MANAGEMENT OF SICKLE CELL DISEASE

NIH Publication No. 02-2117. Revised May28, 2002 (Forth Edition) National Institutes of Health, National Heart, Lung, and Blood Institute. Download the entire PDF  file for Adobe   Click Here to return to Contents

Chapter 26 FETAL HEMOGLOBIN INDUCTION

Enhanced concentrations of hemoglobin F (Hb F) can inhibit sickle hemoglobin (Hb S) polymerization and red cell sickling and improve the clinical course of sickle cell disease (SCD). In populations such as Bedouin Arabs from the Saudi peninsula and certain tribes from central India, patients homozygous for SCD have elevated amounts of Hb F and fairly mild clinical manifestations. In a cooperative study of the natural history of patients with sickle cell anemia in the United States,the frequency of pain episodes correlated inversely with the Hb F concentration. Based on these epidemiologic studies and understanding the biophysics of Hb S polymerization,a search was launched for pharmacologic agents that could reverse the switch from .- to -globin chain synthesis in erythroidprecursors. The first "hemoglobin switching" agent was the nucleoside analog 5-azacytidine (1), which was followed by butyrate derivatives as compounds which increase Hb F gene expression. 

Other drugs, such as hydroxyurea and erythropoietin, alter maturation of erythroid precursors and promote Hb F production indirectly. The small amount of Hb F in adults is found in rare erythrocytes called F-cells. Rapid erythropoiesis induces F-cell production, probably due to commitment of early progenitors that contain factors that favor .-globin expression and faster maturation and release into the circulation. Many cytotoxic drugs induce Hb F expression without gene hypomethylation, and hydroxyurea is one example that supports erythroid regeneration as a mechanism of Hb F induction.

Hydroxyurea is a ribonucleotide reductaseinhibitor, which blocks ribonucleoside conversion to deoxyribonucleotides and prevents DNA synthesis. In anemic primates, hydroxyurea increased Hb F levels, and in early studies in two patients with sickle cell anemia, a dose of 50 to 100 mg/kg daily increased F-reticulocytes and Hb F concentrations. An important pilot trial defined effective dosages, found increased Hb F in most, but not all, compliant patients, and revealed little shortterm toxicity.

The first drug to be tested was 5-azacytidine (1), an antineoplastic agent which inhibits methylation of cytosines in DNA. Studies on gene regulation had suggested that methylation resulted in repression of transcription and that hypomethylation was associated with active gene expression. It was observed that the inactive gene becomes methylated during the developmental switch from .-globin to -globin production in erythroid cells. The administration of 5-azacytidine caused a marked increase in Hb F in baboons. These results prompted limited clinical trials, which demonstrated significant but less dramatic induction of Hb F in patients with SCD. The antiproliferative activity of this drug may have led to the proposed use of hydroxyurea.

Butyrates appear to modulate globin-gene expression by direct binding to transcriptionally active elements, and by inhibition of histone deacetylase, histone hyperacetylation, and changes in chromatin structure. In sickle cell anemia, early trials of butyrate given bycontinuous infusion over 2 or 3 weeks were inconclusive, but newer studies with pulse butyrate treatment are encouraging. When arginine butyrate was given once or twicemonthly, 11 of 15 sickle cell patients responded with a mean rise in Hb F from 7 percent to21 percent, a level maintained in some people for 1 to 2 years. The studies also suggested butyrate and hydroxyurea are synergistic without cross-resistance; pretreatment with hydroxyurea may select a population of erythroid precursors with active .-globin genes and make them responsive to butyrate. Butyrate does not seem to be cytotoxic, but its use is experimental.

HYDROXYUREA IN SICKLE CELL ANEMIA

A pivotal multicenter efficacy trial of hydroxyurea in 299 adults with sickle cell anemia showed that hydroxyurea reduced by nearlyhalf the frequency of hospitalization and the incidence of pain, acute chest syndrome, and blood transfusions (2). In good responders, hemolysis and leukocyte counts fell, and hemoglobin concentrations increased. Hb F increased from a baseline of 5 percentto about 9 percent after 2 years of treatment; Hb F increased to a mean of 18 percent in the top 25 percent of Hb F responders and to 9 percent in the next highest 25 percent, but changed little in the lower half of Hb F responders. These results may not be typical of all patients because the patients in the study had a mean age of about 30 years, had severe disease, and were treated to the brink of myelotoxicity. After treatment, some individuals had improved physical capacity and aerobic cardiovascular fitness. A modest improvement in general perceptions of health and social function and recall of pain was found.

Moreover, hydroxyurea was cost-effective and clinically beneficial. Studies of hydroxyurea in infants, children, and adolescents lag behind adult studies in the appraisal of clinical efficacy. Most patients reported were adolescents or teenagers treated in unblinded pilot studies, although 25 patients with a median age of 9 years were treated in a single-blinded crossover study with drug or placebo. In all trials, Hb F increased from about 5 percent before treatment to about 16 percent after 6 months to a year of treatment.

A trial of 84 children with a mean age of 10 years gave results similar to those in adults (3). Sixty-eight patients reached the maximally tolerated dose, and 52 patients completed a year of treatment. About 20 percent of enrolled patients withdrew from the study, predominantly because of lack of compliance. Baseline Hb F of 6.8 percent increased to 19.8 percent (range, 3.2-32.4 percent). Mean cell volume (MCV) and hemoglobin concentrationincreased, and the leukocyte count fell. These changes, apparent after 6 months of treatment, were sustained at 24 months. The increment in Hb F was variable, but unlike the adults, the young patients with the highest baseline Hb F concentration had the highest Hb F levels with treatment, and the drop in leukocyte count did not predict the rise in Hb F.

Twenty-nine infants, with a median age of 14 months, were treated with hydroxyurea at adose of 20 mg/kg for 2 years, escalating to 30 mg/kg thereafter. After 2 years, all parents elected to continue treatment, and 19 children completed a median treatment period of 148 weeks. Changes in hemoglobin concentration, MCV, Hb F, and leukocyte count were compared with the changes observed in a historical control group. Hemoglobin increased from 8.5 to 8.9 g/dL (predicted, 8.2 g/dL), MCV increased from 82 to 93 fL (predicted, 88 fL), and Hb F fell from 21.3 to 19.6 percent (predicted, 12.3 percent). Functional asplenia was found in 24 percent of patients before treatment and in 47 percent after treatment (predicted, 80 percent). Nine patients were dropped from the study because of poor compliance or parental refusal to continue; one child died of splenic sequestration. One patient had a transient ischemic attack, one had a mild stroke, eight had episodes of acute chest syndrome, two had splenic sequestration, and three had episodes of sepsis. Growth was normal. Despite moderate levels of Hb F, acute complications of sickle cell anemia still occurred in these very young patients. Perhaps functional asplenia is delayed by treatment, but risks of splenic sequestration and other complications may persist.

The best data on the complications of hydroxyurea treatment and its effect on morbidity and mortality come from the followup of patients in the Multicenter Study of Hydroxyurea in Sickle Cell Disease. After 8 years of followup the data strongly suggest that treatment ofmoderately-to-severely affected adults with sickle cell anemia with hydroxyurea is associated with reduced mortality. Twelve strokes haveoccured, 9 in patients with more than 1 year of hydroxyurea treatment, 2 in patients with less than 1 year of drug exposure, and 1 in a patient who never received hydroxyurea. New adverse effects have not been found. Pulmonary disease was the most commoncause of death. We do not know whether hydroxyurea will prevent or reverse organ damage (4). After 1 year of treatment, splenic function in a group of children who averaged 12 years of age did not change. Of 10 patients with sickle cell anemia who received hydroxyurea for 21 months and had an increase in Hb F from 8 to 17 percent, only 1 recovered splenic function. In another prospective study, some patients had partial return of splenic function, possibly related to Hb F levels. Splenic regeneration was reported in 2 adults with sickle cell anemia who had Hb F levels of about 30 percent after hydroxyurea treatment.

Hydroxyurea does not appear to prevent the cerebrovascular complications of SCD. However, in children ages 5 to 15 years without a history of overt CVA and with more than three painful episodes yearly, hydroxyurea maintained cognitive performance comparable to sibling controls. Performance was found to deteriorate in untreated patients.

Long-term effects of hydroxyurea are still poorly defined. The multicenter trial had power to detect only 100-fold increases in the incidence of leukemia or cancer. Hydroxyurea has been given to 64 children with cyanotic congenital heart disease for a mean duration of more than 5 years without any reports of malignancies. In myeloproliferative disorders, however, the drug may have helped to transform premalignant conditions into acute leukemia in about 10 percent of patients.

There are at least three patients with SCD treated with hydroxyurea who developed leukemia, two after 6 and 8 years of treatment. Cellular changes that may precede neoplastic transformation, such as increases in chromosome breakage, recombination, and mutations, have not been reported in hydroxyurea-treated sickle cell patients.

Adverse effects on growth and development have not been reported. Whether continuous drug exposure at a very young age will beespecially hazardous or beneficial is not known. Contraception should be practiced by both women and men on hydroxyurea, and the uncertain outcome of an unplanned pregnancy should be discussed frankly.

Pregnancy resulting in infants without malformaions has been reported in at least 15 women receiving hydroxyurea; most mothers had myeloproliferative disorders, but 6 had sickle cell anemia.

Table 1 summarizes the treatment protocol and points that should be considered when using hydroxyurea as a treatment for patients with sickle cell anemia.

Table 1. Hydroxyurea in Sickle Cell Anemia

Adults, adolescents, or children (after consultation with parents and expert pediatricians) with sickle cell anemia or SCD-S o-thalassemia and frequent pain episodes, history of acute chest syndrome, other severe vaso-occlusive events, or severe symptomatic anemia. Initial high levels of Hb F (e.g., >10 percent) do not preclude favorable responses to therapy.

Blood counts, red cell indices, percent Hb F, serum chemistries, pregnancy test, willingness to follow treatment recommendations, nonparticipation in a chronic transfusion program.

Hydroxyurea, 10-15 mg/kg/day in a single daily dose for 6-8 weeks; CBC every 2 weeks; percent Hb F every 6-8 weeks; serum chemistries every 2-4 weeks.

Less pain, increase in Hb F to 15-20 percent, increased hemoglobin level if severely anemic, improved well-being, acceptable myelotoxicity.

Consider biological inability to respond to treatment or poor compliance with treatment. Increase dose very cautiously to a maximum dose of 35 mg/kg/day. In the absence of transfusion support or concurrent illness suppressing erythropoiesis, a trial period of 6-12 months is probably adequate.

Special caution should be taken in patients with compromised renal or hepatic function. Contraception should be practiced by both men and women since hydroxyurea is a teratogen and its effects during pregnancy are unknown. After a stable, nontoxic dose of hydroxyurea is reached, blood counts may be done at 4-8 week intervals. Granulocytes should be = 2,500/µL, platelets = 95,000/µL.

COMBINATIONS OF HB F INDUCERS

When both hydroxyurea and erythropoietin were given to patients with sickle cell anemia,an increment in Hb F concentration beyond that seen with hydroxyurea alone occurred (5). It is conceivable that combination therapy with butyrate and hydroxyurea and/or erythropoietin may provide additive effects on Hb F production, although verification of this conclusion must await the results of appropriate clinical trials.

Hydroxyurea is a valuable adjunct in the treatment of severe SCD, although its clinical effectiveness for individuals with SCD has not yet been reported. Meanwhile, it must be used carefully with full appreciation of its toxicity and possible long-term adverse effects.

Many questions about its use and effects remain unanswered. Hydroxyurea is not the final solution in the pharmacologic therapy of SCD, but it is a promising start.

1. DeSimone J, Heller P, Hall L, et al. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemia baboons. Proc Natl Acad Sci USA 1982;79:4428-31.

2. Charache S, Terrin ML, Moore RD, et al. Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317-22.

3. Kinney TR, Helms RW, O’Branski EE, et al. Safety of hydroxyurea in children with sickle cell anemia: Results of the HUG-KIDS study, a Phase I/II trial. Blood 1999;94:1550-4.

4. Steinberg MH. Management of sickle cell disease. N Engl J Med 1999;340:1021-30. 

5. Rodgers GP, Dover GJ, Uyesaka N, et al.Augmentation by erythropoietin of the fetalhemoglobin response to hydroxyurea in sickle cell disease. N Engl J Med 1993;328:73-80.

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Last modified: November 09, 2002