Considerations for using HSCT (hematopoietic stem cell transplantation) in patients with sickle cell disease.
Michael R. DeBaun, MD, MPH: 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.
Transcript Edited for Clarity