind of left with gene therapy, which is as risky, but also less available. Dr. Mojola Omole Yeah. And so we're going to get into these therapies with Kareem. Dr. Blair Bigham But first, we're going to hear the story of Ufuoma Muwhen, a sickle cell patient who underwent stem cell transplant about 10 years ago. Ufuoma Muwhen So the first time I realized that I have sickle cell disease or the fact that I was just different from other children was when I was a kid. I really loved to swim like probably grade one, grade two. I loved the water but I would realize that every time I would go swimming after I would get sick and I would be in a lot of pain and then my mom just took me out of swim lessons and so I just never learned how to swim and I wasn't really allowed to stay in the water for very long so that's when I realized I was definitely different. Dr. Blair Bigham That would have crushed me. I was a fish as a kid. I was always in the water. Ufuoma Muwhen Yeah. Dr. Blair Bigham How else did sickle cell affect the way you grew up, affect you as a child? Ufuoma Muwhen Oh my gosh, how didn't it affect me? I will say my family was really like great with trying to make me feel like a normal kid but we just lived life on red alert. Like I couldn't run, jump, scream, laugh too hard without them. Hey, take it easy. Hey, you know you can get sick, right? My siblings, both my siblings played soccer all the way up until like they finished high school and I wasn't allowed to do that. I wasn't allowed to actually actively play sports or do anything. I thought they put me in ballet instead which I found lame compared to my siblings. I wasn't allowed to play sports until I actually went on hydroxyurea when I was like in end of elementary and teaching year high and that's when I felt like I had a normal life. Dr. Blair Bigham So tell me more about being introduced to hydroxyurea. How did that change this limitation that had been put on you? Ufuoma Muwhen Oh my gosh, hydroxyurea was a game changer for me. Dr. Blair Bigham Really? Ufuoma Muwhen Yeah, I was actually born in Ontario, lived in Toronto for a while, then I moved to Alberta and so it wasn't until when I moved to Edmonton, Alberta that my new pediatrician was like, hey, you're like my hematologist pediatrician. She was like, hey, like I think you know you would be a good candidate for this medication and so whilst there was lots of side effects, I was getting sick probably before that. Like crises that I could manage at home, I was probably having one like once a month and then getting actually admitted, it was probably anywhere from three to four or five times a year I was being admitted in hospital. Dr. Blair Bigham As a kid, you were being admitted to hospital a couple times a year. What was that like? Ufuoma Muwhen Yeah, it was rough. Life stops. My mom has to figure out who's going to care for my other two siblings and then I'm at the hospital. Usually my admissions were from like three to seven days and yeah, it was pretty rough. I was very sick. For me, my protocol, obviously the whole oxygen, IV fluids, but I was always on morphine infusion and so whilst morphine infusion took care of the pain, I also dealt with like constipation and the constipation would exacerbate the crises and like it would be horrible. Sometimes I would have to like go to physiotherapy after and like basically rehabilitate to learn how to use whatever area of my body was in crises like where the pain was concentrated. I would have to learn how to use that after. Sometimes I would be on crutches coming home. I would lose a lot of weight. Dr. Blair Bigham And then after the hydroxyurea came the idea of a transplant. Tell us about that. Ufuoma Muwhen So hydroxyurea did a great job in cutting down my number of crises that I was getting on a regular basis. I moved from like those three to four or five hospital admissions on a yearly basis down to like one. One to two, I could play sports. You know, I had a normal life, but each time I would get sick, it was more extreme. The disease would remind me that it's still here and I guess there was a lot of damage internally that was taking place. I was having more narcosis in various areas of my bones. So the risk was getting higher and so my physicians made that decision to actually advocate for me. And so funny enough, the idea of transplant came up earlier in my life, probably when I was like 12. But at that time, they hadn't had that reduced intensity bone marrow transplant until it was the kind of full blown where essentially I wouldn't be fertile after. I think it's the one where it's like a spinal tap type thing. And so my mom didn't want to make that decision like at that age for me and kind of wanted to be involved with the decision making process. So thankfully she waited because then the idea of this reduced intensity bone marrow transplant that I ended up having came about. And so I remember I was 17. I had just gotten into, just learned that I got into university, was planning for that next stage of life. And they were like, hey, you know, you're actually eligible for a transplant. And ironically, in the beginning, I was like, hell no. I don't want to do this. I'm going to lose my hair, chemo, radiation. It was so scary and daunting to me. And just that fear of the unknown. And also like I couldn't conceptualize how much more this would enhance or change my life. Because as far as I'm concerned, genetically, I still have sickle cell disease. I still have to go through the whole motions of figuring out who I'm going to date, marry, reproduce with. So I just wasn't really interested. And my sister was the one who was eligible to be my donor. And I remember looking at her and being like, girl, don't do it. You're going to lose your hair. But thankfully, my family really advocated for me and helped me understand that while I was able to, you know, they hadn't actually started doing it in adults. And I was transitioning into adults. But they realized the urgency and how my disease was progressing. And yeah, I guess they say the rest is history. In 2016, I had my transplant. My sister was my donor. And yeah, now I'm coming up on 10 years sickle cell free this year. Dr. Mojola Omole Amazing. Wow. Ufuoma Muwhen I haven't had a crisis in 11 years. Dr. Mojola Omole Can you tell us about what the transplant involves? And what was the hardest part for you? Ufuoma Muwhen Yeah. So I live in Edmonton, but they only do bone marrow transplants in the Calgary Centre. So I actually had to move down to Calgary for three months to do the treatment. My mom and I moved down to Calgary. I had to have my grandma come from Nigeria to come and take care of my siblings while we did that. And then they start you off with chemotherapy. So you do about five days of chemotherapy. And then you go for radiation on day. So they start like day negative seven all the way to day zero, which is your transplant. So on like day negative one, I believe around there you have total body irradiation. That was probably one of the worst days of my life. Why? And probably one of the hardest. It sucked. I think number one, I was so scared. Oh my gosh. Like I was right before they kind of started the treatment. I actually had asked them to stop because I just needed to cry because I was just so scared. Like I didn't know what was going to happen to me. And so I was just so scared. And it felt like this, you know, you're in this room with this big machine. I've gone through chemotherapy. My body is changing. And I was just scared. But then after I was hit with the worst headache of my life, it was so bad. Then you're just nauseous. Then everything, like it feels like the room is spinning bright lights. Everything tastes gross after. It was just very difficult and emotionally tumultuous. And then you have a rest day. At that point, I think my tongue started changing colors as we're reacting to some of the treatments I had had. And then day zero, which is your transplant day, the infusion is really chill. It's literally a blood transfusion. The cells just magically know where to go. And yeah, it was chill. And just like that, I had my transplant done. And then you're on that three month race to engraftment and to make sure your body takes well. On the donor side of things, I guess my sister, hers was really chill. They gave her growth hormones for five days. And then she said every day she was 12 at the time. And she said that every day it just felt like she was like working out really hard and then muscle soreness. And then by day five, she was like, it felt like I lightly got thrown at a wall. But she had the day after she she had the actual donation. She went to soccer practice and kicked butt. Dr. Blair Bigham Wow. Ufuoma Muwhen Clearly it wasn't that bad. Dr. Blair Bigham So you go through this super intense week and then you're just sitting around waiting to know if it works. When does it hit you that this was worth it? This actually happened. Ufuoma Muwhen So you're right. You literally just sit around and just wait for your body to not have any side effects. And then also engraft. So every day they come take blood work and you're like just looking at the numbers, waiting for the numbers to get higher. But for me, whilst the numbers were cool and eventually the day of engraftment comes and you're excited, I think there were two instances where I was like, oh my gosh, like this is working. The first was definitely so essentially you're in isolation. You can't really go anywhere, see anyone, do anything. And so we actually were living in kind of like a care house. We were in in Calgary. There's like a river valley. So we're down by the river valley. And they allowed me to go for walks when it was at a low traffic time. And so the first day I took a walk and I just remember for the first time that it suddenly felt like in that moment I realized, oh my gosh, you have been sick your entire life. It felt like there was this like weight or something or that I could just breathe better and just feel normal was it was mind blowing. And then the second thing was obviously with one of the symptoms characteristics we have are like the yellowing on the white of our eyes. And so that was sort of how my mom would be like, oh yeah, girl, you're sick and you drink some water was when my eyes would be very yellow. And so I had only ever known myself to look like that, like yellow tinge. And I remember one day waking up and looking in the mirror and the white of my eyes were white for the first time my entire life. I was like 18 years old now. And I just remember like looking in the mirror like, whoa, that's so strange. And till this day, it's been almost 10 years now. That's still I think trips me up because, yeah, like it's just evidence that like I'm not sick anymore. I don't have sickle cell anymore. So yeah. Dr. Blair Bigham It's fair then to say that you don't have sickle cell disease anymore. This genetic disease, you just don't have it. Ufuoma Muwhen I just don't have it. Like my sister had sickle cell, like she has sickle cell traits. So when we look at the blood work, it shows that I have those levels of hemoglobin S. But symptomatically, I don't have sickle cell anymore. I can run, jump like I do. I literally went like bungee jumping off like the side of a mountain. So is that necessary? I just wanted to test it out one year and see if I'm really good. Dr. Blair Bigham Why not? Ufuoma Muwhen You know what I mean? I can travel before the air travel was a problem. If the flight was longer than four or five hours, I would most likely go into crises in the next couple of days. And I can travel now. I've gone to Nigeria, Geneva, like different places. I don't have to worry about bringing an oxygen tank. Like that was so lame back then. Dr. Mojola Omole What do you want physicians to understand about what it takes to get a patient through the process of having sickle cell treatment and then living a very abundantly beautiful life? Ufuoma Muwhen I think number one, I would probably say like with sickle cell disease, there are so many intersections that the patient is living with. And you know, sometimes I know that sickle cell patients can often be difficult. I think I was one of them at a point in time being non-compliant with medication. And it's like your whole life is just soaked up and absorbed by this disease. And so I really do implore physicians to be as patient as possible and to really try to have some of those conversations that exist outside of their disease because they're navigating so many things. Many of these patients are Black, right? They're dealing with systemic issues. There are cultural issues as to why maybe their parents may or may not be supportive of certain treatments and things like that. So I think it really does take a holistic lens to really work with patients living with sickle cell disease. And that applies to when eventually they can have a treatment with sickle cell, like a bone marrow transplant, because I think sometimes with physicians, it's all that you can see is the transplant, the treatment, the medications, but not what it takes for a patient to actually consistently take their medication or to show up in the most suitable way for a treatment. There's so many wraparound supports that are needed for an effective treatment. And I think if physicians knew this and could advocate more to ensure that this is provided for the patient, we'll see more patients have a success story like mine. Dr. Blair Bigham Amazing. Thank you so much for joining us today, Eufuma. Ufuoma Muwhen Thank you. Dr. Blair Bigham Ufuoma Muwhen is a sickle cell patient, or I guess I should say former sickle cell patient. She is the founder of Not Just You, a sickle cell support organization based in Edmonton. And we're going to link that in the show notes. Dr. Mojola Omole Ufuoma's story will no doubt be inspiring to patients with sickle cell, but increasingly, it's not unique. Dr. Kareem Jamani is a haematologist and clinical associate professor at the University of Calgary. He's a current chair of the Cell Therapy Transplant Canada Donor and Collections Committee. Thank you so much for joining us today, Kareem. Dr. Kareem Jamani Thanks so much for having me, Jola. Dr. Mojola Omole So, Kareem, Ufuoma describes her life now. She's swimming, she's travelling, she's playing sports. So she's like your regular, degular, 20-something-year-old. These are the things that for her used to trigger a crisis. What runs through your mind when you hear that? Dr. Kareem Jamani Yeah, it's a profound sense of gratitude that, you know, I can be involved in patient's care where we can see outcomes like this, where we have the technology, the ability to give patients these outcomes that they really deserve. And I guess the second thing I'd say is, come obviously from an oncology background, all of us in cellular therapy, we're very focused on survival outcomes, progression, relapse. And in this case, you know, it's really important to think about quality. And that's what we see with Ufuoma. It's not just about survival. It's about giving patients that quality of life and functioning back. Dr. Blair Bigham So I'm not very familiar with the actual stem cell transplant itself. For physicians who haven't seen this before, how does it work? What's it like? Dr. Kareem Jamani Yeah, so for a stem cell transplant, what we're doing for sickle cell disease is we want to replace those stem cells that are producing cells that have the propensity to turn sickled and cause all of the clinical manifestations of the disease. And of course, all of those cells are arising in the bone marrow. Our goal is just to switch out the cells in the bone marrow so that patients can produce non-sickling haemoglobin. And so the first thing is that we need a donor. So we need a donor who doesn't suffer from sickle cell disease. And that is typically a family donor, like a matched sibling donor, ideally. But sometimes we've used half-matched donors. We call those haploidentical. That could be like a child. It could be a parent. It could be a sibling that's not fully matched. And so once we identify that donor, we need to collect their stem cells. And we'll do that most of the time from the blood. So we give the donor a bit of a white cell booster. And that brings out their stem cells into the blood. And on an apheresis machine, which is basically just a giant centrifuge, we can actually isolate the stem cell layer from the donor's blood and collect it. And then the patient will need to handicap their immune system a little bit and create some space in their bone marrow. And we'll do that using a combination of either chemotherapy and/or antibodies and/or total body radiation, as well as some anti-rejection drugs that would be used in solid organ transplant. And we create that space and we infuse the stem cells. And then we wait. We wait for those stem cells to start growing. There are some early side effects, especially in the first several weeks after the transplant, because there's a transition in the blood-forming stem cells. So there's a period of time where patients are transfusion-dependent. They're having some side effects of the chemotherapy or radiation or antibodies, higher risk of infection and some GI side effects. And these should dissipate over the weeks after transplant. And then there are some risks which we can get into called graft-versus-host disease with transplant when you're transplanting a new immune system into a patient. But at the end of the day, the goal is to basically switch out the red blood cell production. Dr. Blair Bigham So we've heard from you so much. I mean, she feels like she's been cured. Is that the best-case scenario? Can we use the word cured? Dr. Kareem Jamani Yeah. And that actually has been a matter of some discussion now that we have gene therapies as well. And with stem cell transplant, what we can say is it really is a cure. The bone marrow now produces red blood cells exactly as the donor. So this can be considered a cure. When we talk about gene therapy, it's more of a functional cure where the patient's own stem cells are still there, but they've been modified. So that's why we've kind of used the term transformative therapies, because there is a little bit of discussion to be had there. But stem cell transplant certainly would represent a cure. Dr. Blair Bigham And is that sort of like the typical outcome? Is that how most people come out of this? Or is there sort of like a middle road? I mean, obviously, we've heard that some patients can die going through this process. It's like a worst-case outcome. But what's typical? Dr. Kareem Jamani Yeah, so typical is a good outcome. So, you know, meaning that the donor cells start to produce red cells that do not sickle, and the patients move on and have an improved quality of life, and they survive. But we definitely can't ignore the fact that there are toxicities of these therapies that can be fatal, as you've mentioned. With transplant, when you have a fully-matched sibling donor, the rate of death is quite low, because we can be quite gentle with the preparative treatments before the transplant. So the rate of death is far less than 5%. When we're using more mismatched donors, I talked about using half-matched siblings or parents or children, that's when there is more toxicity. So you really have to have that discussion with patients, very frankly, where the risk of death can be in the range of 5–7%. And the other outcome that we worry about a lot is graft-versus-host disease. And so when patients have stem cells transplanted into them, you're giving them a whole new immune system. And that immune system can come into the body of the recipient, and it can look around and say, "Oh, this is totally foreign place for me," and I'm going to attack the organs. And so with the matched sibling donor transplants, the rate of graft-versus-host disease is incredibly low. In fact, it's very rare to see it. But when you're pursuing more of a mismatched transplant, that can be a consideration with up to 10 or 20% of patients having chronic graft-versus-host disease, which can take some years to settle and certainly will delay patients' recovery after transplant and impair quality of life. So these are, again, frank discussions we have to have with patients. And then finally, I'd say the last really important risk to chat about patients with is rejection. So you're, again, transplanting a new immune system, and it's possible for the donor cells to be rejected. And we see that in about 10% of cases when we do a transplant. In that case, it's obviously a very disappointing outcome where the patient goes back to producing their sickle cell. So it's a very tough outcome, unfortunately. So certainly not all patients have a perfect outcome. There are risks involved here. Dr. Mojola Omole So Ufuoma had also mentioned fertility. So what is the risk in terms of fertility? Dr. Kareem Jamani Yeah, so that's, again, thanks for bringing that up. That's a super important point. So for fertility, because we're using what we call conditioning or the preparative treatment before we infuse stem cells, those treatments can certainly impair or completely take away fertility. And it really varies. When we're using the lower-intensity regimens, like for a matched sibling, the risk is not 100%. It might be. It really depends based on patient age. But it's possible to have fertility preserved but not guaranteed. When we're talking about doing the half-match transplants or gene therapy, the risks of infertility are higher because we need to use more heavy, stronger pre-treatment or conditioning chemotherapy that really do impair fertility. So this is an important point that we need to talk about with patients. And I think one of the big challenges is financial. Not all provinces cover fertility preservation prior to stem cell transplant or gene therapy. In fact, the majority of provinces do not. And so, you know, this is another situation, unfortunately, where men are quite lucky in that preserving fertility is, you know, medically much easier to cryopreserve sperm and relatively cheap. For women, preserving oocytes or other forms of fertility preservation are quite medically complicated and very expensive. So this is a big challenge. Dr. Mojola Omole Because I work in the oncology space, it's covered for oncology treatment even in children. So sickle cell is not considered, in terms of when we talk about transplant, as part of oncology. Dr. Kareem Jamani It's not. And this is another big challenge that we run into is we're doing these cell therapies for sickle cell disease in the cancer care world because, of course, that's where all of the technology and the expertise lie because most of what we do in cellular therapy is for cancer. And it's then tough to bring a sickle cell patient into a cancer centre and get them access to all the same resources available to cancer patients. So it's an ongoing, you know, I don't want to say battle, but, you know, it does require ongoing advocacy to make sure we can get our patients the same resources as patients who are being treated for cancer within our programs. Dr. Mojola Omole Well, I see it also as an equity issue because the majority of sickle cell people are Black and brown people. And so, you know, not having that representation to be able to adequately be able to advocate for the people who have no other, like, this is, it is as detrimental and life-limiting as some oncology cases can be, correct? Dr. Kareem Jamani Absolutely. This is a disease. It's not just morbidity, right? It's mortality. I mean, people die from sickle cell disease even in wealthy countries with good medical care. You know, there was a study that came out from U.S. Medicare recipients not that long ago that showed the average survival in the U.S. for publicly insured patients was only 52 years. So you're talking about decades of life lost potentially. So I agree. I think we need to reorient the way we think about cellular therapies, you know, to say that these are not just cancer therapies. We're applying these therapies to highly morbid diseases regardless of whether they're considered cancer or not. So I think we probably need to shift the way we think about cellular therapies. And fundamentally, that will make things hopefully more equitable. Dr. Mojola Omole I'm just going to shift a little bit to gene therapy. So for patients who don't have a match, have a match in terms of a sibling, there's now gene therapy. What exactly is it and how does it work? Dr. Kareem Jamani Yeah, so gene therapy is really cool if you think about it. So again, if you think about sickle cell disease, it's the blood-forming stem cells in the bone marrow that have that mutation in the haemoglobin gene that makes them produce sickle haemoglobin. And so you could go in and fix that gene or interrupt that process in some other way within the DNA. And so that's what gene therapy does. The product that's approved in Canada actually doesn't fix the haemoglobin gene, but it actually disrupts a protein called BCL-11a, which is a potent suppressor of foetal haemoglobin. So when we all are born and we've got foetal haemoglobin, in that first year of life, we're transitioning to adult haemoglobin and BCL-11a really prevents foetal haemoglobin from being produced. So if you can go in with, say, CRISPR and knock out BCL-11a, then you can produce a whole bunch of foetal haemoglobin. And the best thing about foetal haemoglobin in patients with sickle cell disease is that it's been proven time and time again to reduce the morbidity of sickle cell disease and improve survival. So practically speaking, what you need to do is collect stem cells from the patient, just like I talked about collecting stem cells from a donor. So we use growth factors. We get the patient on an apheresis machine and we collect stem cells. Now there can be several rounds of stem cell collection required for a patient with sickle cell disease because that's not a very healthy bone marrow. And so getting stem cells out of that bone marrow is not super easy. But after a number of rounds of collection, hopefully you get enough stem cells and then you ship them off to a manufacturing facility, which is a pharmaceutical manufacturing facility where the gene therapy will be applied to those patients' stem cells. And that process can take months. So there's those months we need to support the patient with transfusions and keep them healthy because when we get those modified stem cells back, we are going to bring the patient into hospital. We're going to get rid of their current bone marrow. And so that does require high-dose chemotherapy. We call it myeloablative because it's going to wipe out the bone marrow. And then we're going to infuse their gene-modified stem cells back into them. Those stem cells are going to then go into the bone marrow and start growing. And with the product that stimulates haemoglobin F production, what you'll see once you infuse the stem cells and they have a chance to grow, you'll see those patients now produce normal amounts of haemoglobin and that's because they have massively upregulated haemoglobin F production. So they'll now have something like 40% haemoglobin F and that dilutes out the haemoglobin S or the haemoglobin and really protects those patients. There is another gene therapy product. It's not approved in Canada but marketed in the U.S. that actually introduces a novel haemoglobin gene that does not sickle. And so that's an alternative. That's introduced into the cells by a lentiviral vector rather than CRISPR. But the process is the same. Collect the stem cells, gene modify them in the lab, and then bring them back to the patient after high-dose chemotherapy. Dr. Mojola Omole So how does success look different in terms of like the gene compared to transplant when we talk about gene therapy? Dr. Kareem Jamani So it should look very much the same. So what the gene therapy trials have shown is that patients have less or no crises in terms of pain crises or acute chest syndrome. Quality of life has been measured in a very standardized way in those clinical trials and has shown that quality of life significantly improves after gene therapy. So practically for the patient, it should feel the same. And it's just that with transplant, you've actually corrected entirely the bone marrow, whereas with gene therapy, you've just, you know, with the haemoglobin F augmenter, you've basically created a functional cure. That patient still produces sickle cells, but the haemoglobin F is protective. So it would be more of a functional kind of cure. And there are some interesting early studies showing perhaps red cell behaviour is not quite normal after some gene therapies. It trends towards normal, but the red cells still are a little bit less deformable than regular red cells. So it might be, you know, you might create red blood cells that are in between normal and sickle, and that's just enough to keep these patients healthy in the long term. Dr. Mojola Omole You can actually access the gene therapy in Canada right now? Dr. Kareem Jamani So no, not yet. So it has been approved by Health Canada. It's been given a positive recommendation for funding by the CDA, Canada Drug Agency. So it's at the point of negotiations now for pricing. Dr. Mojola Omole Okay. Are there some patients that neither therapy is going to be, like, that's going to be good for them? Dr. Kareem Jamani Yeah. And this is the challenge we run into on the adult side, is that unfortunately some patients have had many complications of their sickle cell disease, and we worry that it's perhaps too late. They've had significant injury to organs, you know, like lung disease, cardiac disease, and these patients might just be too sick to tolerate any of the preparative treatment. And so I think, you know, the future hopefully will bring patients being able to access these treatments earlier in the disease course, so we don't get to the point where patients are too sick to access these treatments. Kids do really well with these treatments. So, you know, I think the ideal situation is all of these patients get access to these therapies in childhood, and they don't grow up to be adults with sickle cell disease. Dr. Mojola Omole So you wrote this paper because most Canadian physicians don't necessarily have exposure to these, to necessarily, like, how to manage sickle cell patients and the options that are there for them in terms of long-term cure. What's one thing you want physicians to walk away with? Dr. Kareem Jamani Yeah, I'd say, you know, the one thing I'd say is sickle cell patients struggle in, especially in the acute care system. They, I mean, it's been shown time and time again, access to pain medication and appropriate treatment early on for pain crises is probably too slow. We know there's an element of bias, whether it's, you know, subconscious or probably more subconscious. These patients need good treatment. They need timely treatment. The vast majority of patients with sickle cell disease are not coming into the acute care setting because they're seeking drugs. They truly are suffering from the disease. And these are patients who, you know, when they have difficult interactions in the healthcare system, they sometimes then struggle to follow up with their chronic long-term care that will keep their disease as well-controlled as possible. And they're sometimes very hesitant to have transformative therapies like stem cell transplant or gene therapy. I mean, you can imagine that if patients have had bad interactions with the healthcare system and then, you know, we're telling them, "Don't worry, we're going to give you this high-dose chemo, but we're going to take care of you. We promise, you know, you're going to have all these terrible side effects, but we'll deal with it. We'll get you through it." You know, trust can be a problem. And so I worry sometimes that when patients have bad interactions in the healthcare system, it will dissuade them from having good appropriate long-term care for their sickle cell disease and eventually potentially curative therapy. Dr. Mojola Omole Great. Thank you so much for joining us today. Dr. Kareem Jamani Yeah, I really appreciate it. Thanks for having me on. Dr. Mojola Omole Dr. Kareem Jamani is a haematologist and clinical associate professor at the University of Calgary. He's the current chair of the Cell Therapy Transplant Canada Donor and Collections Committee Dr. Blair Bigham So, Jola, this is, like, this is medicine. Like, this is really cool science. It sounds amazing that you just, like, totally destroy somebody's entire stem cells and then come on in with some new ones and hope that they take. And you're cured. But you know what strikes me most? Dr. Mojola Omole Potentially cured. Dr. Blair Bigham Potentially. Well, yeah. All for this potentially high mortality rate. About 5 to 7 percent, I think Kareem said, die in the process of hoping that their stem cells take. Dr. Mojola Omole But if you do the flip side, that the life expectancy of someone with sickle cell is in their 50s, for some, that's a risk they're willing to take, given that those 50-odd years are in and out of crises and not actually having great quality of life. Dr. Blair Bigham But if the decision to move forward with one of these two amazing therapies is best made in childhood, like, how is an 8-year-old supposed to weigh those benefits? And if an 8-year-old dies during induction, I mean, that's, that's a tragedy. It just seems like such a difficult decision to make. Dr. Mojola Omole I don't disagree that it's a difficult decision, but I do think that we don't view it... Like, if we think about the framework that it's actually being done in oncology, then why would, why do we differ when someone has, you know, when someone has lymphoma at a young age and parents make the decision to go ahead and treat them? Right? So just because you can live with sickle cell doesn't give you quality of life. And, you know, from my perspective, working a lot in equity is that there is inequity in the fact that we don't view sickle cell in the same realm. But if you're undergoing a stem cell transplant, that tells me that this is just as serious and life limiting as other forms of cancers. Right. Dr. Blair Bigham And it's interesting how it's almost orphaned in the sense that you have to show up to a cancer hospital and you don't even have access to the full suite of services because you technically don't have cancer. And so they're kind of finding a workaround for this population within the system. But you're right. Dr. Mojola Omole That's a problem. Dr. Blair Bigham We have to change how we view this. Yeah, absolutely. Dr. Mojola Omole That's a problem that, you know, because it does not affect the majority of people that look like certain people who are being treated, that it becomes an orphan disease. And that is a problem. Dr. Blair Bigham And that's probably the root of why it's orphaned. Dr. Mojola Omole I think also why, you know, fertility is not covered for them. Right. Like they don't have, like there's not fertility across Canada. If you're having any sort of oncology treatment, whether you are seven years old or whether you are 50, no, 40 years old—40 is the cutoff—you have access to fertility preservation. Right. But in this situation, they don't have access to fertility preservation unless it's through whether it's their parents or themselves, depending on their age, to cover. That in itself makes it such a difficult decision. Like you are adding an extra layer onto someone where you're almost removing hope of the future, because for some people, reproduction is part of hope of a long life. Dr. Blair Bigham Yeah, it's interesting how the way we've set systems up for other therapies almost block innovation in a way from from having the same ability to, say, freeze your eggs or have that fertility treatment or be fully, fully wrapped up in a plan of care the way a lot of cancer centres do things so well. Dr. Mojola Omole And I think that's very interesting. These, whether it's the gene therapy or the stem cell transplant, has the ability to—from what Ufuoma is saying and what Kareem is saying—cure sickle cell, that it's no longer a disease that people die at very young ages and people have poor quality of life until they die. So like to me, being able to have a very holistic wraparound care that we often do not... we're not perfect in oncology, but we try. I think peds oncology might be a little better. It should have the same thing, because this can change the trajectory of so many people's lives in our country, but also elsewhere. Dr. Blair Bigham

A hundred percent. That's it for this episode of the CMAJ podcast. The link to the study is in the show notes. Please have a look. And remember: 4:07

follow, subscribe, like, share our podcasts wherever you download. It really goes a long way to helping us get the message out. The podcast is produced for CMAJ by Neil Morrison at PodCraft Productions. Catherine Varner is deputy editor of CMAJ and our senior editor on the podcast. I'm Blair Bigham. Dr. Mojola Omole I'm Mojola Omole. Until next time, be well.