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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1550-1554
Safety of Hydroxyurea in Children With Sickle Cell Anemia: Results of
the HUG-KIDS Study, a Phase I/II Trial
By
Thomas R. Kinney,
Ronald W. Helms,
Erin E. O'Branski,
Kwaku Ohene-Frempong,
Winfred Wang,
Charles Daeschner,
Elliott Vichinsky,
Rupa Redding-Lallinger,
Beatrice Gee,
Orah S. Platt, and
Russell E. Ware for the Pediatric Hydroxyurea Group
From Duke Pediatric Sickle Cell Program, Duke Children's Hospital,
Durham, NC; the Department of Biostatistics and Frank Porter Graham
Child Development Center, University of North Carolina at Chapel Hill,
Chapel Hill, NC; Comprehensive Sickle Cell Center, The Children's
Hospital of Philadelphia, Philadelphia, PA; St Jude Children's
Research Hospital, Memphis, TN; Pitt Memorial Hospital, East Carolina
University, Greenville, NC; Sickle Cell Center of Northern California,
Oakland Children's Hospital, Oakland, CA; the University of North
Carolina Pediatric Sickle Cell Program, University of North Carolina at
Chapel Hill, Chapel Hill, NC; and the Department of Medicine,
Children's Hospital, Harvard Medical School, Boston, MA.
 |
ABSTRACT |
Previous studies have determined the short-term
toxicity profile, laboratory changes, and clinical efficacy associated
with hydroxyurea (HU) therapy in adults with sickle cell anemia. The safety and efficacy of this agent in pediatric patients with sickle cell anemia has not been determined. Children with sickle cell anemia,
age 5 to 15 years, were eligible for this multicenter Phase I/II trial.
HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d unless the
patient experienced laboratory toxicity. Patients were monitored by
2-week visits to assess compliance, toxicity, clinical adverse events,
growth parameters, and laboratory efficacy associated with HU
treatment. Eighty-four children were enrolled between December 1994 and
March 1996. Sixty-eight children reached maximum tolerated dose (MTD)
and 52 were treated at MTD for 1 year. Significant hematologic changes
included increases in hemoglobin concentration, mean corpuscular
volume, mean corpuscular hemoglobin, and fetal hemoglobin parameters,
and decreases in white blood cell, neutrophil, platelet, and
reticulocyte counts. Laboratory toxicities typically were mild,
transient, and were reversible upon temporary discontinuation of HU. No
life-threatening clinical adverse events occurred and no child
experienced growth failure. This Phase I/II trial shows that HU therapy
is safe for children with sickle cell anemia when treatment was
directed by a pediatric hematologist. HU in children induces similar
laboratory changes as in adults. Phase III trials to determine if HU
can prevent chronic organ damage in children with sickle cell anemia are warranted.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HYDROXYUREA (HU) is effective therapy for
adults with sickle cell anemia. In a controlled trial, patients
receiving HU had a lower rate of painful events, acute chest syndrome,
need for transfusion, and hospitalization compared with patients taking placebo.1 The principal toxicities observed in this study
were transient reversible depressions of white blood cells (WBCs), platelets, and hemoglobin concentration.
Several small studies have reported the short-term toxicity and
efficacy of HU for children with sickle cell anemia.2-6
There is appropriate reluctance, however, to use this drug in children because of concerns related to potential toxicities including impaired
growth, teratogenesis, or carcinogenesis.7,8 These concerns
have hindered implementation of clinical trials to test the efficacy of
HU in children.
This report describes the results of a multicenter Phase I/II trial of
HU in children with sickle cell anemia (HUG-KIDS). The study was
designed to determine the maximum tolerated dose (MTD) of HU and to
treat a cohort of 50 severely affected children for 1 year at MTD. The
specific aims were to determine if: (1) HU will elevate the fetal
hemoglobin (Hb F) level, hemoglobin concentration, and red
blood cell mean corpuscular volume (MCV) above baseline
values; (2) hematologic and other toxicities of HU are similar to those
in adults; (3) HU therapy has an adverse effect on growth.
| |
MATERIALS AND METHODS |
Patient selection.
Children with severe sickle cell anemia, ages 5 to 15 years, were
eligible for enrollment. Severe disease was defined as 3 or more pain
events (PEs) within the year before entry, or at least 3 episodes of
acute chest syndrome (ACS) requiring hospital admission within 2 years
of entry, or any combination of 3 episodes of ACS or PEs within 1 year
of the enrollment. Eligible patients also needed a minimum of 6 documented height and weight measurements recorded for at least 2 years
preceding entry.
Exclusion criteria included pregnancy, seropositivity for human
immunodeficiency virus, or another chronic illness that potentially could enhance HU toxicity. Patients also were excluded if they were
taking medications on a regular basis that might enhance HU toxicity,
such as theophylline, estrogen, or calcium channel blockers. Other
exclusion criteria included prior treatment with HU, a serum creatinine
greater than 1.0 mg/dL, serum alanine aminotransferase (ALT) more than
twice the upper limit of normal, a red blood cell transfusion within
100 days of enrollment, or more than 10% Hb A on hemoglobin
electrophoresis at the time of entry.
Enrollment was complete once informed consent had been obtained in
accordance with the guidelines of each participating center's Institutional Review Board, the enrollment criteria had been reviewed by the Study Coordinator (EEO), and the intake form had been received by the Statistical Center. Intake laboratory tests included a complete
blood count, differential white count, absolute reticulocyte count
(ARC), urinalysis, hemoglobin electrophoresis with measurements of Hb
A, Hb A2 and Hb F, F-cell quantitation, serum levels for iron and total iron binding capacity, ferritin, B12,
folate, hepatitis B surface antigen, and a serum chemistry panel. This
panel included creatinine, total protein, albumin, lactic acid
dehydrogenase (LDH), aspartate aminotransferase (AST) and ALT, and
total bilirubin concentration. Other intake laboratory tests included
measurement of serum antibodies to hepatitis A, hepatitis B, hepatitis
C, and Parvovirus B19. Pregnancy tests were performed on menstruating patients before initiating HU treatment.
Patient monitoring.
Interval histories were obtained at biweekly intervals. A complete
physical examination was performed every 4 weeks. Laboratory monitoring
included a complete blood count with differential every 2 weeks, a
serum chemistry panel every 4 weeks, Hb F parameters every 8 weeks, and
an assessment of iron stores every 6 months. Pregnancy tests were
performed if menses were delayed by more than 2 weeks.
Interval histories, physical examinations, and laboratory results were
faxed to the Statistical Center. Values for hemoglobin concentration,
ARC, absolute neutrophil count (ANC), platelet count, serum creatinine,
and serum ALT were checked immediately for toxicity at the
participating center and again on receipt at the Coordinating Center.
To reduce the risk of toxicity, only a 2-week supply of HU was
dispensed at a time. Patients were requested to return all unused HU at
each study visit. A Drug Safety Monitoring Board (DSMB) was appointed
by the National Institutes of Health to oversee the HUG-KIDS trial.
Dosing schedule.
Patients initially were prescribed 15 mg/kg of HU orally as a single
daily dose. The daily dose was increased by 5 mg/kg every 8 weeks in
the absence of toxicity. If a patient experienced a laboratory
toxicity, HU was discontinued for at least 1 week. Once the toxicity
resolved, HU was restarted at a dose 2.5 mg/kg lower than the dose at
which the toxicity occurred. HU doses then were increased subsequently
in 2.5 mg/kg increments every 8 weeks, provided toxicity did not occur.
MTD was defined as the dose 2.5 mg/kg below which 2 successive
hematologic toxicities occurred or when the daily dose reached 30 mg/kg
and was sustained without toxicity for 8 weeks. Once MTD was achieved,
patients were treated for 1 year and then exited from the study.
Laboratory methods.
Blood counts, serum iron studies, and serum chemistries were performed
by standard techniques at each clinical center. The fetal hemoglobin
parameters (Hb F level and F-cell percentage) were measured at the
Children's Hospital of Philadelphia. The Hb F level was determined by
high-pressure liquid chromatography and F cells were assayed by an
immunofluorescence method.9-11
Definition of toxicities, adverse events, and growth failure.
Toxicities were assigned to 1 of 3 groups: hematologic, hepatic, or
renal. Hematologic toxicity was defined as 1 or more of the following:
ANC below 2.0 × 109/L; an ARC below 80 × 109/L unless the hemoglobin concentration was 9.0 g/dL or higher; a platelet count below 80 × 109/L; a 20% decrease in hemoglobin concentration from
entry or previous value, or a hemoglobin concentration below 4.5 g/dL.
Hepatic toxicity was defined as an ALT value that was greater than
twice the upper limit of normal. A 50% increase from baseline in the
serum creatinine and a value of more than 1.0 mg/dL defined renal toxicity.
An adverse event (AE) was defined as death or any life-threatening or
clinical event likely to interfere either temporarily or permanently
with the patient's ability to continue or tolerate HU therapy. Growth
failure was defined as a growth velocity less than the fifth percentile
for age over a 6-month period.
Study coordination, data management, and statistical methods.
The Study Coordinator monitored all clinical aspects of this study.
Staff at the Statistical Center managed all data and correspondence. To
ensure confidentiality, patients were identified only by an acrostic
and unique patient identification number.
Clinic sites faxed forms to both the Study Coordinator and the
Statistical Center. When received at the Statistical Center, these
images were stored in a RhoFAX image database (Rho, Inc, Chapel Hill,
NC). Before data entry, the Study Coordinator and Statistical Center personnel reviewed forms for content, accuracy, and
completeness. The study's database management system used independent
double data entry with a third party referee, followed by
field-specific (valid value, valid range) and multivariate error
detection procedures. Questionable values were faxed to each site's
coordinator and responses were faxed back to the Statistical Center.
Statistical analyses were performed with SAS software (Cary, NC). The
Student's t-test was used to compare means between groups.
| |
RESULTS |
Enrollment.
Eighty-four African-American children with sickle cell anemia were
enrolled from December 14, 1994 through March 31, 1996. The patient
population included 40 females, 7 of whom had attained menarche before
enrollment. The mean patient age (±1 standard deviation [SD]) was
9.8 ± 3.2 years, with a median age of 9.1 years and a range from 5 years to 15 years. Three children, not included in the 84, were
enrolled, but never received HU. One of these patients was not
homozygous for the sickle hemoglobin gene and legal guardians of the
others withdrew their children before administering HU.
HU compliance.
Capsule counts were analyzed as a surrogate for compliance. Patients
were expected to have taken all previously dispensed HU capsules when
they returned to the clinic at each 2-week interval. Of 3,393 medication refill visits, 74% were reported as having no pills
returned. Capsules were returned at 26% of the visits, including 10%
of visits with  10% of pills returned and 10% of visits where 10%
to 25% of pills returned. Only 6% of visits had more than 25% of
pills returned.
Laboratory effects of HU therapy.
Changes in laboratory values are summarized in
Table 1. By 6 months of HU treatment, there
were statistically significant increases in the hemoglobin
concentration, MCV, mean corpuscular hemoglobin (MCH), Hb F level, and
percentage of F cells and significant decreases in the ARC, WBC count,
ANC, platelet count, total bilirubin, and LDH compared with baseline
values (P < .0001). The mean corpuscular hemoglobin
concentration (MCHC), ALT, and creatinine were not significantly
different from baseline values at 6 months.
After 12 months of HU treatment, there was significant difference
(P < .05) in the mean MCV, MCH, LDH, total bilirubin, Hb F,
and F-cell percentage compared with 6 months. There were no significant
changes in the ALT or creatinine after 12 months of treatment compared
with their respective baseline or 6-month values.
MTD.
When this trial ended, 68 patients had attained MTD, 52 of the 84 enrolled patients (62%) had completed 1 year of HU treatment at MTD,
10 patients were still being treated at MTD, and 4 patients were in the
dose-escalation phase.
By protocol design, the minimum time required to attain an MTD of 30 mg/kg was 224 days. The average time for patients to reach MTD was 330 ± 164 days with a median of 263 days. For the 68 patients who
achieved MTD, the mean HU dose was 25.6 ± 6.2 mg/kg, while the
median MTD was 30 mg/kg with a range from 7.5 to 30 mg/kg.
Patient attrition.
Eighteen patients were removed from the study, including 6 patients who
had achieved MTD. These included 10 patients who were noncompliant with
HU administration or unable to meet the required visit schedule and 3 patients who relocated away from a clinical center. The DSMB requested
that 4 patients be removed from the study and 1 other patient had HU
discontinued by the study physician because of sickle cell-related complications.
The first patient withdrawn by the DSMB had received an unsuccessful
bone marrow transplant before enrollment and experienced recurrent
thrombocytopenia while receiving HU. Another patient was removed
because of recurrent elevations of the serum ALT. Review of this
patient's medical records showed a long history of intermittent ALT
elevations before enrollment that were not associated with specific
hepatobiliary complications or clinical events. The third patient
complained of severe recurrent headaches during HU therapy. Cerebral
arteriography demonstrated vasculopathy with a moya-moya pattern. The
patient was placed on a chronic transfusion program. The last patient
had transient aphasia and left-sided weakness immediately after
erythrocytapheresis in preparation for an elective cholecystectomy. His
postapheresis hemoglobin concentration was 13.8 g/dL and the transient
ischemic attack was attributed to hyperviscosity.
The only patient removed by a study physician was a child with
documented hypersplenism and recurrent neutropenia for 18 months before
HU therapy. HU was stopped because the patient remained neutropenic
while receiving a very low dose of HU (2.5 mg/kg/d).
Laboratory toxicity.
Cytopenias were the most common side effect from HU therapy, as would
be anticipated in a Phase I/II trial of a myelosuppressive agent
designed to achieve the MTD (Table 2).
Neutropenia was the most common hematologic toxicity, but only occurred
in 5.2% of all blood count measurements. The majority of neutropenia
toxicities were mild with an ANC value between 1.5 and 2.0 × 109/L. No episode of neutropenia was associated with a
serious infection. Reticulocytopenia and anemia also occurred, but much
less frequently than did neutropenia. Anemia severe enough to warrant
transfusion was observed only in association with episodes of ACS. No
patient was transfused for severe anemia solely due to the
myelosuppressive effect of HU. One patient experienced an episode of
severe thrombocytopenia (6 × 109/L) accompanied by 2 episodes of epistaxis. A platelet transfusion was administered and the
platelet count normalized within 4 days of discontinuing HU. HU was
restarted and the patient experienced no other thrombocytopenic
episodes.
Eleven patients (13%) experienced 17 episodes of ALT elevation (Table
2). The mean ± SD for these abnormal ALT values was 166 ± 97 IU/L with a median of 125 IU/L and range from 60 to 393 IU/L. Sixteen
episodes of ALT elevation resolved within 2 weeks and the other within
3 weeks. One patient with ALT elevations also had gallstones. In no
instance was it possible to attribute an ALT elevation solely to HU
treatment, analgesic usage, or clinical events. No patient experienced
renal toxicity.
Clinical adverse events.
Table 3 summarizes clinical events reported
during the study. There were 90 sickle cell-related events and 127 other events that were not ascribed to sickle cell anemia. The common
sickle cell-related complications included PEs (76 events) and ACS (10 events). Thirty-four (40%) patients experienced PEs and 8 (10%) had
an ACS. Priapism was reported once among the 44 males.
The clinical events that were not believed to be sickle cell-related
included pain, headache, bleeding, gastrointestinal disturbances, unexplained fever, and minor infections. Fifty episodes of pain were
not believed to be related to complications of sickle cell anemia, in
the opinion of the patient and staffs at the participating centers
(Table 3). The abdomen was the most common site of pain, although pain
was also noted in the trunk, joints, and extremities. There were no
clear precipitating factors for these painful events, although on many
occasions the pain occurred along with vasoocclusive pain. No patient
experienced alopecia. Five patients had skin rashes, but no rash was
attributed to HU. There were 32 occurrences of mild gastrointestinal
complaints, including 25 episodes of nausea and 7 of diarrhea. In 2 instances, nausea was ascribed to HU. Both patients had less nausea
when HU was taken at bedtime. No patient had gastrointestinal
complaints severe enough to warrant withholding HU treatment.
As illustrated in Table 4, HU did not have
an adverse effect on growth. At each 6-month interval, then mean weight
and height increased significantly (P < .0001). Four girls,
ages 11.1 to 14.1 years, reached menarche while receiving HU. No
patient became pregnant.
Comparison of HU in adults and children.
The mean changes from baseline of hematologic values, total bilirubin
concentration, and Hb F parameters in our pediatric population are
compared with the patients in the adult Phase I/II HU trial in
Table 5.12 It was only possible
to compare data on those patients who were receiving HU when their
respective studies were closed. The laboratory changes for both patient
populations are similar in all categories. The mean increase in the
hemoglobin concentration was identical. Both groups had increases in
the MCV, Hb F, and F cells. The WBC count, platelet count, ARC, ANC, and total bilirubin declined in both populations.
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|
Table 5.
Comparison of the Phase I/II Hematologic Values of
Children and Adults With Sickle Cell Anemia Who Were Receiving
Treatment at the End of Their Respective Studies
|
|
| |
DISCUSSION |
The HUG-KIDS trial addressed each of its aims. We showed that HU
significantly increases the hemoglobin concentration, MCV, Hb F, and
F-cell percentage above pretreatment values. In addition, we showed
that pediatric and adult patients had similar hematologic toxicities.
Finally, no adverse effect on growth was observed during the treatment period.
HU therapy produces a highly significant increase in the total
hemoglobin concentration, MCV and MCH (Table 1). Each of these hematologic effects of HU in children is similar to those in adults (Table 5). The decrease in LDH, total bilirubin, and ARC suggest that
the increase in hemoglobin concentration is associated with a decreased
rate of hemolysis. HU causes an increase in the amount of Hb F and the
percentage of red blood cells that contain Hb F. Increases in the
intracellular Hb F concentration would be expected to reduce hemolysis
by inhibiting Hb S polymer formation.
Most hematologic effects of HU on red blood cells were manifested
within 6 months of initiating treatment (Table 1), well before the MTD
was typically attained. In addition, there did not appear to be a
substantial enhancement or diminution of these effects after 12 or 24 months of HU therapy. These observations have important implications.
First, they suggest that frequent adjustments of the HU dose to reach
the threshold of myelotoxicity may not be necessary. Second, once the
patient is observed to respond to HU, there does not appear to be any
evidence of "marrow exhaustion" during the treatment period of 1 year at MTD. Finally, a daily oral dose of 25 to 30 mg/kg generally is
well tolerated by most children.
Patients continued to gain weight and height while taking HU for at
least 1 year at MTD (Table 4). Further trials with HU being
administered for longer periods of time, however, are needed to define
with a greater degree of certainty the effects of HU on growth.
One to 2 years of HU therapy appears to be relatively safe in children
with sickle cell anemia who are monitored closely by experienced
pediatric hematologists. The most commonly observed toxicities were
those related to its myelosuppressive effects (Table 2). These
toxicities were transient and resolved quickly once HU was
discontinued. Effects of HU on kidney and liver function were
negligible during this study. Except for 1 episode of severe thrombocytopenia, there were no unusual or life-threatening toxicities observed during this study with over 100 patient-years of close monitoring. There remains the potential, however, that administration of HU for longer periods of time may be associated with major side
effects that were not seen in this relatively short-term study.
Acute complications continued to occur in HUG-KIDS participants as they
do in adult patients taking HU. Although we would expect that HU would
reduce the frequency of acute complications and possibly prevent, or
delay, organ damage in pediatric patients, the demonstration of such
efficacy warrants a rigorous Phase III clinical trial. This trial also
should attempt to define the complications related to long-term
administration of HU.
| |
APPENDIX |
Children's Hospital, Boston: Susan Kurth, NP; Children's Hospital of
Philadelphia: Lorien Moore, RN, Leslie Parkin, and Sonya Whitehead, RN;
Duke University Medical Center: William H. Schultz, PA-C, MHS and Amy
Walker, CCRA; East Carolina University: Diana Gordon, RNC and Cynthia
Brown, CCRA; Oakland Children's Hospital: Ekua Hackney Stephens, MS,
PNP; St Jude Children's Research Hospital: Kristy Cupples, RN and Lynn
Wynn, RN; Memorial Hospital, University of North Carolina at Chapel
Hill: Susan Jones, RN; Statistical Center, University of North
Carolina, Department of Biostatistics and the Frank Porter Graham Child
Development Center: Lisa Brooks, BA, Katherine Gover, MS, Elizabeth
Gunn, BS, Mary Helms, BS, and Marsha McMurray, BS, MA.
| |
ACKNOWLEDGMENT |
The authors acknowledge the important contribution to this study of
Hazumi Horiuchi, PhD, from the Children's Hospital of Philadelphia in
whose laboratory the Hb F measurements and F-cell assays were
performed. The authors also are grateful for the support and vision of
Clarice Reid, MD, and the supervision and guidance of the Drug Safety
Monitoring Board and Duane Bonds, MD, Program Leader for the Sickle
Cell Section of the Heart Lung and Blood Institute. DSMB members
included George Buchanan, MD (Chair); Robert Baumiller, SJ, PhD; George
Dover, MD; Bertil Glader, MD, PhD; Genell Knatterud, PhD; and Doris
Wethers, MD. In addition there were several key members from the
clinical centers and the Statistical Center whose tireless efforts made
this study possible. These individuals are listed in the Appendix by
their participating institution.
| |
FOOTNOTES |
Submitted March 17, 1999; accepted May 5, 1999.
Supported in part by Comprehensive Sickle Cell Center Awards from the
National Heart, Lung and Blood Institute, National Institutes of
Health, Bethesda, MD (Boston P60 HL 15157, Duke-UNC P60 HL 28391, Philadelphia P60 HL 38632, Northern California P60 HL 20985).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Thomas R. Kinney, MD, Department of
Pediatrics, PO Box 3462, Duke Children's Hospital, Duke University
Medical Center, Durham, NC 27710; e-mail: kinne001{at}mc.duke.edu.
| |
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S. A. Zimmerman, W. H. Schultz, S. Burgett, N. A. Mortier, and R. E. Ware
Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia
Blood,
August 1, 2007;
110(3):
1043 - 1047.
[Abstract]
[Full Text]
[PDF]
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M. J. Telen
Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease
Hematology,
January 1, 2007;
2007(1):
84 - 90.
[Abstract]
[Full Text]
[PDF]
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M. R. DeBaun and J. J. Field
Limitations of Clinical Trials in Sickle Cell Disease: A Case Study of the Multi-center Study of Hydroxyurea (MSH) Trial and the Stroke Prevention (STOP) Trial
Hematology,
January 1, 2007;
2007(1):
482 - 488.
[Abstract]
[Full Text]
[PDF]
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A. D. Villella
Hydroxyurea Therapy for Infants with Sickle Cell Anemia
AAP Grand Rounds,
April 1, 2006;
15(4):
39 - 40.
[Full Text]
[PDF]
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H. Fathallah and G. F. Atweh
Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease
Hematology,
January 1, 2006;
2006(1):
58 - 62.
[Abstract]
[Full Text]
[PDF]
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J. S. Hankins, R. E. Ware, Z. R. Rogers, L. W. Wynn, P. A. Lane, J. P. Scott, and W. C. Wang
Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study
Blood,
October 1, 2005;
106(7):
2269 - 2275.
[Abstract]
[Full Text]
[PDF]
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A. D. Villella
Mortality in Sickle Cell Patients on Hydroxyurea Therapy
AAP Grand Rounds,
August 1, 2005;
14(2):
14 - 15.
[Full Text]
[PDF]
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B. Gulbis, D. Haberman, D. Dufour, C. Christophe, C. Vermylen, F. Kagambega, F. Corazza, C. Devalck, M.-F. Dresse, K. Hunninck, et al.
Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events: the Belgian experience
Blood,
April 1, 2005;
105(7):
2685 - 2690.
[Abstract]
[Full Text]
[PDF]
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R. S. Weinberg, X. Ji, M. Sutton, S. Perrine, Y. Galperin, Q. Li, S. A. Liebhaber, G. Stamatoyannopoulos, and G. F. Atweh
Butyrate increases the efficiency of translation of {gamma}-globin mRNA
Blood,
February 15, 2005;
105(4):
1807 - 1809.
[Abstract]
[Full Text]
[PDF]
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M de Montalembert, C Maunoury, P Acar, V Brousse, D Sidi, and G Lenoir
Myocardial ischaemia in children with sickle cell disease
Arch. Dis. Child.,
April 1, 2004;
89(4):
359 - 362.
[Abstract]
[Full Text]
[PDF]
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S. A. Zimmerman, W. H. Schultz, J. S. Davis, C. V. Pickens, N. A. Mortier, T. A. Howard, and R. E. Ware
Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease
Blood,
March 15, 2004;
103(6):
2039 - 2045.
[Abstract]
[Full Text]
[PDF]
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N. Perelman, S. K. Selvaraj, S. Batra, L. R. Luck, A. Erdreich-Epstein, T. D. Coates, V. K. Kalra, and P. Malik
Placenta growth factor activates monocytes and correlates with sickle cell disease severity
Blood,
August 15, 2003;
102(4):
1506 - 1514.
[Abstract]
[Full Text]
[PDF]
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S. K. Selvaraj, R. K. Giri, N. Perelman, C. Johnson, P. Malik, and V. K. Kalra
Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor
Blood,
August 15, 2003;
102(4):
1515 - 1524.
[Abstract]
[Full Text]
[PDF]
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D. L. Weiner and C. Brugnara
Hydroxyurea and Sickle Cell Disease: A Chance for Every Patient
JAMA,
April 2, 2003;
289(13):
1692 - 1694.
[Full Text]
[PDF]
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K. J. Helton, W. C. Wang, L. W. Wynn, R. B. Khan, and R. G. Steen
The Effect of Hydroxyurea on Vasculopathy in a Child with Sickle Cell Disease
AJNR Am. J. Neuroradiol.,
November 1, 2002;
23(10):
1692 - 1696.
[Abstract]
[Full Text]
[PDF]
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P. Venigalla, B. Motwani, A. Nallari, S. Allen, M. Agarwal, M. Alva, M. Westerman, and L. Feldman
A patient on hydroxyurea for sickle cell disease who developed an opportunistic infection
Blood,
June 17, 2002;
100(1):
363 - 364.
[Full Text]
[PDF]
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G. B. Segel, M. G. Hirsh, and S. A. Feig
Managing Anemia in a Pediatric Office Practice: Part 2
Pediatr. Rev.,
April 1, 2002;
23(4):
111 - 122.
[Abstract]
[Full Text]
[PDF]
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Section on Hematology/Oncology and Committee on Ge
Health Supervision for Children with Sickle Cell Disease
Pediatrics,
March 1, 2002;
109(3):
526 - 535.
[Abstract]
[Full Text]
[PDF]
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M. C. Walters, A. W. Nienhuis, and E. Vichinsky
Novel Therapeutic Approaches in Sickle Cell Disease
Hematology,
January 1, 2002;
2002(1):
10 - 34.
[Abstract]
[Full Text]
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R. E. Ware, B. Eggleston, R. Redding-Lallinger, W. C. Wang, K. Smith-Whitley, C. Daeschner, B. Gee, L. A. Styles, R. W. Helms, T. R. Kinney, et al.
Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy
Blood,
January 1, 2002;
99(1):
10 - 14.
[Abstract]
[Full Text]
[PDF]
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M. de Montalembert and S. C. Davies
Is hydroxyurea leukemogenic in children with sickle cell disease?
Blood,
November 1, 2001;
98(9):
2878 - 2879.
[Full Text]
[PDF]
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A. Ferster, P. Tahriri, C. Vermylen, G. Sturbois, F. Corazza, P. Fondu, C. Devalck, M. F. Dresse, W. Feremans, K. Hunninck, et al.
Five years of experience with hydroxyurea in children and young adults with sickle cell disease
Blood,
June 1, 2001;
97(11):
3628 - 3632.
[Abstract]
[Full Text]
[PDF]
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R. J. Adams
Stroke Prevention and Treatment in Sickle Cell Disease
Arch Neurol,
April 1, 2001;
58(4):
565 - 568.
[Full Text]
[PDF]
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V. N. Hanft, S. R. Fruchtman, C. V. Pickens, W. F. Rosse, T. A. Howard, and R. E. Ware
Acquired DNA mutations associated with in vivo hydroxyurea exposure
Blood,
June 1, 2000;
95(11):
3589 - 3593.
[Abstract]
[Full Text]
[PDF]
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W. F. Rosse, M. Narla, L. D. Petz, and M. H. Steinberg
New Views of Sickle Cell Disease Pathophysiology and Treatment
Hematology,
January 1, 2000;
2000(1):
2 - 17.
[Abstract]
[Full Text]
[PDF]
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K. M. Sullivan, R. Parkman, and M. C. Walters
Bone Marrow Transplantation for Non-Malignant Disease
Hematology,
January 1, 2000;
2000(1):
319 - 338.
[Abstract]
[Full Text]
[PDF]
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J. S. Hankins, R. E. Ware, Z. R. Rogers, L. W. Wynn, P. A. Lane, J. P. Scott, and W. C. Wang
Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study
Blood,
October 1, 2005;
106(7):
2269 - 2275.
[Abstract]
[Full Text]
[PDF]
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TOP
ABSTRACT
INTRODUCTION