Hydroxyurea therapy for sickle cell anemia

Abstract

Introduction: Sickle cell anemia (SCA) is a severe, inherited hemoglobin disorder affecting 100,000 persons in the US and millions worldwide. Hydroxyurea, a once daily oral medication, has emerged as the primary disease-modifying therapy for SCA. The accumulated body of evidence over 30 years demonstrates that hydroxyurea is a safe and effective therapy for SCA, but hydroxyurea remains underutilized for a variety of reasons.

Areas covered: In this review, we summarize the available evidence regarding the pharmacology, clinical, and laboratory benefits, and safety of hydroxyurea therapy for the treatment of SCA. The purpose of this review is to provide the reader a comprehensive understanding of hydroxyurea and to reinforce the fact that hydroxyurea is a safe and effective medication for the treatment of SCA.

Expert opinion: In our opinion, hydroxyurea therapy should be considered standard-of-care for SCA, representing an essential component of patient management. Early initiation and broader use of hydroxyurea will alter the natural history of SCA, so affected children can live longer and healthier lives. In addition, hydroxyurea use should be extended to low-resource settings such as sub-Saharan Africa, where the burden of SCA and the need for hydroxyurea is arguably the greatest.

Keywords: fetal hemoglobin; hemoglobinopathies; hydroxyurea; sickle cell anemia.

Figure 1

Multiple mechanisms of action byhydroxyurea for SCA. (1) Fetal hemoglobin induction through soluble guanylyl cyclase activation and altered erythroid kinetics; (2) lower neutrophil and reticulocyte counts from ribonucleotide reductase inhibition and marrow cytotoxicity; (3) decreased adhesiveness and improved rheology of circulating neutrophils and reticulocytes; (4) reduced hemolysis through improved erythrocyte hydration, macrocytosis, and reduced intracellular sickling; and (5) nitric oxide (NO) release with potential local vasodilatation and improved vascular response. Illustration courtesy of Alice Y. Chen. Reproduced from [47] © the American Society of Hematology.

Figure 2

Peripheral blood smear changes with hydroxyurea therapy. Panel A illustrates the severe anemia and frequent irreversibly sickled erythrocytes commonly observed in untreated patients with SCA. Panel B demonstrates the improvement in anemia and increases in both the size and hemoglobin content of erythrocytes while on hydroxyurea therapy.

Figure 3

Concentration-time profiles of hydroxyurea in young patients with SCA. Shown are representative examples of ‘Fast’ phenotype with peak concentration at 15–30 min (59% of patients) and the ‘Slow’ phenotype with C_max at either 60 or 120 min (41% of patients). Reproduced with permission from [48] © the American Society of Hematology.