Michael R. DeBaun, MD, MPH, Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease 

 In terms of avoiding complications, a family that is well educated about the disease, the treatments available, the preventive strategies for complications, including nonmedicinal strategies explicitly, such as mindfulness, good eating habits, exercise within moderation, and good sleep habits, they are going to do far better than the family that does not have these in their lives. Most providers are not well informed about sickle cell disease. Thus, a well-informed parent or adult with the disease who provides information in a nonthreatening fashion can improve their own health care. I would stay abreast of the research as another strategy, because treatment of sickle cell disease in 2020 is vastly different than treatment of sickle cell disease in 2010, and I would wager that curative therapy options in the next decade will be better. We will have improved outcomes with less toxicity. 

Lastly, I would consider all the FDA-approved drugs as potential options for treatment. Particularly for those individuals with hemoglobin SS and S beta-zero thalassemia, with each passing year, we learn more about the benefit of this drug. In my opinion, by far this drug should be in the stable of anyone with hemoglobin SS and S beta-zero thalassemia because the benefits far outweigh any of the toxicities or complications in taking the medication. For the other drug, I think it will take time before the research will demonstrate what the specific benefits are in decreasing the rate of CNS [central nervous system] disease, heart, lung, and kidney disease, as well as potentially priapism and other complications of the disease. But I would say stay tuned because we will learn more about how these additional drugs will prevent complications in organ function in the next decade. 

The first recognition for decreasing opioid dependency is acknowledgment that pain occurs. There should be trust between the provider and the patient, and the patient needs to develop a strategy to manage the pain that is not dependent on opioids but is dependent on first, understanding the triggers, and understanding how to use mindfulness and other strategies to decrease the severity and intensity of the pain. Then, the goal is to learn enough about their disease and enough about their treatment to use a stepwise approach to managing their disease when it comes to acute vaso-occlusive pain. That would include the use of nonsteroidal drug, the use of hydrocodone as a stepwise approach, and then eventually morphine. After the pain subsides, it’s important to stop the medications I just mentioned so the use of pain medications will not result in other complications.

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Strategies to avoid complications of sickle cell disease and ensure non-dependency on opioids when treating patients for pain as a result of the disease. 

Unmet Needs in Sickle Cell Disease Management 

 The topic of gene therapy and gene editing in sickle cell disease in and of itself is a misnomer. What has to be acknowledged is that the terminology should probably be referred to as myeloablative gene therapy and myeloablative gene editing. Why is that important? It’s important because as a former oncologist, I know that when you treat someone with myeloablative therapy, in this case, busulfan for both gene editing and gene therapy, you may cause unwanted effects 5 years down the road. The key is to recognize that when you provide myeloablative therapy to a 10-year-old, you would want to follow them for the next 50 years to know what the effects are. We know from late health effects of chemotherapy, specifically hematopoietic stem cell transplant, that there is no plateau for cardiovascular risk and other complications associated with curing a child with hematopoietic stem cell transplant. That’s the first challenge that I think we need to address. Also, families need to understand that it’s not just gene therapy and gene editing; it’s myeloablative gene therapy and gene editing. Furthermore, the field is moving forward so that 5 years from now, maybe 10 years from now, we may have nonmyeloablative gene therapy and gene editing, which we hope would decrease the sequelae associated with myeloablative therapy. 

The second point is that these therapies are experimental. They are the newest approaches to curative therapy in children and adults with sickle cell disease. They were developed because the donor pool was small for individuals who wanted to be cured from sickle cell disease. Specifically, for the gold standard approach, which is myeloablative, matched related donor transplant, which has been in existence for over 25 years in sickle cell disease, you had to have an instantly matched sibling donor. Unfortunately, less than 15% of individuals had donors who met the criteria of being a matched related donor. Thus, there had to be a strategy to increase the donor pool, and gene therapy was the original alternative 25 years ago. There are people who’ve worked in this field for over 2 decades because they recognized that you needed to expand the donor pool. Potentially the best donor would be the patient’s own cells. That’s No. 1. But then No. 2 is this challenge of myeloablative chemotherapy. Apparently, gene therapy and gene editing require myeloablation. As a result, many adults with comorbid conditions of heart, lung, or kidney disease could not undergo curative therapy.

What’s happened in the last decade is that there’s been what we refer to as haploidentical transplant with post-transplant cyclophosphamide. Why is that important? First, this therapy does not require myeloablation. You use a nonmyeloablative preparative regimen, which is much more amenable for adults who have chronic heart, lung, and kidney disease, which many of our adults with sickle cell disease have. Second, the donor can be a half match. Thus, in systematic studies that have been done, not only in the United States but in other areas of the world, the donor pool for patients with sickle cell disease is about 90%. In other words, 90% of individuals who want to have curative therapy, have the availability as a result of having a half match, and that’s typically a parent or it could be a sibling. Or it could be a child of the individual who wants to be cured. Consequently, there’s a much more expansive pool.

Now, when an individual with sickle cell disease comes in, and says, “I want to be cured of my disease,” there’s no longer just a single approach. If you don’t have a matched related donor, you still have these alternative strategies. You have the myeloablative approach, you have a nonmyeloablative approach for a matched related donor. Then, you have the nonmyeloablative haploidentical transplant protocol. I would consider all of these therapies that I just mentioned to be experimental. They should be done in a clinical trial setting with a data and safety monitoring board to address safety and utility of the clinical outcome. I would discourage single center trials as a strategy unless there are high levels of oversight and the benefits clearly outweigh the risks compared to the existing trials available at clinicaltrials.gov.

An expert in hematology/oncology discusses the emerging role of gene therapy to treat sickle cell disease. 

Investigating Strategies to Treat SCD Using Gene Therapy 

 This is a highly debated discussion point, who should undergo a transplant? I will split the world into 2 paths. I will split the world into the adult half, and then I’ll migrate to the other side, which is the world of children. What’s clear in large cohort studies is that the overall survival of adults with sickle cell disease has not dramatically changed in 25 years. The median survival for individuals with hemoglobin SS beta-zero thalassemia especially, and for that matter SC disease, from 2 academic centers that were delivering state-of-the-art care over the last decade, the median survival was 48 years. The median survival of a natural history study with multiple sites across the United States, prior to the use of hydroxyurea, was 48 years. 

I believe that adults with sickle cell disease, who fall into a category of being symptomatic from their disease, and you can pick any one of the manifestations, but just having the disease in and of itself is associated with a shortened lifespan. In light of the fact that hematopoietic stem cell transplants are still experimental, we can’t tell you what the standard approach should be. Because with every 5 to 10 years, we’re improving strategies that decrease the complications associated with a hematopoietic stem cell transplant, that decrease transplant-related mortality, and decrease the short-, intermediate-, and long-term sequelae associated with myeloablative chemotherapy. From where I sit and based on the literature available, adults with sickle cell disease, adults being 18 years of age and older, should have the option for curative therapy based on their own risk profile. 

Now, in children the equation changes. In pediatrics, parents and providers are making decisions for children. Our approach in the United States is typically for a child to be enrolled in a clinical trial where there’s greater than minimum risk, where the benefit of the experimental therapy has to be at least as good as the current therapy. This is a very subjective area because if one takes the point of view of mortality, multiple studies throughout the world in high-income countries, such as the United Kingdom, Europe, specifically Belgium and France, have indicated that the overall survival for children with hemoglobin SS, hemoglobin S beta-zero thalassemia, is 99%. Yet we know that in the performance of hematopoietic stem cell transplant, treatment-related mortality may exceed 1%. We expect it to exceed 1%, with large numbers across multiple sites. Thus, there have to be other components of the disease that tilt the scale as to why you would offer a child curative therapy that could result in premature death, when standard therapy in 2021 would indicate that we can get almost every child to their 18th birthday. 

What are the factors that may tilt the scale to justify curative therapy in a pediatric population? They would include the presence of stroke. We know that in a child who’s had a stroke, the blood transfusions are palliative. We also know that if a child has had a silent stroke, blood transfusions are palliative. Thus, the only option at this point for children who’ve had an overt stroke or a silent stroke is to say to the family, we have to transfuse your child and this young adult, indefinitely. And many families are unwilling to comply. The alternative is that when we don’t transfuse those patients monthly, namely patients with overt stroke or silent stroke, they are at a lifetime risk of having new injury to the brain. 

Likewise, there are children and young adults who have acute chest syndrome that is considered life-threatening. In many cases, there can be 2 or 3 events where they are in the ICU [intensive care unit] with life-threatening complications of acute chest syndrome. There is a small group of children who can have progressive kidney disease and hypertension that is recalcitrant to standard therapy. And then, what we have recently revealed is that children and adults, but specifically children, can have major priapism. That’s priapism that lasts for at least 4 hours, which is considered a urological emergency. We have no antidote for priapism of that duration, other than surgical intervention, which requires a needle to be placed in the penis and for blood to be aspirated from the penis. 

My belief, based on the evidence, is that progressive end-organ disease in children despite best treatment is an indication for curative therapy for those considered minors, namely less than 18 years of age. Of course, that 16- or 17-year-old, who’s less than 18 years of age but is having severe disease and has a sense of autonomy, I think it’s more than reasonable to consider their opinion, if they are mature enough to understand the true implications of a decision that may result in cure or treatment-related death. 

Considerations for using HSCT (hematopoietic stem cell transplantation) in patients with sickle cell disease. 

Stem Cell Transplant: Management of Sickle Cell Disease 

 According to some of the recent guidelines, particularly the American Society of Hematology guidelines on red blood cell transfusion, ideally you would identify the patient’s minor red blood cell antigen phenotype. This is so that, in the event the patient develops red blood cell antibodies, you can know explicitly what would be or would not be compatible with that patient. I cannot underscore enough the importance of establishing an extended red blood cell phenotype, particularly for our adults, who often receive 1 or 2 units of blood, often inappropriately, for an acute vaso-occlusive pain episode while they’re in the emergency department in a non–sickle cell disease center, with the belief that this will abate the pain episode. But there is limited to no evidence that transfusing someone in the midst of a vaso-occlusive pain episode, for the sole reason of decreasing the acute vaso-occlusive pain episode length of time, is effective. Despite that, many adults will have multiple alloantibodies and become extremely difficult to transfuse, which puts their lives in peril, because often when there’s acute chest syndrome or multiorgan disease, the only antidote is the transfusion.

Some of the complications to red blood cell transfusions that we initiate for primary and secondary stroke prevention, and other indications for prevention of disease in this population, include acute red blood cell transfusion reaction, red blood cell alloimmunization, which I just mentioned, and viral-borne disease, which is now extraordinarily rare in the United States. Once you are transfused routinely, let’s say monthly for at least a year and often up to 2 years, typically you have excessive iron stores in your body. Then, we have to give you a treatment for the iron. So, not only do we have to treat you to prevent a complication of the disease, but then we have to give you another treatment to prevent the complications of the treatment. That’s chelation therapy, and that is quite cumbersome for individuals who are being transfused on a monthly basis. Consequently, that presents another barrier for families, having less than high levels of enthusiasm for monthly transfusions in this patient population.

Michael R. DeBaun, MD, MPH, provides insight on the screening and monitoring procedure for red blood cell transfusion for the management of sickle cell disease.  

Michael R. DeBaun, MD, MPH, Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease

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