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Hydroxyurea in the Treatment of Sickle Cell Disease

Hemoglobin F contains two alpha chains and two gamma globin chains.  Following birth, there is a normal switch from gamma to beta chains for production of hemoglobin A instead of hemoglobin F.  There are still some red cells that contain hemoglobin F and are called “F cells” but do not have other characteristics of fetal erythrocytes.  It is well known that children and adults whose red cells still contain a high concentration of hemoglobin F have a mild clinical course.  This led to a search for a drug that would stimulate a switch from beta to gamma globin synthesis.  Production of fetal hemoglobin is  an inherent property of adult red cells and can be induced when there is sudden erythroid regeneration.  Drugs that can trigger rapid erythroid regeneration include cytotoxic agents that are used to treat cancer and are cell cycle specific. Examples are 5-azacytidine, cytosine arabinoside, busulfan, methotrexate, vinblastine and hydroxyurea. Erythropoietin also triggers erythroid regeneration and has been shown to increase total hemoglobin and hemoglobin F  in a small series of patients.

Hydroxyurea is a simple substance that inhibits ribonucleotide reductase and decreases production of all three cell lines in the bone marrow.  It was selected for study in clinical trials because it is much less toxic than  the other chemotherapy drugs mentioned and can be taken by mouth.

In May 1990, a multicenter, placebo-controlled, double-blind trial funded by the National Heart, Lung, and Blood Institute was initiated.  The aim of the trial was to evaluate the effect of hydroxyurea in patients with symptomatic sickle cell disease over a period of 5 years and to determine whether chronic daily oral therapy could decrease the frequency of painful vaso-occlusive episodes by 50%. The results of this trial were published in the New England Journal of Medicine in early 1995. The trial was stopped before all the patients had completed 24 months of therapy and 10 months before the projected end of the study because of the beneficial effects observed in the treated group.

Treatment with hydroxyurea resulted in a 44% reduction in the rate of vaso-occlusive episodes.  Fewer patients assigned to the treatment arm experienced chest syndrome, and fewer underwent transfusion.

As a result of this study, long-term oral daily treatment  with hydroxyurea may be offered to adults with sickle cell disease who experience fairly frequent vaso-occlusive episodes or who have had chest syndrome.  Use of the drug has been extended to patients who have hemoglobinopathies other than hemoglobin SS, such as SC or Sbeta thalassemia.  It has also been provided to children.  There is little question that it has efficacy in attenuating the severity of the disease in the case of SS patients.  However, the responses to hydroxyurea may be extremely variable with some patients having only small incremental increases in HbF, or very gradual increases that do not become apparent for several months. Some patients do not respond.  There is also considerable variation in the dose of drug that individual patients are able to tolerate. Some experience myelotoxicity at only 7.5 mg/kg/day and others are able to take up to 35 mg/kg/day.

Although hydroxyurea has not been shown to be a carcinogen, it is a mutagen and teratogen.  There have been no cases of birth defects reported in children born to women receiving hydroxyurea (not necessarily with sickle cell disease) but both men and women should be advised repeatedly about the need for contraception if they are going to take this medication. In addition, it is still unknown whether there is an increased  risk of long-term adverse effects with treatment, such as the development of leukemia.  This remains a cause for concern, particularly as children are now being treated.  Balanced against these concerns are the possible benefits of treatment which may include fewer crises, higher hemoglobin levels, decreased organ damage and extended life span.

Treatment with hydroxyurea is initiated at a starting dose of 15 mg/kg/day to the nearest 500 mg capsule.  All capsules can be taken once a day,and if necessary, the capsules can be broken open and the contents sprinkled in water.  A complete blood count should be obtained every two weeks and the dose may be increased by no more than 5 mg/kg/day if tolerated (ANC>2.5 K/uL, platelets>150 K/uL, Hb>6.0 G/dL, and retic >95 K/uL). The highest dose level in the clinical trial was 35 mg/kg/day.  Most of the adult patients who have been treated on a long term basis  are on a dose between 500 mg and 1500 mg/day.

The most frequent side effects of hydroxyurea are myelosuppression, gastro-intestinal symptoms and dermatological reactions such as maculopapular rash and facial erythema.

There may not be any evidence of clinical benefit for at least one month and possibly not for three months. The patient must be advised and warned about the possible dangers of treatment, including the unproven but potential risk of leukemogenesis and the possibility of teratogenic effects.   Women of child bearing age and  men who are taking hydroxyurea should be counseled about the use of contraception.  It should also be emphasized that the drug has to be taken on a daily basis and that its beneficial effects will be lost if it is discontinued.  Finally, it should be explained that the mechanism of action of hydroxyurea is not fully understood and that the optimum dose and schedule is still uncertain.

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