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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Long-term hydroxyurea therapy for infants with sickle cell anemia:
the HUSOFTextension study
Jane S. Hankins, Russell E. Ware, Zora R. Rogers, Lynn W. Wynn, Peter A. Lane, J. Paul Scott, and Winfred C. Wang
The long-term efficacy and toxicity of hy-
droxyurea for infants are undefined, and its
role in preventing organ dysfunction is un-
known. Short-term feasibility of hydroxy-
urea administration, toxicities, hematologic
effects, and effect on spleen function in
infants with sickle cell anemia (SCA) were
reported (Hydroxyurea Safety and Organ
Toxicity [HUSOFT] trial). These infants com-
pleting 2 years of hydroxyurea therapy (20
mg/kg/d) were offered study extension with
doseescalationto30mg/kg/d.Patientswere
monitored with laboratory tests and bian-
nual imaging studies. Hematologic indices
were compared with predicted age-specific
values and event rates compared with his-
toric rates. All 21 subjects completing the
original trial enrolled in the extension study:
median age, 3.4 years old (range, 2.6 to 4.4
years); 12 females; 20 with Hb SS, 1 with Hb
S/
0
-thalassemia. Seventeen patients com-
pleted 4 years of hydroxyurea, and 11 com-
pleted 6 years. After 4 years, hydroxyurea
was associated with increased hemoglobin
concentration, percentage of fetal hemoglo-
bin (Hb F), and mean corpuscular volume
(MCV) and decreased reticulocytes, white
blood cells (WBCs), and platelets (P < .01).
Patients experienced 7.5 acute chest syn-
drome (ACS) events per 100 person-years,
compared with 24.5 events per 100 person-
years among historic controls (P
.001).
Treated patients had better spleen function
than expected and improved growth rates.
Infants with SCA tolerate prolonged hy-
droxyurea therapy with sustained hemato-
logic benefits, fewer ACS events, improved
growth, and possibly preserved organ func-
tion. (Blood. 2005;106:2269-2275)
© 2005 by The American Society of Hematology
Introduction
The clinical manifestations of sickle cell anemia (SCA) result
primarily from hemolytic anemia and the effects of repeated
intravascular sickling, causing vasoocclusion and ischemic injury.
Chronic organ damage in SCA is an insidious process that may
affect almost every organ system and can lead to considerable
morbidity and mortality at an early age. Loss of splenic function,
1
sickle nephropathy (proteinuria and renal insufficiency),
2
pulmo-
nary hypertension,
3
and brain ischemic lesions
4
are examples of
long-term end-organ damage observed in SCA. Lower levels of
fetal hemoglobin (Hb F) and higher white blood cell (WBC) counts
are associated with an increased incidence of SCA-related events,
organ damage, and mortality.
5
Hydroxyurea is an antimetabolite chemotherapic agent known
to stimulate fetal hemoglobin production,
6,7
thereby offering a
therapeutic option for the prevention of acute vasoocclusive events
(VOEs) in SCA. Over the past decade, several trials have demon-
strated that hydroxyurea is an efficacious therapy for both adult and
pediatric patients with SCA.
8-13
In the pediatric age group, how-
ever, there have been very few controlled studies of hydroxyurea
therapy, so neither efficacy nor effectiveness has been clearly
defined in this patient population.
Hydroxyurea has the ability to raise Hb concentration and Hb F
values while increasing red-cell mean corpuscular volume
(MCV).
9,11,14,15
Hydroxyurea has additional effects, including low-
ering the WBC, reticulocyte, and platelet counts; increasing nitric
oxide production
16
; decreasing red blood cell intracellular dehydra-
tion
17
; and decreasing red-cell adhesiveness to endothelium.
18
Clinically, hydroxyurea has been shown to decrease the rate of pain
and acute chest syndrome (ACS) events in severely affected adults
and children.
8-11,19,20
Organ damage starts very early in life, and most children with
SCA lose splenic reticuloendothelial function by 2 years of age.
1
The efficacy of hydroxyurea for the prevention of chronic organ
damage in SCA and the potential benefit of dose escalation have
not been fully investigated. Recovery of splenic function during
hydroxyurea therapy has been reported anecdotally,
15,21,22
but
prospective investigation has been limited.
The Hydroxyurea Safety and Organ Toxicity (HUSOFT) trial
was a prospective, multicenter, open-label, single-arm, pilot study
designed to (1) examine the feasibility of liquid hydroxyurea
administration in infants with SCA, (2) determine the toxicities of
hydroxyurea in this very young age group, (3) assess the effects of
hydroxyurea on fetal Hb levels and other hematologic indices, and
(4) obtain pilot data regarding the potential of hydroxyurea to
From St Jude Children’s Research Hospital, Memphis, TN; University of Texas
Southwestern Medical Center, Dallas, TX; Emory University School of
Medicine, Atlanta, GA; and Medical College of Wisconsin, Milwaukee, WI.
Submitted January 3, 2005; accepted May 25, 2005. Prepublished online as
Blood First Edition Paper, June 14, 2005; DOI 10.1182/Blood -2004-12-4973.
A compete list of the members of the Hydroxyurea Safety and Organ Toxicity
(HUSOFT) extension study group can be found in the “Appendix.”
Supported in part by the American Lebanese Syrian Associated Charities (ALSAC)
and General Clinical Research Center grant nos. M01RR00058 and M01RR00069,
National Center for Research Resources, National Institutes of Health.
Presented in part at the 43rd annual meeting of the American Society of
Hematology, Orlando, FL, December 10, 2001, and at the 28th annual meeting
of the National Sickle Cell Disease Program, Cincinnati, OH, April 13, 2005.
An Inside Blood analysis of this article appears in the front of this issue.
Reprints: Jane Hankins, St Jude Comprehensive Sickle Cell Center,
Department of Hematology-Oncology, St Jude Children’s Research
Hospital, 332 N Lauderdale, MS 763, Memphis TN 38105; e-mail:
jane.hankins@stjude.org.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2005 by The American Society of Hematology
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preserve splenic function.
23
In the previously published 2-year pilot
study, 28 infants with SCA, all unselected for disease severity, were
prospectively treated. Hydroxyurea was well tolerated, produced
mild toxicities (predominantly transient neutropenia), maintained
elevated Hb concentration and percent Hb F levels, and possibly
prevented loss of spleen function.
23
All 21 infants completing the
original 2-year pilot study were offered continued liquid hydroxy-
urea therapy. This extension of the original HUSOFT trial investi-
gated the effect of hydroxyurea dose escalation on hematologic
response and provides long-term prospective data regarding the
safety and efficacy of hydroxyurea therapy in this cohort of very
young children with SCA.
Patients, materials, and methods
Patient selection and treatment
The original HUSOFT trial was designed to offer hydroxyurea to infants
aged 6 to 24 months with the diagnosis of homozygous sickle cell anemia
(Hb SS) or Hb S
0
-thalassemia regardless of disease severity.
23
Patients
were enrolled at 4 major pediatric sickle cell programs from November
1996 through June 1997. Using a common protocol approved by each local
institutional review board (IRB), hydroxyurea was given orally once a day
at the fixed dose of 20 mg/kg administered as a flavored liquid formulation
prepared by dissolving the contents of hydroxyurea capsules at a final
concentration of 100 mg/mL. The chemical and functional stability of this
liquid formulation has been reported recently.
24
Twenty-one infants completed 2 years of hydroxyurea treatment in the
original HUSOFT trial, and each family was offered continuation of
hydroxyurea therapy in the HUSOFT extension. All 21 patients were
enrolled, and their hydroxyurea dose was escalated by 5 mg/kg every 6
months to a maximum dose of 30 mg/kg/d. Parents were instructed by
several members of the health care team on how to take the medication,
were given calendars to help remind them, and were asked to return their
medication bottles to help assess compliance. Institutional review board
approval and informed consent were obtained for continued hydroxyurea
treatment, imaging, and laboratory evaluation, in accordance with the
Declaration of Helsinki.
Patient evaluation, monitoring, and toxicity
Patients were followed with biweekly physical examinations, including
weight, height, and head circumference measurements, and blood counts
for the first 2 months after dose escalation and then monthly thereafter. Hb F
and F-cell measurements were performed every 6 months as previously
described.
25
Alanine amino transferase (ALT) and creatinine were measured
quarterly. Splenic sequestration and painful events requiring hospitalization
were documented at each visit. Splenic sequestration was defined by a
decline from baseline of Hb concentration of 2 g/dL (20 g/L) or more, an
increase in reticulocyte count, and an acutely enlarged spleen. ACS was
defined as a new infiltrate on the chest x-ray accompanied by respiratory
symptoms and/or fever. Pain episodes were defined as pain in the
extremities, back, abdomen, chest, or head for which no other explanation
could be found.
Spleen filtrative function was ascertained through technetium 99m
(Tc99m) sulfur-colloid uptake measurement at baseline and after 2 and 4 years of
therapy.Asingle nuclear medicine radiologist, blinded to age of the subjects and
prior liver-spleen scan results, interpreted the films. Splenic uptake was qualita-
tively evaluated as normal, decreased, markedly decreased, or no uptake, as
previously described.
26
At the institutions where magnetic resonance imaging
(MRI) and angiography (MRA) of the brain were readily available, testing was
performed at 2-year intervals and evaluated by local neuroradiologists who were
unaware of the patients’clinical status.
Hematologic toxicity was defined as an absolute neutrophil count
(ANC) less than 1.5
10
9
/L, platelet count less than 80
10
9
/L, decline in
Hb concentration more than 20% from baseline, or a Hb concentration less
than 5.0 g/dL (50 g/L). Renal and hepatic toxicity were defined as an
increase in serum creatinine by more than 50% or ALT greater than twice
the upper limit of normal. If toxicity was identified, hydroxyurea was
temporarily discontinued. Patients were reevaluated weekly until the
toxicity resolved, after which hydroxyurea was resumed at the previous
dose. If toxicity lasted for more than 2 weeks or recurred after the
medication was resumed, the dose was permanently decreased by 2.5
mg/kg/d. Patients were removed from the extension study if they missed
more than 3 clinic visits or otherwise failed to comply with the medica-
tion regimen.
Statistical analysis
The annual mean value of all hematologic parameters (Hb concentration,
MCV, Hb F, F cells, reticulocyte count, WBC count, and platelet count) was
calculated and compared with the expected values for untreated patients
with Hb SS or Hb S
0
-thalassemia at the corresponding age, as reported by
the Cooperative Study of Sickle Cell Disease (CSSCD).
27
The CSSCD was
a prospective multicenter investigation of the natural history of sickle cell
disease from birth through adulthood that collected data from 23 institutions
in a uniform, standardized fashion.
28
Children who were younger than 6
months old at enrollment were followed prospectively and made up the
“CSSCD infant cohort.”
27
Data from the first 5 years of life of this infant
cohort (n
694) were used for comparison with our hydroxyurea-treated
patients. The independent t test was used for comparisons within normally
distributed data and the Wilcoxon signed rank test for non-normally
distributed data.
The observation time was calculated by using the initial 2 years of the
original HUSOFT study and adding the follow-up years during the
extension study. The incidence rate for VOEs in person-years was
compared with those published for age-matched untreated SCA children in
the CSSCD
29
using the normal-theory test for incidence rate comparisons.
The proportion of asplenic patients was compared with the expected
proportion among age-matched untreated patients
27
using Fisher exact test.
All statistical analyses were performed using SAS version 9.1 (SAS
Institute, SAS 2002-2003, Cary, NC).
Results
Study enrollment and retention
Twenty-one patients completing 2 years of hydroxyurea treatment
in the original HUSOFT trial were eligible to participate in the study
extension. The families of all 21 patients agreed to participate in the
extension study and signed an additional informed consent in accor-
dance with the Declaration of Helsinki.Twelve patients were female; 20
hadHbSSand1hadS
0
-thalassemia;allwereAfrican-American.Their
median age at the beginning of the extension study was 3.4 years (range,
2.6 to 4.4 years).
One patient was removed from the study 2 months after dose
escalation to 25 mg/kg/d because of noncompliance. The remaining
20 (95%) subjects completed the stepwise dose escalation to 30
mg/kg/d, resulting in a mean ( SD) maximum dose of 30
1.2
mg/kg/d. The only patient not tolerating the dose increase required
a permanent dose reduction to 27.5 mg/kg/d because of neutrope-
nia. Splenectomized patients did not differ from nonsplenecto-
mized ones in regard to tolerating drug escalation.
Of the 28 patients enrolled on the original HUSOFT study, 21
completed 2 years, 2 did not complete the study due to noncompli-
ance, the parents of 3 patients elected to discontinue participation, 1
patient had a mild stroke and was placed on chronic transfusion
therapy, and 1 died of splenic sequestration.
23
Of the 21 patients
enrolled on the HUSOFT extension, 17 completed an additional 4
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Page 3

years and 11 were treated with hydroxyurea for a total of 6 years.
Reasons for withdrawal from the extension study before 6 years
were noncompliance (4 patients), recurrent ACS (1 patient),
parent’s request to discontinue study drug (4 patients), and death
from pneumococcal sepsis (1 patient). The mean duration of
hydroxyurea therapy among the 21 patients enrolled in the
extension study was 4.9
1.3 years (range, 2.1-6.0 years).
No differences in sex, participating center, age upon study
enrollment, enrollment laboratory tests, splenic uptake on the
spleen scan, or sickle cell genotype were found among patients
completing 6 years of hydroxyurea therapy and those exiting the
extension study early (data not shown).
Hematologic efficacy
Mean annual values for Hb, MCV, Hb F, F cells, reticulocyte count,
WBC count, and platelet count for years 3 and 4 of hydroxyurea
therapy were compared with expected age-matched values for
untreated SCA children (Table 1). In hydroxyurea-treated children
the mean Hb concentration, MCV, Hb F, and F-cell values were
significantly higher, and the mean platelet count, reticulocyte
count, and WBC count were significantly lower during years 3 and
4 of extended hydroxyurea therapy. To evaluate the impact of dose
escalation, all hematologic indices at the end of year 4 were
compared with those at the end of year 2 (Table 2); Hb F values
were significantly higher after dose escalation, and other indices
did not significantly differ from values at the end of year 2. The
mean annual Hb F level for all HUSOFT patients was sustained and
often exceeded 20% during extended hydroxyurea therapy (Figure
1), contrasting with the expected decline characteristic of untreated
children with SCA.
27,30
Splenectomized and nonsplenectomized
patients did not differ in their Hb F levels throughout the study.
Toxicity
Mild to moderate neutropenia (ANC 0.5
10
9
/L to 1.5
10
9
/L)
occurred 21 times in 10 patients during year 3 (6.7% of all blood
counts performed during year 3) and 21 times in 9 patients during
year 4 (9% of all blood counts performed during year 4).
Neutropenia was usually associated with a viral illness. Severe
neutropenia (ANC less than 0.5
10
9
/L) did not occur. Thrombo-
cytopenia was not observed during years 3 and 4 of hydroxyurea
therapy but occurred twice during year 5 (platelet counts 36
10
9
/L and 68
10
9
/L) and once during year 6 (platelet count
68
10
9
/L). Thrombocytopenia resolved after temporary dose
reduction on both occasions, enabling reescalation of hydroxyurea
dosing. Severe anemia was unusual during hydroxyurea treatment,
occurring 3 times in 3 patients during year 3, 4 times in 1 patient
during year 4, and not at all thereafter. Half of the severe anemia
cases were associated with reticulocytopenia, suggesting aplastic
crisis as the etiology. Episodes of severe anemia had a mean
duration of 5 weeks. No cases of creatinine or ALT elevation were
noted, and no cases of myelodysplasia or cancer were observed
during this extension study.
Figure 1. Fetal hemoglobin (Hb F) levels during extended hydroxyurea therapy
in infants with SCA. The upper curve ( ) represents the study patients receiving
extended hydroxyurea therapy (mean
SD values for Hb F), while the bottom 2
curves represent the expected values for untreated American
27
(f) and Jamaican
children
30
(Œ) with SCA. Average fetal hemoglobin levels remain close to 20% during
extended hydroxyurea therapy.
Table 1. Hematologic parameters in young children with sickle cell anemia receiving extended hydroxyurea therapy
Mean values
Baseline;
n
28
Year 3*;
n
19
Year 4;
n
17
Expected at ages
48 to 60 months†
Year 5;
n
13
Year 6;
n
11
Hb level, g/dL
8.5
1.4
9.1
1.3
9.1
1.4*
8.1
8.5
1.6
9.0
1.6
MCV, fL
81.7
8.0
92.1
9.7
95.1
10.4*
88.0
93.7
9.3
96.0
9.9
Hb F level, %
21.8
7.8
22.7
6.4
23.7
7.4*
9.0
22.8
9.4
23.3
7.8
F cells, %
80.6
14.1
82.6
14
82.6
7.9*
49.4
NP
NP
Reticulocyte count, %
9.2
4.8
9.4
9.9
8.2
5.2*
12.4
6.6
4.6
5.5
2.3
WBC count,
10
9
/L
12.6
4.4
10.2
5.0
10.1
7.3*
14.3
11.0
6.0
8.9
4.2
Platelet count,
10
9
/L
410.0
169
374.3
169.0
373.0
238.9*
424.0
333.2
144.0
300.2
133.7
Baseline (pretreatment) values and annual values for years 2 to 6 of therapy are reported as mean
SD. Years 3 and 4 of hydroxyurea therapy are compared with
expected age-matched mean values for untreated children. No expected values are available for statistical comparison in years 5 and 6 of therapy.
NP indicates not performed.
*P
.001.
†Calculated on the basis of data extracted from the CSSCD
27
(see “Patients, materials, and methods”) and from the Duke University Pediatric Hematology Research
Laboratory (for F cells).
25
Table 2. Hematologic effects of hydroxyurea dose escalation
Mean values
Year 2; n
21
Year 4; n
17
Change in mean value
Hb level, g/dL
8.8
9.1
0.3
MCV, fL
90.0
95.1
5.1
Hb F level, %
20.3
23.7
3.4*
F cells, %
76.2
82.6
6.4
Reticulocyte count, %
8.6
8.2
0.4
WBC count,
10
9
/L
10.1
10.1
0.0
Platelets,
10
9
/L
352.0
373.0
21.0
Values at the end of year 4 (hydroxyurea dose: 30 mg/kg/d) are compared with
those at the end of year 2 (hydroxyurea dose: 20 mg/kg/d).
*P
.05.
EXTENDED HU THERAPY FOR INFANTS WITH SCA
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One case of acute splenic sequestration occurred during the
HUSOFT extension study. Twenty-five months after starting treat-
ment with hydroxyurea, a 32-month-old girl without previous
splenomegaly presented with spleen enlargement, a decrease in Hb
concentration from 10.5 to 7.9 g/dL (105-79 g/L), and a platelet
count drop from 147
10
9
/L to 84
10
9
/L. She was hospitalized,
received one erythrocyte transfusion, and subsequently improved.
She did not require splenectomy, and her spleen became nonpal-
pable a few months after this episode. She remained on hydroxy-
urea therapy without further problems.
One death occurred during the extension study, caused by sepsis
in a 4-year-old girl. This child began hydroxyurea therapy at age 6
months, received 23-polyvalent pneumococcal vaccine (Pneumo-
vax; Merck, White House Station, NJ) at age 2 years, and was
judged compliant with both penicillin and hydroxyurea therapy.
She had developed an acute episode of splenic sequestration during
the original HUSOFT study and underwent elective splenectomy.
23
Almost 3.5 years after starting hydroxyurea therapy, and just before
the availability of the 7-valent protein-conjugated pneumococcal
vaccine (Prevnar; Wyeth Pharmaceuticals, Philadelphia, PA), she
developed fever and progressed to cardiovascular collapse within 2
hours. Resuscitation in the emergency department was unsuccess-
ful. Her peripheral blood smear showed diplococci in the neutro-
phils. Of note, during a routine study visit that occurred only 2 days
before this event, she was clinically well and had an ANC of
4.1
10
9
/L.
Clinical events
For the entire treatment period, there were 106.4 person-years of
observation for this cohort. Thirty-six pain and 8 ACS events were
recorded, yielding rates of 33.8 and 7.5 events per 100 person-
years, respectively. The expected incidence of pain and ACS for
untreated age-matched patients is 32.4 and 24.5 events per 100
person-years, respectively.
29
The observed and expected incidence
rates were not significantly different for pain events (P
.87).
However, unlike the CSSCD study,
29
only painful events requiring
hospitalization were considered. HUSOFT patients had signifi-
cantly fewer ACS events (P
.001).
Organ function
Four patients had undergone surgical splenectomy before enroll-
ment in the original HUSOFT study. There were 17 usplenecto-
mized children enrolled in the extension study, 14 of whom had
spleen function assessed at baseline, year 2, and year 4. After 4
years of hydroxyurea therapy, 3 of the 14 (21.5%) children had
normal splenic uptake, 3 (21.5%) had decreased uptake, and 2
(14%) had markedly decreased uptake. Only 6 (43%) patients were
functionally asplenic (absent uptake) upon study completion, in
contrast to the expected 94% incidence of asplenia among un-
treated age-matched children with SCAbased on red-cell pit counts
(P
.001).
27
Remarkably, one infant with markedly decreased and
another with absent splenic uptake prior to hydroxyurea treatment
regained normal splenic uptake after 4 years of hydroxyurea
therapy (Figure 2). Neither of these 2 patients received erythrocyte
transfusions during the extension study.
Fourteen patients had brain MRI and MRA evaluation after 4
years of hydroxyurea therapy. These patients did not differ in age
upon study enrollment, sex, disease genotype, and baseline labora-
tory values with those who did not have brain imaging. Three of the
14 patients (21%) had radiographic evidence of silent infarcts. One
girl developed a small focus (less than 0.5 cm) of increased MRI
T2-weighted signal in the right periatrial white matter during the
study extension. Her transcranial Doppler velocities were normal,
and she remained clinically asymptomatic. Another patient with
mild stenosis of the proximal right A1 and P2 segments on MRA at
year 4 resolved these lesions after 2 more years of hydroxyurea
therapy. No radiographic evidence of brain atrophy was observed.
Growth
The average weight gain was 2.15 kg per year, height gain 7.9 cm
per year, and head circumference increase 1.7 cm per year. These
growth rates were within normal limits when plotted on standard
pediatric growth curves (Figure 3). Boys (n
10) demonstrated
substantial gains in growth during hydroxyurea treatment, starting
therapy at the 25th percentile for weight and 40th percentile for
height and reaching the 50th percentile for both weight and height
after 4 years of hydroxyurea therapy. The patients treated with
hydroxyurea weighed more and were taller than untreated children
with Hb SS or Hb S
0
-thalassemia from 2 to 5 years old as reported
by the CSSCD.
31
Our patients’growth pattern was similar to that of
children with Hb S -thalassemia and healthy controls.
Discussion
This prospective open-label study demonstrates that prolonged
liquid hydroxyurea therapy in very young children with SCA has
sustained hematologic efficacy and, in general, limited toxicity.
Hydroxyurea dose escalation to 30 mg/kg/d was tolerated in 95%
of the children. Hydroxyurea dose escalation to this maximum dose
has previously been shown to elicit significantly better hematologic
responses in older children than lower doses of 15 to 20 mg/kg/d,
13
and among our patients a significant increase in Hb F was observed
Figure 2. Radionuclide liver-spleen scan showing normalization of splenic
uptake after extended hydroxyurea therapy. A 7-month-old child with markedly
decreased splenic uptake at baseline (arrow in top panel) regained splenic uptake
after 4 years of hydroxyurea therapy (bottom panel). The arrow in the lower panel
denotes the location of splenic uptake and indicates a slightly enlarged spleen
measuring 9.3 cm in length.
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after dose escalation to 30 mg/kg/d (Table 2). Increased and
sustained values of Hb, MCV, Hb F, and F cells were observed
during this extension trial, whereas WBC count, platelet count, and
reticulocyte values remained lower than expected for untreated
children (Table 1). There was a decrease in reticulocyte, WBC, and
platelet counts at year 6 compared with year 3, possibly due to the
dose escalation. It is unlikely that these decreases will continue
during subsequent years of hydroxyurea therapy, based on the
recent publication by Zimmerman et al that reported no evidence of
cumulative toxicity or marrow exhaustion.
13
After escalation to 30
mg/kg/d, continued monitoring of these and other hematologic
indices for possible toxicity is advised, however. The sustained
response to hydroxyurea suggests good compliance, but adherence
to treatment should be prospectively and formally measured in
future studies. Taken together, our extended data demonstrate the
sustained long-term significant hematologic benefits of hydroxy-
urea therapy in unselected young children with SCA.
The average percentage of fetal hemoglobin never declined in
treated patients, remaining at approximately 20% from the time of
study enrollment (Figure 1), and none of the patients showed
decline in Hb F values. Sustained Hb F levels of 20% and above
have been associated with reduced clinical events
32
and may
translate into less organ damage among these infants. However,
long-term follow up will be critical to characterize the effect of
pharmacologically elevated Hb F in the prevention of organ
dysfunction. All patients who tolerated drug dose escalation
responded to hydroxyurea by raising the percentage of Hb F, contrasting
with studies in adults, in which some patients were unable to sustain a
hydroxyurea response.
33
Better compliance, higher dosing, higher
starting Hb F values, less gene silencing, and/or increased marrow
reserve may be related to the superior response rates observed among
children, but further investigation is needed.
HUSOFT patients had significantly fewer ACS events than
untreated SCA children. This is an important finding due to the
morbidity of ACS events. In contrast, however, there was no
difference in the incidence of pain, perhaps due to the method of
event collection. In the CSSCD study, pain frequency was queried
and recorded retrospectively during an annual evaluation; hence,
mild events were likely to be forgotten and not always recorded. In
HUSOFT, pain was queried and recorded during each monthly
visit. It is possible, therefore, that CSSCD relatively underesti-
mated the true pain frequency while HUSOFT relatively overesti-
mated the true pain frequency among young children with SCA.
Hydroxyurea was generally well tolerated, with possibly fewer
cases of neutropenia observed in the extension study (8%) than
during the first 2 years of therapy (10%), despite the increase in
dose. This observation, although not statistically significant, sug-
gests that age may be an important factor for the development of
hematologic toxicity, with less myelotoxicity occurring as children
become older. The incidence of neutropenia in the study extension
approaches the 5.2% rate observed in the HUG-KIDS study, in
which school-aged children were treated with hydroxyurea.
14
The
incidence of sepsis in this group (0.9 cases per 100 patient-years) is
within the reported range of 0.0003 to 6.34 cases per 100
person-years among children with SCA on penicillin prophy-
laxis,
34,35
suggesting no increased risk of sepsis among hydroxyurea-
treated patients.
We believe hydroxyurea is a relatively safe drug for children
with SCA but requires periodic monitoring of blood counts and
physical examinations. As with any new treatment, hydroxyurea
therapy needs to be closely monitored for toxicity, which may
prove difficult in developing countries. Improving the care of SCA
patients in underprivileged areas of the world and providing access
to new therapies are worthy goals that underscore the need for
developing research partnerships among rich and poor countries.
36
The possibility of myelodysplasia or malignancy as a long-term
side effect of prolonged hydroxyurea use is an ongoing concern.
However, a survey of 16 613 patients with sickle cell disease
receiving medical care at 52 institutions identified 52 cases of
cancer but only 3 patients had any previous exposure to hydroxy-
urea therapy.
37
Among our patients, no cases of cancer developed;
however, a longer follow-up is necessary to assess the true incidence of
this potential complication. Continued observation should occur for
all children with SCA who receive hydroxyurea therapy.
Growth was not impaired among these children treated with
hydroxyurea. Using standard growth curves, there was no evidence
of growth delay; on the contrary, our patients (especially boys)
experienced improved growth, suggesting hydroxyurea may allow
growth at rates comparable to those of healthy children and higher
than untreated historic controls with SCA. Hydroxyurea has been
demonstrated previously to allow weight gain in adult women with
SCA,
6
to have no adverse effect on growth in school-age children,
15
and to promote significantly greater weight and height gain in boys
compared with their nontreated counterparts.
38
Because the care of
sickle cell patients has improved over the past 2 decades, growth
comparison with old cohorts has limitations, but more contempo-
rary data are not available for comparison. Hence, prospective
studies need to be performed to confirm our findings of possible
growth benefit from hydroxyurea.
Possible delay in the progression toward functional asplenia and
actual recovery of splenic function in 2 cases were observed during
the hydroxyurea extension study. This observation, coupled with
the lower proportion of asplenic patients after 4 years of hydroxy-
urea therapy (43% versus the expected 94%), suggests that
hydroxyurea therapy can prevent loss of spleen function or even
restore it as reported in older patients.
21,22,39
However, the mainte-
nance or recovery of splenic function raises the possibility that
these children will be at prolonged risk for acute splenic sequestra-
tion. While prospective comparison with untreated patients re-
mains necessary to define if such a risk exists, the management of
Figure 3. Growth curves for children with sickle cell anemia receiving extended
hydroxyurea therapy. The 3rd (f), 50th (Œ), and 97th (F) percentiles for healthy
children are illustrated as dotted lines, while the patients ( ) are illustrated as a solid
line. Boys increased their average growth rate during hydroxyurea therapy from the
25th percentile for weight and 40th percentile for height to about the 50th percentile
for both weight and height after 4 years of hydroxyurea therapy. Girls maintained
average growth rates during the treatment period.
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acute and chronic splenomegaly could emerge as a treatment-
associated problem for children with SCA receiving hydroxyurea
therapy. Children with prolonged and significant splenomegaly
may not tolerate full-dose hydroxyurea therapy
14
and may be at
long-term risk for acute splenic sequestration. Partial splenectomy
could become a therapeutic option for these children, because it
offers the advantage of preserving some immune function while
controlling acute symptoms of splenomegaly.
40,41
Central nervous system abnormalities (ischemic lesions and
stenoses) were identified in a few patients, but no cases of brain
atrophy were observed. After 4 years of hydroxyurea therapy, the
prevalence of silent infarcts was 21% at a median age of 5 years,
similar to the prevalence reported among untreated SCAchildren.
42
In one patient stenosis was noted after 4 years of HU therapy but
subsequently resolved. Longer follow-up on larger cohorts of
young children, coupled with central review of imaging studies,
will be needed to determine the risks and benefits of hydroxyurea
treatment for the development of cerebrovascular disease in SCA.
In conclusion, the use of oral liquid hydroxyurea at a dose of 30
mg/kg/d in young children with SCA is feasible, results in
sustained hematology efficacy with relatively limited adverse
events, decreases theACS rate, and may improve growth. Hydroxy-
urea possibly decreases the incidence of chronic organ dysfunction
such as loss of splenic filtrative function, perhaps by precluding the
physiologic decline of fetal hemoglobin. The results of the ongoing
National Heart, Lung, and Blood Institute (NHLBI)–sponsored
multicenter, randomized, double-blinded clinical trial for very
young children with sickle cell anemia (BABY HUG) will further
define the role of hydroxyurea in preventing chronic organ damage
to the spleen, kidney, and brain.
Acknowledgments
The authors thank Susan Strawn, RN, William Schultz, PA-C,
MHS, Juanita Dale, PhD, CPNP, RN, and Evelyn Brown, RN, for
outstanding care offered to our patients; Chin-Shang Li, PhD, and
Andy Bush, PhD, for assistance with data analysis; and Julie Groff
for help with preparing the figures.
Appendix
The HUSOFT extension study group members were Evelyn Brown, RN,
MSN (Children’s Hospital of Wisconsin, Milwaukee, WI); Susan Strawn,
RN, and William Schultz, PA-C, MHS (Comprehensive Sickle Cell Center,
Saint Jude Children’s Research Hospital, Memphis, TN); Juanita Dale,
PhD, CPNP, RN (University of Texas, Southwestern Medical Center,
Dallas, TX); and Sherri Zimmerman, MD (Duke Pediatric Sickle Cell
Program, Division of Hematology-Oncology, Duke University Medical
Center, Durham, NC).
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