Will new therapies for sickle cell disease lead to a change or reduction in use of hydroxyurea for the management of pain?
Over the last 20 years, strong and consistent evidence has demonstrated when children and adults with sickle cell disease are adherent to hydroxyurea and receive the correct dose of hydroxyurea, they experience a decrease in incidence of serious acute vaso-occlusive pain, acute chest syndrome, and blood transfusion needs.
Additionally, in large cohort studies in Belgium and Paris, children receiving hydroxyurea, typically the group with more severe disease, had increased survival compared with children not receiving hydroxyurea. Further, there is strong evidence that children taking hydroxyurea have a clinically relevant decrease in transcranial Doppler measurement, with concomitant increase in baseline hemoglobin levels, a risk factor for ischemic strokes in children with hemoglobin SS or hemoglobin SB0 thalassemia. Lastly, emerging evidence is accumulating that hydroxyurea can decrease the rate of albuminuria. These are the clear benefits of hydroxyurea, and I don’t see any drug on the horizon achieving all these benefits that would lead to the end of hydroxyurea for children and adults with sickle cell disease.
That said, I believe there could be changes in how we use hydroxyurea, typically as single-agent therapy. From decades of treating chronic diseases, we have learned that combination therapies often attenuate the progression of the disease compared with single therapy. I could easily see the use of hydroxyurea plus additional agents affecting different pathways.
Two combination therapies that come to mind include hydroxyurea and crizanlizumab, a therapy that could complement the use of hydroxyurea, and L-glutamine, which increases the amount of free glutamine circulating in the blood.
Of course, prescribing hydroxyurea is not without limitations and risks. We have not identified the optimal dosing schedule for an individual, but rather the optimal dose for a group, typically 25 mg/kg to 30 mg/kg, with some individuals at risk for myelosuppression at even lower doses. Hydroxyurea should not be used when a woman is planning pregnancy or is pregnant, and there is clear evidence that hydroxyurea decreases sperm count in men.
One can imagine a factorial clinical trial design that uses one, two or all three agents where the cumulative benefits and risks of these agents can be defined. The future looks bright with wonderful opportunities for innovative trials to better understand the benefit of these new drugs, and others, in combination with hydroxyurea.
Michael DeBaun, MD, MPH, is a professor of pediatrics and medicine, vice chair for clinical and translational research, J.C. Peterson chair in pediatric pulmonology, and director of the Vanderbilt Center of Excellence in Sickle Cell Disease at Vanderbilt University. He can be reached at 2200 Children’s Way, Nashville, TN 37232; email: firstname.lastname@example.org. Disclosure: DeBaun reports no relevant financial disclosures.
I do not believe drugs like crizanlizumab to treat sickle cell disease will lead the way out from hydroxyurea. Crizanlizumab will hopefully be an important and useful drug, because it blocks an important molecule, P-selectin, implicated in sickle cell disease pathophysiology. However, sickle cell disease has complex, devastating, multi-organ pathophysiology involving a multitude of molecules and pathophysiological processes, and P-selectin is not the most important of these molecules.
That molecule is sickle hemoglobin. All the complexity and mayhem of sickle cell disease has a single root cause of sickle hemoglobin polymerization. A logical approach to disease modification, therefore, is to interdict this single root cause. Hydroxyurea is attempting to do just this, by shifting red blood cell precursor hemoglobin manufacturing away from sickle hemoglobin and toward fetal hemoglobin, which intercalates with and inhibits sickle hemoglobin polymerization.
The limitation of hydroxyurea is not that it is attempting to increase fetal hemoglobin to interdict sickle cell disease root-cause pathophysiology, but that it is trying to do so indirectly and crudely — erythropoiesis recovering from the cytotoxic and cytostatic effects of this antimetabolite drug is enriched for fetal hemoglobin, but the capacity of bone marrow to recover from repeated cytotoxic/cytostatic stress is naturally finite, and diminished further by sickle cell disease pathophysiology in the bone marrow and in the kidneys, and by age.
Thus, it is indicated and imperative to try to develop new noncytotoxic treatments for sickle cell disease. But, if such treatments are going to substitute for hydroxyurea, they will also have to address root-cause pathophysiology, and not just one facet of multifaceted downstream processes.
Yogen Saunthararajah, MD, is a medical oncologist and hematologist at Taussig Cancer Institute. He can be reached at Cleveland Clinic Main Campus, 9500 Euclid Ave., Cleveland, OH 44195. Disclosure: Saunthararajah reports stock ownership in and consultant roles with EpiDestiny.