Treating Sickle Cell Disease: Current Available Therapies

Michael R. DeBaun, MD, MPH: Hydroxyurea is essentially the Amazon of therapies for sickle cell disease. Many of the benefits associated with the use of voxelotor and crizanlizumab also occur in individuals who receive hydroxyurea. But specifically, hydroxyurea is associated with a decrease in red blood cell adhesion to the endothelial molecule as well as a decrease in the overall number of red blood cells in individuals with sickle cell disease. Hydroxyurea also causes a decrease in reticulocyte production. Reticulocytes, which are newly formed red blood cells, are among the most adhesive in the development of the lifespan of red blood cells. Hydroxyurea increases the hemoglobin F level, and an increase in hemoglobin F level results in a decrease in red blood cell polymerization. This is very similar to the mechanism of action of voxelotor, which causes a decrease in the red blood cell and intracellular hemoglobin polymerization. Hydroxyurea also increases the total hemoglobin level in individuals with hemoglobin SS and hemoglobin S beta-zero thalassemia.

As mentioned earlier, when you increase the amount of hemoglobin, you increase the oxygen delivery to the brain, which would decrease the likelihood of having a neurological complication as well as improving cognitive status. Hydroxyurea is an NO [nitric oxide] donor, and based on the fact that individuals with sickle cell disease have chronic hemolysis, and as a result of the chronic hemolysis have a decrease in nitric oxide, which is associated with endothelial dysfunction, the increased availability of nitric oxide with the use of hydroxyurea is advantageous as an approach to improve the care of individuals with the disease.

Last but not least, individuals with sickle cell disease often have an inflammatory state. They have chronic inflammation. The hydroxyurea is a myelosuppressive agent, and thus will decrease the background rate of inflammation in individuals with sickle cell disease. In terms of the safety of hydroxyurea, it’s an extremely safe therapy. It’s been used now for multiple decades in children and adults with sickle cell disease, with only…report signals of adverse outcomes. This drug is very well tolerated in infants, children, and adults. Occasionally, there are children and adults who have GI [gastrointestinal] distress or nausea and vomiting with the drug, but these are far and few between when compared to the vast majority of individuals who are taking hydroxyurea.

In terms of adverse outcomes, the major concern when I talk to our families with children and adults with sickle cell disease, is that it’s sex-dependent. In adolescents and young women of child-bearing age, hydroxyurea has been associated with teratogenic effects in animal models, and so typically we would stop the drug in individuals who are thinking about becoming pregnant or have been documented as being pregnant. Then in men, hydroxyurea has been shown to decrease the sperm health as well as cause some dysmorphology in the sperm. Thus, for men with sickle cell disease, who want to have children, there may be a window of time where they may have to be off the hydroxyurea to reach the level of sperm that’s required to impregnate a woman. The other complications are far and few between. We haven’t documented any excessive bleeding associated with thrombocytopenia with this myelosuppressive agent. There are occasionally concomitant viral infections, which will drop both the reticulocyte count and the hemoglobin. Often just holding hydroxyurea for a brief window, typically a week, is sufficient. We’ve not seen any increase in viral infections associated with hydroxyurea because of its myelosuppressive nature. The profile is actually quite good.

L-glutamine is the first drug approved by the FDA after hydroxyurea for use in sickle cell disease. It’s typically our go-to therapy for our children and adolescents with hemoglobin SC who have multiple vaso-occlusive pain episodes. It has almost no known adverse effects. We also prescribe L-glutamine to our adults. The major challenge in adherence to the drug is that you have to mix it twice a day, and it’s not very tasty. Patients typically have to come up with strategies through their own tastes that will allow them to mix the drug with certain other foods so they can’t actually taste the drug. Then of course you have to travel with the food if you expect them to take the drug when they’re out or visiting family members.

But there is an advantage, and the advantage is that in a phase 3 double-blind randomized- controlled trial, the L-glutamine did decrease the rate of vaso-occlusive episodes in children and adults with sickle cell disease. I think importantly for about a third of the patients with hemoglobin SC or hemoglobin S beta-plus thalassemia, you can offer this drug, particularly for children who are below the age where the FDA says you can use crizanlizumab. You can offer this as a reasonable option, where there is evidence that there could be benefit.

Transcript Edited for Clarity