John J. Strouse, MD, PhD

 For take-home messages, the first and foremost is that people with sickle cell disease want to live normal, active lives. They don’t want to spend their time in the hospital. If you’re seeing them in front of you, there’s a reason, and there are always strategies to try to improve the overall quality of life for people with sickle cell disease. We should provide them with all of the opportunities available to try to make their lives better. There has been a lot of structural racism that has affected how patients with sickle cell disease are treated, both in the emergency department and in lots of places. We have to overcome that structural racism and make sure our patients have every opportunity to live a long healthy life.

 It is so important for hematologists and primary care providers who take care of patients with sickle cell disease to first, establish the trust. Many of our patients suffer from what they perceive to be bias against them when they come in for crisis. Please take the time to listen to them and to get to know them because once you can establish that trust, we can really improve the lives of our patients with sickle cell. Second, sickle cell disease-modifying therapies are needed. We can no longer think that sickle cell pain is simply, “Am I in a painful event, or am I not in a painful event?” Please understand the importance that the organ complications over time are the life-limiting complications of sickle cell. Getting patients to accept sickle cell disease-modifying therapies from an early stage of life is vital.

Third, understand the impact of sickle cell on quality of life. Please pay attention to schoolwork, how sickle cell affects their relationships, how it can affect them holding a job, and view our patients in the whole because sickle cell impacts every aspect of their lives. In several cases, we’re the only providers they have to turn to for addressing this multi-socioeconomic impact of sickle cell. Please look out for the entire patient, not just the sickle cell pain event.

 It’s important that we take a life span perspective when we treat people with sickle cell disease. Many of the complications that we see in adulthood start in pediatrics, but don’t necessarily cause problems for children. But that doesn’t mean that they aren’t important. I’ll take the kidney as an example. We start seeing a lot of microscopic proteinuria, the microalbuminuria in children with sickle cell disease as adolescents. It can be almost a third of adolescents who have sickle cell anemia who develop microalbuminuria, but they don’t have renal insufficiency as children. Many of them still have hyperfiltration, where their creatinine levels are lower than normal. As those patients move into their 20s and 30s, we see the development of chronic renal disease, and with that, worsening anemia and disease progression in other ways. It’s important that we intervene when people with sickle cell disease are children because that’s where these end-organ complications start.

Videos

Sophie M. Lanzkron, MD, MHS; Jeffrey D. Lebensburger; and John J. Strouse, MD, PhD, share key takeaways and closing thoughts for the management of sickle cell disease.

Advice for Sickle Cell Disease Management

 The first thing that our patients can do to prevent sickle cell complications is to be accepting of sickle cell disease-modifying therapies. It is important for our patients to appreciate that sickle cell disease is not just pain, but something that can impact your entire body and your quality of life. Being accepting of a sickle cell modifying therapy is vital. There’s a lot of work that we have to do as clinicians and health care providers to gain the trust of our patients because trust is the most important thing in our patient relationship, to build that trust and to get them to understand the importance that this is not just a disease of pain events, but that this is a multisystem and life-limiting disease. We strongly recommend a very healthy lifestyle. Many patients try to shy away from very strenuous exercise, which we agree with, but making sure that they have a healthy lifestyle has to include at least some moderate level of exercise. Being well hydrated is important for a patient with sickle cell disease and to maintain hydration even during sickle cell events.

Another thing that’s anecdotal, but very prevalent, is other healthy lifestyle things. For example, when patients are swimming, making sure they come out and get themselves warm. During the cold months, making sure that they’re very well dressed, so they don’t have the complications that can happen when they get themselves very cold. Or in the summer months when it’s very hot, maintaining that hydration despite being out in in the hot summer months is important.

High altitude also can put patients at risk for events. A very healthy lifestyle is important to our patients with sickle cell disease. That starts with sickle cell disease modifying therapy, but then doing other things in terms of eating right, exercising, and maintaining their body’s temperature are vital to protecting the lives of our patients.

 I did both combined pediatric and adult hematology training. For the first 14 years of my career, I was more pediatric-focused with just a toehold in adult sickle cell. For the last 5 years, I’ve been directing an adult sickle cell program, with a little bit of pediatric sickle cell disease in my practice. It’s quite clear that as people with sickle cell disease get older, we see disease progression, which includes developing more of a chronic pain phenotype that’s generally in adolescents and young adults. We see that developing, which leads to more daily impact of their pain, and more chronic pain that can really affect their quality of life and their ability to complete their daily activities, things like school, work, and family. We also see progressive organ dysfunction, such as elevations in creatinine, which are relatively uncommon in children, but become much more common in adults. We see more pulmonary hypertension. We see the long-term impact of anemia on the brain. All of that is progressive into adulthood. We see this progression in disease that affects multiple systems. We see orthopedic complications, such as avascular necrosis requiring joint replacement, which is relatively uncommon in children, but becomes more frequent decade by decade as people get older. We see more venous thromboembolism as people go from being adolescents, to young adults, and to older adults. One of the things that has been occurring in sickle cell disease is, with effective newborn screening and early preventive care, and better disease-modifying therapies, it’s rare that we see children with sickle cell disease die from complications of the disease. We have this increasing group of adults and older adults, where the progressive organ dysfunction from sickle cell disease is causing impact in their daily life, and that can be on physical functioning, cognitive functioning, or their activities of daily living.

This is what we think disease-modifying therapy helps with. We think that therapies that make their sickle cell disease more mild and help prevent acute complications will likely have positive impacts on some of the disease progression. It’s hard to study disease progression because it happens gradually, and it takes long studies and long-term follow-up. We don’t have as much evidence as I would like about the impact of disease-modifying therapies on chronic organ dysfunction, because of these challenges with studying. But we have little bits and pieces that being on hydroxyurea can lower your cerebral blood flow velocity. Maybe it helps prevent silent cerebral infarct, and it can certainly help prevent a second stroke after people have had one stroke. We have some information that being on hydroxyurea can lower the amount of albumin that is in people’s urine. Once people develop albuminuria, then putting them on hydroxyurea can decrease that. We know from other disease settings, such as diabetes, that if we decrease the amount of albumin in people’s urine, that that can decrease their progression of renal disease. We have these suggestions that hydroxyurea, and potentially some of the newer disease-modifying therapies, can prevent disease progression.

 Lots of people have concern about dependency on opioids for people with sickle cell disease. Data suggest that the risk of developing dependency on opioids is less, or at most, the same as the general population. When you’re using opioids for any patient population, you have to pay attention to the risks of the misuse of opioids. Sadly, we don’t have great therapies to manage patients’ pain. At this point, we don’t have a medication that can stop a crisis once it has started. So, we have to rely on opioids to treat people who are presenting with acute pain. I see it as my job to keep an eye on my patients who are on opioid therapy, not the emergency department’s job. The primary sickle cell doctor and some pain management people should pay attention to how patients are using their opioids and whether the opioids are working. In the acute setting that is the primary therapy, but probably about 60% to 70% of adults with sickle cell disease develop chronic everyday pain. We don’t have great therapies to manage chronic everyday pain. We are often relying on chronic opioid therapy. We all have to be careful about our use of opioids. In patients who are functional, taking care of their families, going to work, who happen to take chronic everyday opioid therapy, the key is that they’re functional and able to do the things that they need to do despite the fact that they require chronic opioid therapy. The people we should be thinking about alternative therapies for are people who don’t respond to chronic opioid therapy and still have pain that’s a 7 out of 10 every day, who are in the hospital a lot, who aren’t able to go to work, which suggests that the chronic opioid therapy isn’t working for that population. You need a good team to think about alternatives to the use of chronic opioid therapy.

Experts in hematology address unmet needs and precautions patients can take to avoid complications of sickle cell disease.

Unmet Needs in the Management of SCD

 Gene therapy is really exciting. The holy grail of treating people with sickle cell disease is to be able to put something in that gets rid of that point mutation that causes the problem. There are a couple of different mechanisms that are being used for gene therapy. One is to try to insert a hemoglobin A gene. There’s also thought about increasing a fetal hemoglobin gene, and thenthere’s gene editing to try to turn off 

 in order to increase the body’s own production of fetal hemoglobin. Different folks are trying to approach this in different ways, all of which are very interesting, some with the goal of increasing the amount of hemoglobin A and some with the goal of trying to increase fetal hemoglobin levels.

 The goal for all of us needs to be, first, can we cure every patient with sickle cell disease who wants to be cured? Second, can we improve the quality of life of our patients? And third, can we prevent organ dysfunction? Anything that we can do to be able to cure our patients, whether this is gene therapy or a stem cell transplant, has to be a research priority. There are several studies going on looking at either gene modification or other forms of gene therapy. In February of 2021, Bluebird Bio had to suspend its clinical trial as they analyze the safety of gene therapy, and the concern is that some of the patients who underwent gene therapy developed leukemia. What we really need to understand is why, and is this due to the busulfan conditioning regimen? There was some suggestion that it was due to the busulfan. But there is still this question of whether it’s either the lentiviral insertion, or whether there are other gene therapy adverse effects that lead to leukemia. There’s a recent postulation that maybe it’s the switch from a homeostatic mechanism to regenerative mechanism that would promote potential leukemogenesis. Even though the Bluebird therapy trial was suspended, and the hope is that they are able to open it again, there are inherent issues whether it’s stem cell transplant or gene therapy. But that shouldn’t deter us from also wanting to pursue what our patients need, which is to be cured of their disease. We believe that most patients with sickle cell disease, if not all patients, deserve sickle cell modifying therapy. The hope is that someday we can safely and effectively offer curative therapies.

Any of the curative therapies should be able to be disease modifying, and we believe that in looking at our patients with sickle cell trait. While these patients for their own reasons may have kidney issues, overall, most patients with sickle cell trait are not impacted by sickle cell disease. The great thing about gene therapy is that we likely do not need to fully correct our patients. If we can just get them to a low enough sickle cell disease level, similar to many of their parents, where they don’t have sickle cell complications, then this would definitely be a disease-modifying therapy.

 It’s going to be expensive, and substantially more expensive in the short run than a blood transfusion, and substantially more expensive than stem cell therapy in the long run. We don’t know what the cost of gene therapeutic would be in the US. But the 1 agent that’s been approved in Europe for beta thalassemia, Bluebird Bio’s LentiGlobin, was just shy of $2 million, and that’s the acquisition of the gene therapeutic. You still need to do the autologous transplant and give people the high-dose busulfan and support them through that. Let’s say $2 million for gene therapy, if the cost is similar to Europe. This is substantially more than your average bone marrow transplant, where I typically think of cost for the first year in the $300,000 to $500,000 range. It’s also a curative therapy. Gene therapy will be substantially more expensive than other stem cell therapies we are using for people with sickle cell disease, such as match-related donor, or match-unrelated donor transplant, or haploidentical transplant. When we compare the cost, blood transfusion is a fairly expensive therapy because we often need to do chelation as well. I use a figure in my head with the cost of chelation of about $100,000 per year. It may be that gene therapy becomes cost-effective over time compared to blood transfusion, but it still is going to have an incremental cost even compared with blood transfusion for people with sickle cell disease. I do think that it has a potential for decreased toxicity compared to stem cell therapy, and potentially blood transfusion as well. Using a longer economic outlook, it may turn out to be cost-effective. But in the short and medium term, it’s going to certainly increase the cost for people who receive it for sickle cell disease.

Drs Sophie M. Lanzkron, Jeffrey D. Lebensburger, and John J. Strouse, share insights on the safety profile and cost of gene therapy for the management of sickle cell disease.

Role of Gene Therapy in Sickle Cell Disease

 Crizanlizumab is a humanized monoclonal anti–P-selectin antibody. We don’t think of it as just being the red cells getting stuck; we know that there’s a lot more going into this. One of the big players in vaso-occlusion is P-selectin. Crizanlizumab is a medication that’s given IV [intravenously] and blocks P-selectin binding, which can prevent vaso-occlusion. We believe that if you’re blocking vaso-occlusion, you can then reduce the likelihood of having an acute pain event. In the crizanlizumab study, looking at patients who had 2 to 10 pain events per year, they randomized between placebo and crizanlizumab. They showed that crizanlizumab reduced the likelihood of having an earlier sickle cell pain event and reduced the total number of pain events.

 This is a more recent analysis of data from the SUSTAIN trial. The SUSTAIN trial led to the approval of crizanlizumab for the treatment of people with sickle cell disease, and vaso-occlusive events requiring health care utilization. It was one of the drugs approved late in 2019, and this is looking at the data from that initial clinical trial, but a different end point. Instead of looking at the rate of vaso-occlusive events published in 2017, they are looking at the use of opiates for the management of pain associated with these vaso-occlusive events. They compared the people who received the dose that was approved for crizanlizumab, which was 5 mg/kg given IV every 2 weeks for the first 2 doses and then every 4 weeks, compared to the placebo group. They showed that the mean annualized days with opiate use in the treated population was decreased by 57% compared to the placebo group. However, that wasn’t statistically significant. They looked at prn [as needed] opiate use, and they showed that was lower in the crizanlizumab compared to the placebo arm, with an absolute reduction of just over 2 days and a relative reduction of 50%. That was statistically significant with a 

 value of just under .05. What does this mean for patients? In general, patients are getting opiates when they’re having severe pain from their sickle cell disease. This reflects the decreased rate of severe pain in people with the sickle cell disease being treated in these studies. And they were just looking at their opiate use when they were having health care utilization. This doesn’t reflect their home opiate use. But they did show that there was a meaningful reduction. A reduction of 50% for [as needed] opiates and 57% for total opiates in numbers of days means that they’re having less pain and less impact on their life and quality of life.

Crizanlizumab has a different mechanism of action than voxelotor and actually affects more of the downstream problems that we see because of the hemolysis and the hemoglobin abnormalities in the red cell. We have an increased expression of adhesion molecules, and crizanlizumab is a P-selectin inhibitor that decreases expression of those adhesion molecules, with the idea that if you decrease the adhesion molecules, you will decrease the stickiness of the environment and you will have fewer crises. The initial study and some follow-up studies have demonstrated that the drug overall is safe and decreases crisis frequency by about 50%. One thing to keep in mind when you look at both the data for voxelotor and for crizanlizumab is that the number of individuals who were in the high-dose arms of those studies was less than 100. A recent ASH [American Society of Hematology] publication did demonstrate that there were no additional safety signals seen with crizanlizumab, but the number of subjects who were studied was small. We know from being in the community and treating patients that there are some patients who can have significant pain when crizanlizumab is infused. But they did demonstrate that there were patients who had pain in the initial studies, but most of those people were able to be treated with Tylenol and Benadryl and their pain improved. In the community in real-world settings with this drug, we have noticed that there are some patients who develop more severe pain. There is a case report published demonstrating a young person who actually ended up hospitalized because of pain that started during their infusion of crizanlizumab. It’s something to be mindful for as a potential adverse effect of the drug. It’s poorly understood at the moment, but something that most of us who take care of people with sickle cell disease are mindful about and keeping an eye on, and talking to patients about the potential that it could cause increased pain. In the short term, most people who are going to have this sort of painful response usually have it after the first or second dose and then after that, they do fine with their infusions.

 Crizanlizumab is approved by the FDA for patients aged 16 and above. Therefore, we have a little bit less experience in the pediatric setting than we do in the adult. Patients who have had multiple pain events we will try to put on crizanlizumab. In our patients with chronic pain, we still are seeing some pain events, but we’re looking into whether it can reduce the total number of hospitalizations. But the adults are having a little bit more anecdotal success with crizanlizumab in treating patients with pain. Now voxelotor, while it has a benefit for reducing pain events, it also has a benefit of improving hemoglobin through hopefully reducing hemolysis. We have several patients who either are not doing well on their hydroxyurea or are not getting a great hydroxyurea response. I find that patients who have very low hemoglobin, so those who are severely anemic, are at high risk for organ complications. For those patients, I prefer voxelotor because from a mechanism of action standpoint, these are the patients with severe hemolysis for whom we think we need to do something to prevent heme-induced injury. While both of them may have benefits for pain, as somebody who really worries about organ damage because that’s going to lead to mortality in our patients with sickle cell disease, in those situations I’m interested in continued research on voxelotor, to see whether it can reduce pain events, kidney damage, pulmonary hypertension, CNS [central nervous system] events. That’s an exciting opportunity to prevent organ disease, especially for someone who believes in the power or the problem of free hemoglobin.

Expert hematologists comment on the use of crizanlizumab in reducing painful crisis frequency in sickle cell disease and share their experience with the drug in clinical practice.

John J. Strouse, MD, PhD

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