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ORIGINAL ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 4  |  Page : 227-232

To assess the efficacy of hydroxyurea, in children with homozygous sickle cell disease, in the age group of 1 year to 18 years, at tertiary care hospital


Department of Pediatrics, Maharajah's Institute of Medical Sciences (MIMS), Nellimarla, Vizianagaram, Andhra Pradesh, India

Date of Web Publication27-Dec-2012

Correspondence Address:
Sunil K Pondugala
54-3-15/6/16, SF-5, TSR Sadvilas Apts, Isukathota, Visakhapatnam, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2277-8632.105107

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  Abstract 

Aims: To evaluate the increase in fetal hemoglobin percentage and MCV in children of sickle cell disease treated with hydroxyurea. To observe the safety of hydroxyurea in treated children. To arrive at the therapeutic dose of the drug to produce the beneficial effects.
Settings and Design: A single blind randomized controlled trial of 12 months duration was designed to study the effect of hydroxyurea on sickle cell patients which aims to study the clinical and laboratory effects, in tertiary care hospital.
Materials and Methods: Sixty children with severe sickle cell disease in the age group of 1-18 years were studied. Outcomes were measured in terms of decrease in number of vaso-occlusive crises, necessity of blood transfusions, laboratory parameters for different organ functions, blood cell counts and toxicity of hydroxyurea.
Results: In patients of sickle, cell disease treated with hydroxyurea there was significant reduction in number and severity of vaso- occlusive crises and necessity of blood transfusions. Total hemoglobin, MCV and fetal hemoglobin percentage were raised significantly. Bone marrow suppression as reflected by the decrease in white blood cell and reticulocyte counts occurred but it was not below the defined toxicity levels. Serum bilirubin was decreased significantly.
Conclusions: In the present study, we concluded that, hydroxyurea decreases number of vaso-occlusive crises and need for blood transfusions in children with severe sickle cell disease. It increases total, fetal hemoglobin concentration and MCV. It causes bone marrow suppression thereby decreasing white blood cell and reticulocyte count. However, this fall was never below defined toxicity levels. It causes no hematological, hepatic, renal or general toxicities when given on short-term basis. Overall, hydroxyurea has proved to be safe and efficacious in children between the age groups of 1-18 years.

Keywords: Fetal hemoglobin, hydroxyurea, sickle cell anemia


How to cite this article:
Pondugala SK, Varanasi PK, Rao K M, Vegesna S. To assess the efficacy of hydroxyurea, in children with homozygous sickle cell disease, in the age group of 1 year to 18 years, at tertiary care hospital. J NTR Univ Health Sci 2012;1:227-32

How to cite this URL:
Pondugala SK, Varanasi PK, Rao K M, Vegesna S. To assess the efficacy of hydroxyurea, in children with homozygous sickle cell disease, in the age group of 1 year to 18 years, at tertiary care hospital. J NTR Univ Health Sci [serial online] 2012 [cited 2020 Sep 21];1:227-32. Available from: http://www.jdrntruhs.org/text.asp?2012/1/4/227/105107


  Introduction Top


Anemia is the major burden of hemolytic morbidity in children. Sickle cell disorder is a genetic disorder, it is well documented that the gene for sickle cell hemoglobin is located on theshort arm of chromosome 11 and has an autosomal recessive inheritance.It is caused by point mutation at the sixth position of beta globin chain leading to the substitution of valine residue for glutamic acid. It leads to shortened life span of red blood corpuscles and constitutes significant proportion of total anemia in India.

Children with sickle cell disease have high morbidity, punctuated by mortality. Common presentation is progressive anemia, fever, icterus, arthritis and multi center osteopathy usually phalanges are involved. Spleen is initially enlarged and shrink later due to repeated infarcts (auto-splenectomy). Frequent infections, growth retardation are added complications.

This study aims to evaluate the efficacy and safety of hydroxyurea in sickle cell disease in children in the age group of 1-18 years on the basis of hematological and clinical responses and side effects.


  Materials and Methods Top


A single blind randomized controlled trial of 12 months duration and was designed to study the effect of hydroxyurea on sickle cell patients.

Control group was given placebo, as multi-vitamin capsules, while intervention group was given hydroxyurea capsules.

Outcomes were measured in terms of decrease in number of vaso-occlusive crises, necessity of blood transfusions, laboratory parameters for different organ functions, blood cell counts and toxicity of hydroxyurea.

Sample size

According to statistical analysis sample size required was 29. Therefore, 30 subjects were recruited in each group.

Study population

Sixty children with severe sickle cell disease, in the age group of 1-18 years, irrespective of sex were enrolled in our study conducted at a tertiary care hospital.

At each monthly follow-up, interval histories were taken, complete physical examination was performed, laboratory monitoring including a complete blood count, liver and kidney function tests, hemoglobin and fetal hemoglobin were done. Height and weight of child was noted and recorded in investigator's sheet. Inquiries regarding any vaso-occlusive crisis, blood transfusion and hospitalization, if any, were made.

Patients were prescribed a dose of 15 mg/kg/d of hydroxyurea orally which was minimum required dose at which subjects showed clinical improvement and was stepped up further, only if there was no clinical and hematological response. If no clinical or hematological response, the dose was escalated by 5 mg/kg/d once in 4 weeks.


  Results Top


In our study, age distribution was between 1 to 18 years, with mean age for hydroxyurea group 7.69 with standard deviation 3.43 years and placebo group 8.26 with standard deviation 3.42 years. 18 were males and 12 were females in both hydroxyurea group and placebo group. Eighteen (60%) were from scheduled castes, 6(20%) were from scheduled tribes, 4(13.3%) were from backward class and 2(6.7%) were OC in hydroxyurea group whereas 17(56.7%) were from scheduled castes, 8(26.7%) were from scheduled tribes, 4(13.3%) were from backward class and 1(3.3%) was from OC.

In hydroxyurea group, mean weight (in kg) after 12 months was 21.77 ± 7.64 as opposed to entry mean weight of 20.77 ± 7.84 (P < 0.001) and in placebo group, mean weight (in kilograms) after 12 months was 19.67 ± 6.75 as opposed to entry mean weight of 19.13 ± 7.08 (P = 0.013), there by reflecting statistically significant difference in weight after 12 months of hydroxyurea and placebo, but highly significant in hydroxyurea group.

In hydroxyurea group, mean height (in centimeters) after 12 months was 111.67 ± 17.19 as opposed to entry mean height of 110.63 ± 18.91 (P = 0.166) whereas in placebo group, mean height (in centimeters) after 12 months was 104.27 ± 19.76 as opposed to entry mean height of 104.13 ± 19.58 (P = 0.696), thereby, reflecting no statistically significant difference after 12 months of hydroxyurea.

In hydroxyurea group, mean vaso-occlusive crises after 12 months was 0.57 ± 0.68 as opposed to entry mean vaso-occlusive crises of 5.7 ± 1.44. Whereas in placebo group, it was 5.00 ± 1.95 after 12 months and 5.40 ± 2.72 at the entry time. This clearly points to statistically significant decrease in crisis after 12 months of hydroxyurea therapy (P < 0.001) with no significant change in placebo group (0.322).

In hydroxyurea group, mean blood transfusions after 12 months was 0.30 ± 0.47 as opposed to entry mean blood transfusions of 2.90 ± 2.93 (P < 0.001). Whereas in placebo group, mean blood transfusions after 12 months was 1.90 ± 1.45 as opposed to entry mean blood transfusions of 2.60 ± 3.18 (P = 0.283). There was statistically significant decrease in number of blood transfusions required, after 12 months treatment with hydroxyurea (P < 0.001) with no significant difference in blood transfusions required in placebo group (P = 0.283).

In hydroxyurea group, mean fetal hemoglobin percentage after 12 months was 39.77 ± 8.92 as opposed to entry mean fetal hemoglobin percentage of 28.38 ± 8.85 reflecting a statistically significant increase in mean fetal hemoglobin percentage (P < 0.001). Whereas in placebo group, mean fetal hemoglobin percentage after 12 months was 24.91 ± 5.28 as opposed to entry mean fetal hemoglobin percentage of 24.52 ± 4.81 (P = 0.297) showing a statistically significant increase in mean fetal hemoglobin percentage after 12 months.

In hydroxyurea group, mean MCV after 12 months was 93.63 ± 7.10 as opposed to entry mean MCV of 76.32 ± 6.85 reflecting a statistically significant increase in mean MCV (P < 0.001). Whereas in placebo group, mean MCV after 12 months was 84.19 ± 6.70 as opposed to entry mean MCV of 83.40 ± 8.27 (P = 0.392) showing a statistically significant increase in mean MCV after 12 months both the groups.

In hydroxyurea group, mean WBC count after 12 months was 8023.33 ± 2245.41 (cells/cu mm) as opposed to entry mean WBC count of 11546.67 ± 5399.86 (cells/cu mm) reflecting statistically significant decrease in mean WBC count after 12 months of hydroxyurea (P < 0.001).Whereas in placebo group, mean WBC count after 12 months was 7523.33 ± 1247.81 as opposed to entry mean WBC count of 9173.33 ± 3728.36, thereby showing statistically significant difference (P = 0.005) but, not as much as in hydroxyurea group.

In hydroxyurea group, reticulocyte count after 12 months was 0.89 ± 0.38 as opposed to entry mean of reticulocyte count 2.33 ± 1.65 (P < 0.001).Whereas in placebo group mean reticulocyte count after 12 months was 1.45 ± 0.80 as opposed to entry mean reticulocyte count of 1.74 ± 1.13 (P = 0.099). Therefore, there was a statistically significant decrease in mean reticulocyte count after 12 months of hydroxyurea therapy.

In hydroxyurea group, mean red blood cell count at entry was 2.74 ± 0.59(million/cu mm) and after 12 months was 2.43 ± 0.55 (P = 0.013). Mean platelet count at entry was 2.17 ± 0.75 (lac/cu mm) and 1.57 ± 0.54 (lac/cu mm) after 12 months of hydroxyurea (P < 0.001) reflecting statistically significant difference in either. In placebo group, mean red blood cell count at entry was 2.77 ± 0.86 (million/cu mm) and after 12 months was 2.64 ± 0.51 (P = 0.377). Mean platelet count at entry was 1.72 ± 0.51 (lac/cu mm) and 1.82 ± 0.27 (lac/cu mm) after 12 months (P = 0.334) reflecting no statistically significant difference in either.

In hydroxyurea group, mean serum bilirubin (mg/dl) after 12 months was 1.10 ± 0.50 as opposed to entry mean serum bilirubin of 1.93 ± 1.46 (P = 0.001).Whereas in placebo group, mean serum bilirubin (mg/dl) after 12 months was 1.17 ± 0.62 as opposed to entry mean serum bilirubin of 1.80 ± 1.28 (P = 0.003). This indicates a statistically significant decrease after 12 months of treatment with hydroxyurea.

In hydroxyurea group, mean SGPT after 12 months was 24.53 ± 5.82 as opposed to entry mean SGPT of 27.10 ± 10.14 (P = 0.07) while in placebo group, mean SGPT after 12 months was 25.93 ± 8.15 as opposed to entry mean SGPT of 27.40 ± 5.59 (P = 0.304). In hydroxyurea group Alkaline phosphatase, Aspartic transaminase levels after 12 months were 104.77 ± 7.78, 33.57 ± 5.21 while in placebo group, these were 105.47 ± 8.60, 29.33 ± 6.06 respectively, with significant difference (P = 0.029) in alkaline phosphatase, but no significant difference in aspartate transaminase (P = 0.37).

In hydroxyurea group, mean blood urea and mean serum creatinine (mg/dl) after 12 months was 30.03 ± 2.53 and 0.87 ± 0.12 as opposed to entry values of 30.10 ± 3.46 (P = 0.919) and 0.95 ± 0.19 (P = 0.02). In placebo group, mean blood urea and mean serum creatinine after 12 months was 29.47 ± 2.92 and 0.88 ± 0.21 respectively, as opposed to entry values of 29.37 ± 2.36 (P = 0.889) and 0.95 ± 0.25 (P = 0.211), reflecting significant difference in serum creatinine but no significant difference in blood urea after 12 months, when compared to baseline mean values.

In present study, no toxicities were found in children, receiving hydroxyurea except reversible myelosuppression causing mild decline in white blood cells and reticulocyte count, which was not below defined toxicity levels


  Discussion Top


Sickle cell disease remains associated with high morbidity and early mortality. Patients with 2 or more painful crises per year, infections and sequestration crisis will have a reduced life expectancy, with median age for men and women with SCD being 42 years and 48 years respectively. In addition, high morbidity rate is related to vascular complications including multiple chronic organ damage affecting the brain, heart, kidneys, liver, eyes, skin, skeleton and lungs. With early enrollment in comprehensive health care, the life expectancy of those afflicted with these disorders can be prolonged to a great extent. Moreover, the quality of life can be made much better.

Charache et al., [1] published the results of multi-center, prospective, double blind, randomized, placebo-controlled clinical trial with hydroxyurea in 299 adults with sickle cell anemia having >3 painful crisis per year. 152 patients were assigned to hydroxyurea treatment and 147 patients were assigned to placebo group. Initial oral dose was 15 mg/kg/day, which was increased by 5 mg/kg/day every 12 weeks, unless marrow suppression was present. Doses of hydroxyurea ranged from 0 to 35 mg/kg/day. Trial was stopped after a median follow-up of 21 months, due to observed beneficial effects. The active treatment group had a lower annual rate of crisis than did the placebo group (49.5 vs. 57.0 per year, P < 0.001). The median time to the first crisis (3.0 vs. 1.5 month, P = 0.01) and the second crisis (8.8 vs. 4.6 month, P < 0.001) were longer with hydroxyurea treatment. Fewer subjects assigned to hydroxyurea group required transfusions (48 vs. 73, P = 0.001). Reversible bone marrow suppression occurred in almost all patients whoreceived hydroxyurea. The researchers concluded that hydroxyurea therapy can improve clinical course of sickle cell anemia in some adults with more than 3 painful crises per year, but the long-term safety of this drug is uncertain.

Ferster et al. [2] published the first pediatric, single blind, randomized cross over pilot study in 22 patients aged 2 to 22 years with severe sickle cell anemia. Children with more than 3 vaso-occlusive crises in the year before entry into study and/or aprevious history of stroke, acute chest syndrome, recurrent crises or splenic sequestration were included in the trial. Subjects were randomized into two groups, group 1 (n = 10) received hydroxyurea 20 mg/kg/day for 6 months followed by placebo for next 6 months. Group 2 (n = 12) received placebo for 6 months followed by hydroxyurea 20 mg/kg/day for next 6 months. If fetal hemoglobin did not increase by at least 20 percent after 2 months of therapy, the dose was increased to 25 mg/kg/day and the dose was reduced by 50 percent if bone marrow suppression occurred. They evaluated hemoglobin, fetal, Hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell count, platelet and reticulocytes count at the time of enrollment and then at monthly intervals.

Kinney et al. [3] published results of multi-center phase I/II trial of hydroxyurea in children with sickle cell anemia (HUG-KIDS). They selected 84 children between 5-15 years, with median age group of 9.1 years with severe disease i.e. more than 3 painful events within the year before entry or at least 3 episodes of acute chest syndrome requiring hospital admission within 2 years of entry or any combination of 3 episodes of acute chest syndrome or pain events within one year of enrollment. Eligible subject also needed a minimum of 6 documented height and weight measurements for at least two years preceding study. Subjects initially were prescribed 15 mg/kg/d of hydroxyurea orally as a single dose. The dose was increased by 5mg/kg every 8 weeks in absence of toxicity. For 68 subjects, who achieved maximum tolerated dose, the mean hydroxyurea dose was 25.6 ± 6.2 mg/kg. The median maximum tolerated dose was 30 mg/kg with range from 7.5 to 30 mg/kg. Interval histories were obtained at biweekly intervals, complete physical examination was done every 4 weeks, complete blood counts every 8 weeks and assessment of iron status every 6 months.

In the present study, which was a single blind, randomized controlled trial, 60 children with homozygous sickle cell disease irrespective of sex in the age group of 1 to 18 years were enrolled. These were sicklers with hemoglobin SS pattern and more than 2 vaso-occlusive crises in last one year.

As compared to other studies, the mean age group was 7.69 ± 3.43 in hydroxyurea group and 8.26 ± 3.42 in placebo group. Dose of hydroxyurea was 15 mg/kg/d initially which was increased only when there was no clinical or hematological improvement which was different in our study. We also took into consideration the social status of children, which showed high prevalence of sickle cell disease in schedules castes and scheduled tribes.

The follow-up of subjects in our study was excellent, with all 60 subjects attending the monthly follow-up schedule. Compliance was assessed at every follow-up and was found to be good with no capsules returned.

Kinney et al. [3] reported similar good compliance in HUG-KIDS study. Out of 3,393 medication refill visits 74% were reported as having no pills returned.

Ferster et al. [2] in the first published study in children reported complete disappearance of vaso-occlusive events requiring admission in 16 out of 22 patients (73%) within first month of hydroxyurea treatment, the number of hospitalization were reduced when patients were on hydroxyurea therapy (0-19 days) as compared with placebo (0-104 days). During first 6-month period, the mean number of days in hospital was 5.3 for hydroxyurea, as compared with 15.2 days in placebo while during second 6 months 1.8 days per hydroxyurea and 8.2 days for placebo.

Kinney et al. [3] in HUG-KIDS did not make much observation on clinical outcomes.

Present study also demonstrated similar clinical outcomes with significant reduction in number of vaso-occlusive crises and its severity. This study emphasized similar decrease in vaso-occlusive crises in hydroxyurea group. Total number of crises in hydroxyurea group also decreased. The mean number of vaso-occlusive crises decreased significantly (0.57 ± 0.68 from of 5.7 ± 1.44) in hydroxyurea group (P < 0.001). In the requirement of blood transfusions, it was observed that there was tremendous decline of the same, in hydroxyurea group. The mean number of blood transfusions also decreased to 0.30 ± 0.47 from 2.90 ± 2.93 after 12 months in hydroxyurea group (P < 0.001).

Ferster et al. [2] in pediatric control trial showed that after 6 months of hydroxyurea treatment, the mean hemoglobin level increased to 8.5 gm/dl from mean initial hemoglobin level of 8.1 gm/dl. Similarly, mean fetal hemoglobin percent raised to 15% from 4.7%.

PED-HUG study by Kinney et al., [3] concluded that hydroxyurea therapy for one year produces a highly significant increase in total hemoglobin concentration (9.0 ± 1.1 from 7.8 ± 1.0), mean corpuscular volume (98.9 ± 9.1 from 85.9 ± 6.6), fetal hemoglobin (15.5 ± 7.3 from 7.3 ± 4.9) and F cell percentage (62.2 ± 18.1 from 34.6 ± 17.8).

In present study mean hemoglobin, mean fetal hemoglobin percentage and MCV raised significantly from their base line values. (9.03 ± 0.69 from 7.69 ± 0.85), (39.77 ± 8.92 from 28.38 ± 8.85) and (93.63 ± 7.10 from 76.32 ± 6.85) respectively.

Ferster et al. [2] in pediatric control trial, noted that reticulocyte count however decreased from 149 ± 54% to 103 ± 49%. White blood cell count also decreased from 12.47 ± 4.58 to 8.90 ± 2.51, which shows statistically significant bone marrow suppression. Platelet count and mean corpuscular hemoglobin concentration were unaltered, while mean corpuscular volume was significantly increased.

PED-HUG study by Kinney et al., [3] noted a significant bone marrow suppression shown by statistically significant decrease in WBC count ( × 109/kg) 9.2 ± 3.0 from 13.6 ± 3.9 and reticulocyte count to 215 ± 92 from 354 ± 144.

As in previous studies, we also reported a statistically significant bone marrow suppression reflected by decrease in white blood cell count (thousand/cu mm) of 8023.33 ± 2245.41 from 11546.67 ± 5399.86 and reticulocyte count (%) of 0.89 ± 0.38 from 2.33 ± 1.65). However, the decline was not below the defined levels of toxicity.

Pediatric controlled trial by Ferster et al. [2] showed that, no clinically relevant toxicity was associated with hydroxyurea therapy. However, organ functions like liver and kidney function tests were not monitored in this study.

PED-HUG study by Kinney et al. [3] showed that effects of hydroxyurea on kidney and liver functions were negligible during study.

In this study, total bilirubin (mg/dl) decreased to 1.10 ± 0.50 from 1.93 ± 1.46. Serum creatinine was unaffected after one year of therapy.

Kinney et al. [3] recorded, minimum of 6 documented, height and weight measurements for at least 2 years preceding entry. The mean weight and height were 32.3 ± 15.8, 134.7 ± 16.9 respectively. They concluded that hydroxyurea does not adversely affect growth parameters like height and weight (P < 0.001). There was a statistically significant increase in these parameters.

In the present study, there were no adverse effects on growth parameters like height and weight as shown by 12 months value of 111.67 ± 17.19 for height (P = 0.166) and 21.77 ± 7.64 for weight (P < 0.001), from baseline values of 110.63 ± 18.91 and 20.77 ± 7.84 respectively, in hydroxyurea group. There was no significant difference in height; there was significant difference in weight (P < 0.001).

Among kidney function tests, blood urea was unaltered P = 0.919, but serum creatinine was decreased P = 0.02. Also in liver function tests, SGPT and SGOT were unaltered. Serum bilirubin was decreased to 1.10 ± 0.50 from 1.93 ± 1.46, which was a statistically significant difference showing decrease in rate of hemolysis. Alkaline phosphatase also showed significant decrease of 104.77 ± 7.78 from 111.63 ± 13.55.

In HUG-KIDS study Kinney et al. [3] noted infections in 20 patients, headache in 12 patients, diarrhea in 6 patients, skin rash in 5 patients, bleeding in 1 patient and growth failure was not noted in any patient.

In pediatric randomized trial by Ferster et al. [2] noted no clinically relevant toxicity was associated with hydroxyurea therapy.

In our present study, minimal side effects involving gastrointestinal tract were noted in 10% of patients. Thus, inspite of differences in ethnicity and dosage of hydroxyurea there were definite clinical and hematological responses in favor of subjects of sickle cell disease treated with hydroxyurea, in all above studies. The most commonly observed effects were of reversible myelo-suppression, with white-blood cell count never falling below the toxic levels i.e. <2500/cu mm. The organ functions remained unaltered in all studies. The decrease in white blood cell, reticulocytes and serum bilirubin was indicative of decreased rate of hemolysis.

Thus, hydroxyurea is effective in treating children with sickle cell disease, on short term basis. However, unanswered questions remain concerning the long-term effects of the treatment especially it's sustained efficacy and toxicity.

Kinney et al. in HUG-KIDS study initially prescribed 15 mg/kg/d of hydroxyurea orally as a single dose. The dose was increased by 5 mg/kg/d once in every 8 weeks in the absence of toxicity. The mean dose of hydroxyurea was 26.6 ± 6.2 mg/kg/d.

In this study, the initial dose was 15 mg/kg/d and dose was increased by 5 mg/kg/d once in 4 weeks only if there was no clinical response. We increased in only 3 patients.

The mean dose of hydroxyurea was 16.08 ± 3.45, which suggest that there was clinical response even with minimal dose.


  Conclusion Top


In the present study, we concluded that, hydroxyurea decreases number of vaso-occlusive crises and need for blood transfusions in children with severe sickle cell disease. It increases total, fetal hemoglobin concentration and MCV. It causes bone marrow suppression thereby decreasing white blood cell and reticulocyte count. However, this fall was never below defined toxicity levels. It causes no hematological, hepatic, renal or general toxicities when given on short-term basis. Overall, hydroxyurea has proved to be safe and efficacious in children between the age groups of 1-18 years. However, a double blind study involving a larger number of children is necessary to demonstrate both its efficacy in decreasing the frequency of vaso-occlusive crises and its safety with long-term use in children

 
  References Top

1.Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effects of hydroxyurea on the frequency of painful crisis in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Engl J Med 1995;332:1317-22.  Back to cited text no. 1
[PUBMED]    
2.Ferster A, Vermylen C, Cornu G, Buyse M, Corazza F, Devalck C, et al. Hydroxyurea for treatment of severe sickle cell anemia: A pediatrics clinical trial. Blood 1996;88:1960-4.  Back to cited text no. 2
[PUBMED]    
3.Kinney TR. Safety of hydroxyurea in children with sickle cell anemia: Results of HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group. Blood 1999;94:1550-4.  Back to cited text no. 3
    




 

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