Sickle Cell Disease

Sickle cell disease is a genetic disorder that decreases life expectancy by 25 to 30 years and affects approximately 80,000 Americans.^{1, 2} Sickle cell disease refers to a group of disorders in which the red blood cell undergoes sickling when deoxygenated. The existence of these abnormally shaped cells was first reported in 1910, when Herrick described their occurrence in a black dental student. The abnormality was subsequently identified as the result of an exchange of the amino acid valine for glutamine in the β-globin chain of the hemoglobin molecule. This abnormal hemoglobin becomes polymerized, causing the red blood cell to assume a sickle shape and making the cell both rigid and fragile. These distorted cells obstruct the blood vessels and may disrupt endothelial cell function, leading to tissue hypoxia and clinical complications. The fragile red cells have a markedly short life span, leading to the development of anemia and the release of free hemoglobin into the circulation, a phenomenon that is also injurious to the endothelium.

The term sickle cell anemia refers to the disease that occurs in patients who are homozygous for the Hb S mutation (SS disease). There are several other hemoglobin mutations that, when present in heterozygous form with an Hb S mutation, lead to the same disease but exhibit a milder phenotype. The most common of these other genotypes are Hb SC disease, sickle cell β thalassemia, and Hb SD disease. There is great variability in the clinical course of these various conditions, and it is not uncommon for patients with these Hb variants to experience frequent painful events and life-threatening complications.

A Brief History of Hydroxyurea

Hydroxyurea was first synthesized in 1869 in Germany by Dressler and Stein. ¹³ A century later, phase I and II trials began testing the safety of this drug in humans with solid tumors. It was first approved by the FDA in 1967 for the treatment of neoplastic diseases. ¹⁴ In subsequent years, clinical trials demonstrated the efficacy of this drug for the treatment of CML, psoriasis, and polycythemia vera. Although there have been reformulations of this drug, there were no labeling revisions until 1996. In February 1998, hydroxyurea received a new indication, for the treatment of sickle cell disease. ¹⁵ It is approved for use in reducing the frequency of painful crises and the need for blood transfusions in adult patients with recurrent moderate-to-severe painful crises (generally at least three during the preceding 12 months). Hydroxyurea is also approved for use in the treatment of melanoma, resistant CML, and recurrent, metastatic, or inoperable carcinoma of the ovary.

Mechanism of Action

The precise mechanism by which hydroxyurea produces its varied effects is unknown. Assays conducted in cell-free bacterial systems have demonstrated that its target is the enzyme ribonucleotide reductase, with hydroxyurea acting as a free radical that is specific for the tyrosyl groups of this enzyme. ¹⁶ Ribonucleotide reductase is essential for deoxyribonucleic acid (DNA) synthesis, and its inhibition by hydroxyurea results in S-phase cell cycle arrest. Other mechanisms may be responsible for the fact that this drug acts as a radiation sensitizer, inhibiting the repair of damaged DNA.

The efficacy of hydroxyurea in the treatment of sickle cell disease is generally attributed to its ability to boost the levels of fetal hemoglobin (Hb F,α₂γ₂). This lowers the concentration of Hb S within a cell resulting in less polymerization of the abnormal hemoglobin. However, the mechanisms by which it increases Hb F are unclear. Early studies suggested that hydroxyurea is cytotoxic to the more rapidly dividing late erythroid precursors, an effect that leads to the recruitment of early erythroid precursors with an increased capacity to produce Hb F. Others have suggested that it acts directly on late precursors to reprogram them to produce Hb F. Alternatively, it may interrupt the transcription factors that selectively bind to promoter or enhancer regions around the globin genes, thereby altering the ratio of Hb A to Hb F (reviewed in Dover and Charache). ¹⁷ A recent study has provided evidence for a nitric oxide-derived mechanism for Hb F induction by hydroxyurea. ¹⁸ Another study has suggested that increases Hb F production by inhibiting ribonucleotide. ¹⁹ Alternatively, it may be of benefit in sickle cell disease for reasons unrelated to Hb F production, including its ability to increase the water content of red blood cells, decrease the neutrophil count, and alter the adhesion of red blood cells to the endothelium.

Pharmacokinetics

When used to treat sickle cell disease, hydroxyurea is administered orally and is readily absorbed. ¹⁵ Peak plasma levels are reached in 1 to 4 hr after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and areas under the curve are observed. The drug is distributed rapidly and widely in the body and concentrates in leukocytes and erythrocytes. Up to 60 percent of an oral dose undergoes conversion through metabolic pathways that are not yet fully characterized. One pathway is probably saturable hepatic metabolism, and another minor pathway may involve degradation by the urease found in intestinal bacteria. Excretion of hydroxyurea in humans is likely a linear first-order renal process.

Current Labeling

The current labeled dosing of hydroxyurea for sickle cell disease calls for the administration of an initial dose of 15 mg/kg/day in the form of a single dose, with monitoring of the patient's blood count every 2 weeks. ¹⁵ If the blood counts are in an acceptable range, the dose may be increased by 5 mg/kg/day every 12 weeks until the MTD of 35 mg/kg/day is reached. If blood counts are between the acceptable range and the toxic range, the dose is not increased. If blood counts are found to be in the toxic range, treatment is discontinued until hematologic recovery. It may then be resumed after the dose is reduced by 2.5 mg/kg/day from the dose associated with hematologic toxicity. The drug may then be titrated up or down every 12 weeks in increments of 2.5 mg/kg/day until the patient is at a stable dose that does not result in hematologic toxicity. Counts considered to be acceptable are: neutrophils greater than or equal to 2500 cells/mm³, platelets greater than or equal to 95,000/mm³, hemoglobin greater than 5.3 g/dl, and reticulocytes greater than or equal to 95,000/ mm³ if the hemoglobin concentration is less than 9 g/dl. Counts considered to be toxic are: neutrophils less than 2000 cells/ mm³, platelets less than 80,000/ mm³, hemoglobin less than 4.5 g/dl, and reticulocytes less than 80,000/ mm³ if the hemoglobin concentration is less than 9 g/dl. ^{15, 20}

In 1998, the FDA issued a Written Request for voluntary pediatric studies of many drugs¹⁵; included on this list was hydroxyurea. There is as yet no indication for the use of this drug in children.

Purpose of Evidence Report

In the pivotal randomized trial upon which the FDA based its approval of hydroxyurea, adult patients taking hydroxyurea were found to have fewer hospitalizations and fewer episodes of acute chest syndrome, and they required fewer transfusions than those who were not on hydroxyurea. ²¹ The authors projected an almost 50 percent reduction in hospitalizations if every eligible patient with sickle cell anemia in the United States was taking hydroxyurea, with a concomitant cost savings of 26 million dollars annually. ²²This study led to hydroxyurea's receiving an FDA indication for the treatment of patients with sickle cell disease, as well as the development of the National Heart, Lung, and Blood Institute recommendations for the use of the drug in this disease. ²³ However, the response by physicians has been consistent with published studies that have shown high levels of physician non-adherence to a variety of clinical practice guidelines²⁴ and have demonstrated that physician practice is slow to change after the publication of a clinical study. Specifically, investigators have found that a lack of familiarity, lack of agreement with a treatment modality, and lack of outcome expectancy affect physician adherence to guidelines. ²⁵

To improve physicians' adherence to guidelines regarding the use of hydroxyurea and to clarify its role in the treatment of patients with sickle cell disease the Office of Medical Applications of Research (OMAR) at the National Institutes of Health (NIH) scheduled an NIH Consensus Development Conference: Hydroxyurea Treatment for Sickle Cell Disease, to be held in February 2008. The EPC of the Bloomberg School of Public Health of the Johns Hopkins University (JHU) was asked to prepare an evidence report for this conference in response to a request by the OMAR and AHRQ. We were asked to review and synthesize the evidence on the following questions, described in greater detail in Chapters 2 and 3:

1.

What is the efficacy (results from clinical studies)of hydroxyurea treatment for patients who have sickle cell disease?

2.

What is the effectiveness (in everyday practice) of hydroxyurea treatment for patients who have sickle cell disease?

3.

What are the short- and long-term harms of hydroxyurea treatment?

4.

What are the barriers to the use of hydroxyurea treatment (and other therapies) for patients who have sickle cell disease and what are the potential solutions?

5.

What are the future research needs?

Our goal was to provide the OMAR with a comprehensive review of the literature regarding these questions, so that this complex topic can be addressed with the available evidence.