Hydroxyurea in Sickle Cell Disease

Ifeyinwa (Ify) Osunkwo, MD, MPH: I want to switch to treatment options available for sickle cell disease. We’ve had 1 drug available from the mid-1990s, and thankfully we have a couple more. Pat, can you discuss the mechanism of action and the use of hydroxyurea in targeting the pathophysiology of sickle cell disease and its history, how it works, why we use it, and what the outcomes were?

Patrick McGann, MD, MS: Yes. It’s a really old medication. It’s been used since the 1950s, primarily to treat cancers, and part of the notoriety of hydroxyurea as a chemotherapy agent is because of that. It was found through some nice experiments in the 1980s to induce fetal hemoglobin. We know that babies express fetal hemoglobin, and it is a type of hemoglobin that binds oxygen more tightly so that fetuses can extract oxygen from the mother’s circulation. Then when the baby is born, they no longer need that, and they make adult hemoglobin. If you have sickle cell disease, you make sickle hemoglobin. And we know from the experiment of nature that babies don’t have sickle cell symptoms until that fetal hemoglobin goes away, which usually happens by 6 months of age, though in varying degrees with different people.

There are also some people who inherit a high fetal hemoglobin, hereditary persistence of fetal hemoglobin. And if you have that with sickle hemoglobin, you have no symptoms. Fetal hemoglobin is a great target. Hydroxyurea was a medicine found to induce that in 1980s, and a multicenter study of hydroxyurea in adults showed that it was highly effective in reducing pain, time to pain events, and many studies thereafter have proven those benefits. There’s always been a bit of a concern because of its label as a chemotherapy medicine that it will suppress your blood counts, that it will have long-term effects, and we now have 35 years of data with hydroxyurea basically that it shows it’s safe. The primary possible adverse effect is that it might reduce your blood counts, your white blood cells or your neutrophils, your reticulocyte count, especially in some older patients whose kidneys might not work well or whose bone marrow might be tired. But you can modulate that and adjust the dose. The other effects that are suggested sometimes have not panned out with 30 years of evidence so far.

Now in pediatrics, and I’m a pediatric hematologist, we use it routinely starting in the first year of life. These babies, when I talk to the parents at diagnosis, I tell them we’re going to start hydroxyurea and keep their baby healthy and let them grow up and live an essentially normal life. So far we have about 50 or 60 patients for whom we’ve done this in the last 5 or 6 years, and they’re doing quite well, with fetal hemoglobin levels of 30% to 40%. In adults, especially older patients who have chronic organ damage, it’s often a bit more challenging, and sometimes patients don’t tolerate it as well. Medication adherence becomes a concern obviously with many oral medications. It is once a day, but that once a day is quite a bugaboo for some. But it is a good medicine, and we have lots of new exciting medicines. It’s important not to forget about hydroxyurea, and it still should be the foundation to these other therapies until we have new evidence.

Ifeyinwa (Ify) Osunkwo, MD, MPH: I like that you mentioned it’s been around for a while. We have new medicines coming, but this is a foundational medication that works only if you take it. The medicine must get from the bottle into the body for it to work.

Transcript Edited for Clarity