Evolution of Therapies in Sickle Cell Disease


Wally Smith, MD, reviews the goals of treatment and discusses current disease-modifying therapies for SCD.

Ifeyinwa Osunkwo, MD, MPH: Let’s move into treatment options. You mentioned this was the first genetic disorder discovered, over 100-plus years ago. We have a limited number of treatments. Let’s talk about what those treatments are. Dr Smith, what are the goals of treating sickle cell disease? What are the treatment options that are available right now for sickle cell disease?

Wally Smith, MD: Treatment of sickle cell disease has evolved from symptom management in the late 1940s through the 1970s to disease modification, meaning stopping some of the manifestations of the disease by giving medications that deal with the sickling phenomenon. It has now advanced to what I’m going to call disease arrest. I’m going to avoid using the term cure, and I’ll explain what I mean by that. In my mind, disease arrest means that the ravages of the disease are stopped in their tracks, even though the old damage doesn’t go away. That’s a consistent theme with what you’ve heard. When it comes to things like your organ failure and your post-traumatic stress syndrome, your background is your background. But I might be able to stop further damage with medications or with disease-arresting therapies that completely stop the sickling process. That’s my goal. If I can, I’m going to try to do that.

That leads to the order of medications that we got. The first drug we got was hydroxyurea. That was a disease-modifying therapy. It works by basically decreasing the amount of sickling by increasing the production of fetal hemoglobin, which is a baby hemoglobin. I don’t want to go into too many details, but it basically interrupts all those funny-shaped cells, stops them from forming little sticks inside the red blood cell, and stops it from stretching the red blood cell out of shape so that even in low oxygen situations, the cell keeps its normal shape. It accomplishes that to the degree that we were able to show that it decreases the amount of time you’re in the hospital, stops you from coming to the hospital and emergency department for pain and vaso-occlusive crises, and decreases the amount of blood you need for transfusion, because this is a disease that cuts the amount of blood. Another name for sickle cell disease is sickle cell anemia. It improves the anemia a bit. It decreases the white blood cell count, which makes the cells less sticky.

It was an all-around home run drug because in the study, we were able to show that it decreased the number of hospitalizations by 50%, the amount of transfusions by nearly as much, and it prolonged life over a 10-year period. The prolonged life was not an expected result when they started out. It took 10 years or longer to show that this drug prolonged life. It also can be used to prevent strokes. You can use it instead of transfusions to prevent strokes in children. We’re discovering that it may prevent organ failure in children who are given it early. It’s now thought that if you start hydroxyurea in a 6-month-old child or a 2-year-old child, and they stay on it for their whole life, they may never get kidney disease, strokes, heart and lung disease, or any of those ravages. That’s not a cure, but it’s a disease arrest. It’s very similar to what would happen if you completely replace their bone marrow, which is called hematopoietic stem cell transplantation. That is a big, hairy deal because you have to have chemotherapy radiation, and you need somebody to donate their bone marrow to you. You wipe out your own bone marrow and then you accept somebody else’s bone marrow, and they make normal red blood cells for you. Those red blood cells, of course, would not sickle. Hematopoietic stem cell transplantation has been around for about 20 years. We’re doing more and more of them. The donor pool is terrible. About 1 in 4 people who want a bone marrow transplantation can find a compatible donor, so we’re finding ways to do it without having complete compatibility. They call that a haploidentical transplant. These transplantations have revolutionized sickle cell disease because if you do them in a child, you might be able to keep that child from ever going through many of the ravages.

Until 2 or 3 years ago, that’s all we had. We had bone marrow transplantation and hydroxyurea. But now we have other drugs. If you don’t want to have to take blood all the time, there’s a drug that increases your hemoglobin. It’s called voxelotor. We’ll talk more about that in a minute. If you want an alternative to hydroxyurea, which decreases the number of vaso-occlusive crises you have, we have 2 alternatives. We have L-glutamine and crizanlizumab. I recognize these are long, big words, but just think of them as crisis-decreasing drugs. We have 3 of those available now. Hydroxyurea is the OG. L-glutamine was approved in 2017. That’s the “new G.” And the “really new G” is crizanlizumab, or Adakveo. That’s the only 1 that’s an infusion. Everything else is taken by mouth.

If you really want to have a bone marrow transplant, you can have 1 in as many places that do them in the United States. There are several. We’ll get to this, but you can even have gene therapy, which is really experimental. These are all therapies that are designed to arrest the process of sickling as soon as we can to decrease the amount of damage that happens and to stop all the pain, anemia, and those symptoms that we talked about from happening.

Ifeyinwa Osunkwo, MD, MPH: Thank you very much, Dr Smith. That’s a really nice comprehensive overview of the different treatment options available.

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Transcript Edited for Clarity

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