How I use hydroxyurea to treat young patients with sickle cell anemia

Abstract

Hydroxyurea has many characteristics of an ideal drug for sickle cell anemia (SCA) and provides therapeutic benefit through multiple mechanisms of action. Over the past 25 years, substantial experience has accumulated regarding its safety and efficacy for patients with SCA. Early proof-of-principle studies were followed by prospective phase 1/2 trials demonstrating efficacy in affected adults, then adolescents and children, and more recently infants and toddlers. The phase 3 National Heart, Lung and Blood Institute-sponsored Multicenter Study of Hydroxyurea trial proved clinical efficacy for preventing acute vaso-occlusive events in severely affected adults. Based on this cumulative experience, hydroxyurea has emerged as an important therapeutic option for children and adolescents with recurrent vaso-occlusive events; recent evidence documents sustained long-term benefits with prevention or reversal of chronic organ damage. Despite abundant evidence for its efficacy, however, hydroxyurea has not yet translated into effective therapy for SCA. Because many healthcare providers have inadequate knowledge about hydroxyurea, patients and families are not offered treatment or decline because of unrealistic fears. Limited support for hydroxyurea by lay organizations and inconsistent medical delivery systems also contribute to underuse. Although questions remain regarding its long-term risks and benefits, current evidence suggests that many young patients with SCA should receive hydroxyurea treatment.

Figure 1

Time line of hydroxyurea therapy for SCA. Clinical experience with hydroxyurea for patients with sickle cell anemia (SCA) has been accumulating for more than 25 years involving adults, children and adolescents, and even infants. Several multicenter randomized clinical trials are ongoing.

Figure 2

Multiple beneficial effects of hydroxyurea 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.

Figure 3

Laboratory and morphologic changes during hydroxyurea dose escalation to MTD. Increases in hemoglobin (Hb), mean corpuscular volume (MCV), and percentage fetal hemoglobin (HbF) occur simultaneously with decreases in white blood cell count (WBC), absolute neutrophil count (ANC), ARC, and lactate dehydrogenase (LDH). Morphologic changes to the erythrocytes include nonreticulocyte macrocytosis, increased numbers of target cells, fewer sickled forms, and relative “blunting” of the sickled cells that remain in circulation. (A-C) Changes from baseline through dose escalation to maximum tolerated dose (MTD) for a child with high HbF response (∼ 30% HbF at 30 mg/kg/d). (D-F) Changes for a child with low HbF response (∼ 15% HbF at 25 mg/kg/d). Despite the differences in HbF response, both patients have marked improvements in the peripheral blood smear morphology. For all panels, images were visualized using an Olympus BX40 microscope (Olympus America) with a 100×/1.25 numeric aperture oil-immersion objective (Resolve Microscope immersion oil, Thermo Scientific); photographs were taken with an Olympus DP20-SE digital camera, processed using Olympus DP2-BSW application software, and displayed using Microsoft Office PowerPoint 2003. Photographs courtesy of Nicole A. Mortier.

Figure 4

Interindividual variation in response to hydroxyurea treatment. Data are shown for 95 children with SCA treated at St Jude Children's Research Hospital, judged to be more than 80% adherent to hydroxyurea therapy. (A) Percentage HbF response, showing a broad distribution of percentage HbF values at hydroxyurea MTD, ranging from approximately 10% to more than 40%. (B) LDH response again showed a broad distribution of values at hydroxyurea MTD (normal < 310 U/L). Data analysis and graphs courtesy of Dr Cheng Cheng.