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Segal JB, Strouse JJ, Beach MC, et al. Hydroxyurea for the Treatment of Sickle Cell Disease. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Feb. (Evidence Reports/Technology Assessments, No. 165.)

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Hydroxyurea for the Treatment of Sickle Cell Disease.

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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.

Clinical Characteristics

Patients with sickle cell disease experience both chronic and episodic pain and have a reduced quality of life. 3 Painful crisis is the most common reason for emergency department use by patients with sickle cell disease. 4 The pathophysiology of a painful crisis is not entirely clear, and its determinants are uncertain. Some patients have frequent crises and severe disability, whereas others are able to lead relatively normal lives. Much of what we have learned about the incidence of complications in people with sickle cell disease comes from the Cooperative Study of Sickle Cell Disease (CSSCD).5 (See list of acronyms.) This federally funded study, begun in 1979, was a large multi-institutional prospective study of the clinical course of sickle cell disease. In this study, the frequency of painful crises was variable: 0.8 episodes per person-year for sickle cell anemia, 1.0 episodes per person-year for Hb Sβ0 thalassemia, and 0.4 episodes per person-year for Hb SC disease. 6 In a study of 1,056 patients with Hb SS disease in California, 70 percent of patients were admitted for a crisis; the overall rate of hospitalizations for crisis was 57 admissions per 100 years of observation. 7

Acute chest syndrome is the most common cause of death and hospitalization in patients with sickle cell disease. 8 In a large multicenter study of acute chest syndrome, the working definition was a new pulmonary infiltrate in a patient with chest pain, with a temperature of more than 38.5°C and tachypnea, wheezing, or cough. 8 In the study in California, the incidence rate of acute chest syndrome was 14 per 100 years of observation. 7 In the CSSCD, acute chest syndrome occurred in nearly 30 percent of 3,751 patients. Its incidence was highest in patients with Hb SS disease (12.8 per 100 patient-years). 9

Stroke is another serious consequence of sickle cell disease and is seen more often in children than adults. In the CSSCD, the prevalence of stroke was 4 percent in those with Hb SS disease, with an incidence of 0.61 per 100 patient-years. 5 Investigators noted that stroke was associated with all the common genotypes. In the Powars7 study in California, 11 percent of patients had suffered a stroke. Children who have had a stroke or who are at risk for stroke (as determined by transcranial Doppler [TCD] flow velocity) are typically treated with a chronic prophylactic transfusion regimen.

Another complication of sickle cell disease that affects patients' quality of life is the development of leg ulcers. In the Powars7 study, 14 percent of the patients suffered from this complication. In the CSSCD, 25 percent of all patients had leg ulcers. 5 People with Hb SS disease or Hb Sβ0 thalassemia are at higher risk of developing leg ulcers than are those with other genotypes. 10 The ulcers usually occur between the ages of 10 and 50 years and are more common in men than in women. 5 Therapy is supportive, involving local care of the ulcer, but many of these ulcers become chronic.

Established Treatments

Most of the therapies offered to patients with sickle cell disease are supportive and do little to change the underlying pathophysiology of the disease. These supportive measures include the use of penicillin prophylaxis in children to prevent pneumococcal disease, routine immunizations, and hydration and narcotic therapy to treat painful events. Some treatments, such as penicillin therapy, have improved both quality of life and survival. 11

Transfusions are often used to increase the oxygen-carrying capacity of the blood and to decrease the concentration of cells with abnormal hemoglobin. In patients with repeated, severe complications of sickle cell disease, simple transfusions or exchange transfusions are often used to preserve organ function and prolong life. In the multicenter study looking at the treatment of acute chest syndrome, 72 percent of the patients received red cell transfusions to treat this acute event. 8 As mentioned above, children with a stroke history are treated with chronic transfusion therapy. 12 Despite the usefulness of chronic transfusion, its long-term effects include iron overload, which can damage the liver.

Currently, hydroxyurea is the only disease-modifying therapy approved for sickle cell disease. Hence, there is great interest in understanding more about its use in treating patients with this group of disorders.

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.


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:


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


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


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


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?


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.

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