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CLINICAL TRIALS AND OBSERVATIONS

CME article

Impact of hydroxyurea on clinical events in the BABY HUG trial

Courtney D. Thornburg,1 Beatrice A. Files,2 Zhaoyu Luo,3 Scott T. Miller,4 Ram Kalpatthi,5 Rathi Iyer,6 Phillip Seaman,7
Jeffrey Lebensburger,8 Ofelia Alvarez,9 Bruce Thompson,3 Russell E. Ware,10 and Winfred C. Wang,11 for the BABY HUG
Investigators
1Department

of Pediatrics, Duke University Medical Center, Durham, NC; 2Department of Pediatrics, Emory University School of Medicine, Atlanta, GA;
Trials and Surveys Corp, Baltimore, MD; 4Department of Pediatrics, State University of New York Downstate Medical Center/Kings County Hospital
Center, Brooklyn, NY; 5Department of Pediatrics, The Childrens Mercy Hospitals and Clinics, Kansas City, MO; 6Department of Pediatrics, University of
Mississippi Medical Center, Jackson, MS; 7Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; 8Department of Pediatrics,
University of Alabama, Birmingham, AL; 9Department of Pediatrics, University of Miami, Miami, FL; 10Department of Pediatrics, Baylor College of Medicine,
Houston, TX; and 11Department of Hematology, St Jude Childrens Research Hospital, Memphis, TN
3Clinical

The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebocontrolled clinical trial of hydroxyurea in
infants (beginning at 9-18 months of age)
with sickle cell anemia.An important secondary objective of this study was to compare
clinical events between the hydroxyurea and
placebo groups. One hundred and ninetythree subjects were randomized to hy-

droxyurea (20 mg/kg/d) or placebo; there

were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial
and recurrent episodes of pain, dactylitis,
acute chest syndrome, and hospitalization;
even infants who were asymptomatic at
enrollment had less dactylitis as well as
fewer hospitalizations and transfusions if
treated with hydroxyurea. Despite expected

mild myelosuppression, hydroxyurea was

not associated with an increased risk of
bacteremia or serious infection. These data
provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children
with sickle cell anemia. This clinical trial is
registered with the National Institutes of
Health (NCT00006400, www.clinicaltrials.
gov). (Blood. 2012;120(22):4304-4310)

Continuing Medical Education online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for
Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology.
Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.
Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians
should claim only the credit commensurate with the extent of their participationin the activity.
All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity:
(1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum
passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME
questions, see page 4448.
Disclosures
The authors, the Associate Editor Narla Mohandas, and CME questions author Laurie Barclay, freelance writer and reviewer,
Medscape, LLC, declare no competing financial interests.
Learning objectives
Upon completion of this activity, participants will be able to:
1. Describe the effect of hydroxyurea on rates of sickle cell complications for infants with sickle cell anemia (SCA) on the basis of
a phase 3, multicenter, randomized trial.
2. Describe the effect of hydroxyurea on rates of hospitalizations and transfusions for infants with SCA on the basis of a phase 3,
multicenter, randomized trial.
3. Describe the safety of hydroxyurea for infants with SCA on the basis of a phase 3, multicenter, randomized trial.
Release date: November 22, 2012; Expiration date: November 22, 2013

Introduction
The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG;
clinicaltrials.gov no., NCT00006400) was an National Heart,
Lung, and Blood Institute (NHLBI) and National Institute of

Child Health and Human Development (NICHD)sponsored

multicenter, randomized, double-blind placebo-controlled study of
daily oral hydroxyurea in children with sickle cell anemia (SCA;

Submitted March 28, 2012; accepted August 7, 2012. Prepublished online as

Blood First Edition paper, August 22, 2012; DOI 10.1182/blood-2012-03-419879.

payment. Therefore, and solely to indicate this fact, this article is hereby
marked advertisement in accordance with 18 USC section 1734.

The publication costs of this article were defrayed in part by page charge

2012 by The American Society of Hematology

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BLOOD, 22 NOVEMBER 2012 VOLUME 120, NUMBER 22

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BLOOD, 22 NOVEMBER 2012 VOLUME 120, NUMBER 22

HbSS, and S0 thalassemia) 9 to 18 months of age. The primary

aim of the trial was to determine whether daily hydroxyurea would
reduce by 50% spleen and renal damage as measured by
radionuclide scanning. Although failing to achieve this aim, there
were significantly fewer sickle cell diseaserelated clinical events
in the hydroxyurea group including painful events, acute chest
syndrome (ACS), hospitalizations, and transfusions.1
Based on the results of the BABY HUG trial, the authors
concluded that hydroxyurea can now be considered for all patients
starting at a young age.1 However, there are barriers to implementation into clinical practice including patient and provider misconceptions about toxicity.2,3 We now report detailed analysis of sickle cell
diseaserelated clinical events and other adverse events (AEs) from the
BABY HUG trial, which further documents the beneficial effects and
lack of toxicity of hydroxyurea for very young patients with SCA.

Methods
Study population
Subjects with HbSS or HbS0-thalassemia 9 to 18 months of age were
recruited without regard to clinical severity and enrolled into the BABY
HUG study.4 The trial began in October 2003 and was completed in
September 2009. All children were taking prophylactic penicillin and
received age-appropriate immunizations. Each participating site obtained
local institutional review board approval to conduct the study. Consent was
obtained before any study procedures, and all studies were conducted in
accordance with the Declaration of Helsinki.
Data collection
Data regarding AEs, including sickle cellrelated clinical events, were
collected as part of the AE reporting process. AEs were determined as
required by 21 CFR 312 and in accordance with 45 CFR 46.5 For this trial,
serious adverse events (SAEs) included the sickle cellrelated clinical
events of splenic sequestration, stroke, transient ischemic attack (TIA), and
ACS. SAEs also included any AE that resulted in death, was lifethreatening, or required hospitalization 7 days or intensive care unit
admission. Because of the unique manifestations of SCA and expected
admissions for the primary disease process, the standard SAE reporting
requirement was changed from any inpatient hospitalization or prolongation of existing hospitalization to hospitalization 7 days or requiring
intensive care unit admission. Any AE that was both treatment-related and
unexpected was classified as an SAE.
AEs were captured by parent report at routine visits every 2 weeks until
a stable dose of hydroxyurea was established, then every 4 weeks, and by
review of emergency department, hospital, and clinic records. The Clinical
Center staff determined the degree of severity. SAEs were reported to the
Medical Coordinating Center (MCC) at Clinical Trials and Surveys
Corporation within 24 hours of the Clinical Center becoming aware of the
event and were reviewed by an independent classification committee. In
addition, AEs were reviewed by the NHLBI project officer and the MCC
medical consultants who were aware of treatment assignment. These
individuals determined whether an AE should be reclassified as an SAE.
Definitions of sickle cellrelated clinical events
Pain and dactylitis. Parents and caregivers were educated about dactylitis
and painful events including home management with fluids, ibuprofen and
acetaminophen with codeine, and were questioned about occurrence of
episodes at each visit. Initially, painful events were defined as pain lasting
2 hours or more without obvious cause and requiring the use of one or more
doses of nonsteroidal or narcotic pain medications, while dactylitis was
defined as pain and tenderness with or without swelling of the hands and/or
feet. In 2005, at the request of the National Institute of Child Health and
Human Development (NICHD) to help support Food and Drug Administration (FDA) approval of a pediatric indication for hydroxyurea, criteria for

BABY HUG EVENTS

4305

reporting pain were expanded to include any mention of pain, whether or

not it was treated or required a medical visit.
ACS. Parents and caregivers were educated about signs and symptoms
of ACS at regular clinic visits and advised to seek medical attention if these
occurred. ACS was defined by a new pulmonary infiltrate and at least 3 of
the following findings: chest pain, temperature elevation 38.5C, tachypnea, wheezing, or cough.
Fever. Fever was defined by a temperature 38.5C. Parents were
advised to seek urgent medical attention for their childs fever, which was
managed as per local institutional protocol.
Splenic sequestration. Splenic sequestration was characterized by an
increase in spleen size by 2 cm below the costal margin compared with
previous measurement and a reduction of hemoglobin level by 2.0 g/dL
or 20% from recent steady-state values, with or without a drop in platelet or
leukocyte counts. Parents and caregivers were instructed in techniques of
spleen palpation at each clinic visit and asked to feel for the childs spleen
daily. Parents were asked to immediately report a newly palpable spleen or
one larger than previously noted.
Gallbladder disease. Cholelithiasis was defined by the presence of
biliary stones in the gallbladder or common bile duct, with minimal or no
symptoms.
Other adverse events. Gastroenteritis was defined as at least 2 episodes of
nausea, vomiting (excluded if it occurred with cough or medication dosing), or
diarrhea (excluded if it occurred with laxative use). Constipation was defined as
decreased stool frequency as determined by the caretaker or healthcare provider.
There were no protocol definitions of eczema or asthma.
Hematologic toxicity. Mild to moderate neutropenia was defined as
absolute neutrophil count (ANC) 0.5-1.249 109/L and severe neutropenia
was defined as ANC 0.5 109/L. Thrombocytopenia was defined as
platelet count 80 109/L. Severe anemia was defined as hemoglobin
7 g/dL and absolute reticulocyte count (ARC) 80 109/L.
Definition of asymptomatic at baseline. Asymptomatic subjects
were defined as those who had no history of pain, dactylitis, ACS, or splenic
sequestration before enrollment.
Statistical methods
2 or Fisher exact tests were applied to compare the frequency of AEs
between the hydroxyurea and placebo groups. The Fisher exact test and the
Wilcoxon rank-sum test were used to compare associated symptoms,
complications, and treatments of ACS. The Fisher exact test was used to
evaluate the proportion of neutropenic events associated with viral illness.
Logistic regression was used to evaluate predictors of thrombocytopenia.
Cox models were used to compare febrile and infectious events between
treatment groups, as well as clinical events of children who were
asymptomatic at enrollment in both treatment groups. The log-rank life test
was used to compare time to first event. The Wilcoxon rank-sum test was
used to compare the number of hospitalizations per subject associated with
pain, dactylitis, and ACS and length of hospitalizations in the 2 groups. A
Cox model was used to compare the rate of prolonged hospitalizations
between the 2 groups. A generalized estimating equation (GEE) model
using Poisson regression to model serial outcome counts and a logarithm
link function for the model parameterization was performed for multivariate analyses of baseline predictors of multiple pain events. A GEE model
was also performed for multivariate analysis of gastroenteritis events. This
model included the use of time-dependent variables including age at event,
hemoglobin, white blood cell count (WBC), ANC, ARC, and absolute HbF
(all calculated as the moving average of the 3 steady-state values before the
event time). Absolute HbF was calculated using the percentage of HbF and
hemoglobin concentration.
All analyses used SAS Version 9.2 (SAS Institute). Analyses were conducted
by Z.L. and B.T. All authors had access to primary data on request.

Results
One hundred ninety-three subjects were randomized and 192 began
study medication. Subjects received placebo or hydroxyurea for a

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BLOOD, 22 NOVEMBER 2012 VOLUME 120, NUMBER 22

THORNBURG et al

Table 1. Hydroxyurea effects on pain, dactylitis, ACS, and

hospitalization
Hydroxyurea,
N 96, n (%)

Placebo,
N 97, n (%)

Total events
Subjects with 0 events

177

375

34 (35)

22 (23)

Subjects with 1 event

29 (30)

15 (15)

Subjects with 2 or 3 events

20 (21)

19 (20)

Subjects with 4 events

13 (14)

41 (42)

24

123

Subjects with 0 events

82 (86)

55 (57)

Subjects with 1 event

6 (6)

14 (14)

Subjects with 2 events

6 (6)

8 (8)

Subjects with 3 events

2 (2)

6 (6)

Subjects with 4 events

0 (0)

14 (14)

27

Subjects with 0 events

89 (93)

79 (82)

Subjects with 1 event

6 (6)

10 (10)

Subjects with 2 or 3 events

1 (1)

8 (8)

232

324

Subjects with 0 events

27 (28)

13 (13)

Subjects with 1 event

22 (23)

16 (17)

Subjects with 2 or 3 events

26 (27)

28 (29)

Subjects with 4 events

21 (22)

40 (41)

.001

Dactylitis
Total events

ACS events
Total events

.03

Hospitalizations
Total events

P
.001*

Pain

.008*

ACS indicates acute chest syndrome.

*P value was derived from the 2 test comparing difference in frequency of events
between hydroxyurea and placebo groups.
P value was derived from the Fisher exact test comparing difference in
frequency of events between hydroxyurea and placebo groups. There were a total of
374 patients-years of on study observation; the median follow-up was 2 years/
patient.

planned duration of 2 years; 86% of enrolled subjects completed

24 months of study treatment.6
Baseline characteristics of the study population have previously
been reported with no significant differences in age, sex, genotype,
clinical severity, laboratory values, or physical findings between
the 2 groups.1 In addition, there were no differences in baseline
rates of hospitalization, dactylitis, pain, ACS, splenic sequestration,
or transfusion. At baseline, 52 (54%) of 96 children in the
hydroxyurea group and 49 (51%) of 97 children in the placebo
group were clinically asymptomatic.
Overall, there were 2560 AEs and 107 SAEs reported during a
total of 374 patient-years of on-study observation. None of the AEs
were classified by the investigators, NHLBI project officer or the
MCC medical consultants as both unexpected and treatment related.

14.6 per 100 patient-years in the placebo group (HR 0.36; P .02),1 and
a higher proportion of subjects in the placebo group had multiple
ACS events (P .03; Table 1). Both rates were lower than that seen in
similarly aged children in the Cooperative Study of Sickle Cell Disease
(CSSCD); the rate of ACS in the CSSCD was 27-34 events per
100 person-years for children ages 1-3 years.7 Characteristics of subjects
with ACS are summarized in Table 2.
Neurologic events. A 3-year-old male child in the placebo
group was diagnosed with acute ischemic stroke after 102 weeks
on study. He was subsequently started on chronic blood transfusion
therapy. There were no reported TIAs in the BABY HUG trial.
There were 4 children (3 receiving placebo) with abnormal TCD
results at study exit (ages 35, 36, 39, and 42 months). The impact of
hydroxyurea on TCD velocity was previously reported; at baseline,
TCD velocity was negatively correlated with hemoglobin level.8,9
The average increase in TCD velocity during the study was
significantly lower in the hydroxyurea group.1,8,9
Gallbladder disease. On abdominal ultrasound at study exit,
8 children in the hydroxyurea group and 6 children in the placebo
group had sludge and 5 children in the hydroxyurea group and
5 children in the placebo group had cholelithiasis.
Splenic sequestration. There were 12 splenic sequestration
events in 8 subjects in the hydroxyurea group (median age
28 months; range 12-36 months) and 12 splenic sequestration
events in 9 patients in the placebo group (median age 22 months;
range 11-34 months).
Hospitalizations. Sixty-nine subjects in the hydroxyurea group
had a total of 232 hospitalizations (123 hospitalizations per
100 patient-years) compared with 84 subjects in the placebo
group with 324 hospitalizations (175 per 100 patient-years; HR
0.73; P .05). There was no statistically significant difference
in the rate of prolonged hospitalization ( 7 days) between the
groups (2.7 per 100 patient-years in the hydroxyurea group and
4.3 per 100 patient-years in the placebo group; P .40). When
the primary reason for hospitalization was evaluated, hydroxyurea
therapy was associated with fewer hospital admissions for fever (181 vs
240, P .01), pain (73 vs 128, P .001), and ACS (8 vs 27, P .02).
There was no difference in length of hospital stay between the 2 groups
Table 2. Characteristics of acute chest syndrome events
Hydroxyurea,
N 96
No. (%)

Pain. The incidence of pain was 94 events per 100 patient-years in

the hydroxyurea group compared with 203 per 100 patient-years in
the placebo group (hazard ratio [HR] 0.59; P .002).1 Data
regarding frequencies of painful events are shown in Table 1. In the
hydroxyurea group, there were no baseline parameters that predicted multiple pain events.
Dactylitis. The rate of dactylitis was 12.7 per 100 patient-years
in the hydroxyurea group compared with 66.5 per 100 patient-years
in the placebo group (HR 0.27; P .001).1 Data regarding the
frequency of dactylitis are shown in Table 1.
Acute chest syndrome. The incidence of ACS was 4.2 per
100 patient-years in the hydroxyurea group compared with

27 (27.8)

Median age at event, mo (range)

26 (15-30)

27 (12-39)

.67

Median visit week (range)

46 (2-80)

55 (0-99)

.22

7 (87.5)

25 (92.6)

.55

1 (3.7)

1.00

7 (25.9)

.23

Associated symptoms
Fever
Dactylitis
Pain

Sickle cellrelated clinical events

8 (8.3)

Placebo,
N 97

4 (50)

Absolute neutrophil count, 0.5 109/L

9 (33.3)

.08

Sepsis

1 (3.7)

1.00

12 (44.4)

1.00

Pulmonary
1 lobe involved
Oxygen saturation at onset, %
Oxygen therapy

4 (50)
96 (91-99)

94 (84-100)

.51

3 (37.5)

9 (33.3)

1.00

Any hospitalization

8 (100)

27 (100)

1.00

Hospitalization 7 days

2 (25)

2 (7.4)

.22

Antibiotics

8 (100)

27 (100)

1.00

Transfusions

2 (25)

12 (44.4)

.43

Management

Simple

12

.14

Exchange

.14

P values for categorical variables were derived from the Fisher exact test.
P values for continuous variables were derived from the Wilcoxon rank-sum test.

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BLOOD, 22 NOVEMBER 2012 VOLUME 120, NUMBER 22

BABY HUG EVENTS

4307

Table 3. Etiology of febrile events

Hydroxyurea, N 96

Fever

Placebo, N 97

Events

Incidence rate*

Subjects, n (%)

Events

Incidence rate*

Subjects, n (%)

Hazard ratio

352

186.2

86 (90)

402

217.4

88 (91)

0.89
0.96

Aplastic crisis, parvovirus

2.1

4 (4)

2.2

4 (4)

Acute osteomyelitis

1.1

2 (2)

Bacteremia/sepsis/meningitis

1.6

2 (2)

3.2

5 (5)

0.40

P
.5
1
.2
.3

Viral syndrome

41

21.7

30 (31)

48

26.0

31 (32)

0.92

.7

Gastroenteritis

26

13.8

18 (19)

70

37.9

41 (42)

0.35

.001

Otitis media

76

40.3

36 (38)

99

53.5

45 (46)

0.73

.2

*Per 100 patient-years.

The hazard ratio (hydroxyurea vs placebo) was generated from a Cox model and the P value from the log-rank life test to compare the time to first event between the two
treatment groups.

for pain (hydroxyurea 4.0 days, placebo 3.6 days), dactylitis

(hydroxyurea 3.9 days, placebo 3.4 days), and ACS (hydroxyurea
5.5 days, placebo 4.7 days).
Transfusions. Twenty (21%) of 96 patients in the hydroxyurea
group received a total of 35 transfusions compared with 33 (34%)
of 97 patients in the placebo group (63 transfusions; P .04).
Seven of 20 transfused patients (35%) in the hydroxyurea group
and 17 (52%) of 33 patients in the placebo group received 2 or
more transfusions (P .06). The most common reasons for
transfusion were splenic sequestration/splenomegaly (18 in each group)
and ACS (2 in the hydroxyurea group and 12 in the placebo group).
Mortality. There were no deaths during the treatment period.
Infections. A summary of infectious complications is shown
in Table 3. There were a total of 754 febrile events with 47 (24%) of
193 children having 6 or more episodes of fever over the 2-year
study period. Fever was the main reason for 421 hospitalizations
during the trial. The rate of gastroenteritis was 13.8 per 100 patient-years
in the hydroxyurea group and 37.9 per 100 patient-years in the placebo
group (HR 0.35; P .001). In multivariate analysis, ANC (P .006)
and placebo group (P .002) positively correlated and WBC (P .006)
negatively correlated with gastroenteritis.
There were 8 episodes of bacteremia/sepsis (hydroxyurea group
3, placebo group 5), accounting for 1.1% of febrile episodes. Three
children had blood cultures positive for Streptococcus pneumoniae.
All 3 S pneumoniae infections occurred in children not taking
hydroxyurea (2 in the placebo group and one assigned to, but not
yet exposed to hydroxyurea). These children were 17, 22, and
33 months old at the time of bacteremia/sepsis and all were
up-to-date with age appropriate immunizations including proteinconjugated pneumococcal vaccines. Overall, the rate of pneumococcal
bacteremia/sepsis for the entire cohort was 0.8 cases per 100 patient-

years. Two children had blood cultures positive for Salmonella. One child
had bacteremia with Hemophilus parainfluenzae in the setting of acute
chest syndrome and hemoglobin of 4.9 g/dL. Two children had blood
cultures positive for Streptococcus viridans; these were probably skin
contaminants because neither child had a central venous access device.
In addition, a 19-month-old child in the placebo group was
treated for presumed bacterial meningitis. The child was given
ceftriaxone in the setting of fever before presenting one day later
with fever, irritability, and neck stiffness. Twenty-four hours after
the parenteral antibiotics cerebrospinal fluid showed one red blood
cell and 52 white blood cells with 66% neutrophils and 34%
mononuclear cells; bacterial gram stain, culture, and antigen testing
were negative. Two children in the placebo group were diagnosed
with and treated for acute culture-negative osteomyelitis. No
patients required vasopressor support, mechanical ventilation, or
dialysis.
Hematologic toxicities

The numbers of subjects with neutropenia, thrombocytopenia, and

severe anemia were previously reported.1 In the hydroxyurea
group, 3 of 5 neutropenic events were associated with viral illness
compared with one of 2 in the placebo group (P 1.0). Neutropenia was never associated with invasive bacterial infection. Severe
anemia occurred in 3 subjects with aplastic crises: a 19-month-old
child in the hydroxyurea group with a hemoglobin of 3.8 g/dL and
ARC of 16 109/L; a 30-month-old child in the placebo group
with a hemoglobin of 3.3 g/dL and ARC of 71 109/L, and a
36 month old child in the placebo group with a hemoglobin of
3.3 g/dL and ARC of 4 109/L. Thrombocytopenia occurred in
11 children in the hydroxyurea group and 7 children in the placebo
group. Thrombocytopenia was associated with lower hemoglobin

Table 4. Clinical events in children who were asymptomatic at enrollment

Hydroxyurea, N 52,
patient-year 100

Placebo, N 49,
patient-year 96

Analysis

Adverse event

Events

Subjects

Events

Subjects

Hazard ratio (95% CI)*

P*

Pain (all events)

61

30

128

31

1.3 (0.8, 2.1)

.35

Pain alone

31

17

46

24

1.6 (0.9, 3.0)

.14

Dactylitis

35

14

4.2 (1.4, 12.9)

.006

ACS

10

2.5 (0.7, 9.7)

.17

Hospitalization

80

31

149

43

1.9 (1.2, 3.0)

.006

Transfusion

11

27

14

2.7 (1.0, 6.9)

.04

Splenomegaly

37

12

42

17

1.6 (0.7, 3.3)

.24

Splenic sequestration

10

3.8 (0.8, 18.4)

.07

Sepsis

ACS indicates acute chest syndrome; and CI, confidence interval.

*The hazard ratio (hydroxyurea vs placebo) and 95% CI were generated from a Cox model and the P value from the log-rank life test to compare the time to first event
between the 2 treatment groups.

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4308

THORNBURG et al

(P .001). Of 11 subjects treated with hydroxyurea who also had

thrombocytopenia, none had concomitant neutropenia, whereas
one of 7 placebo-treated subjects with thrombocytopenia had
concomitant neutropenia.
Clinical events in children who were asymptomatic at baseline

When only the children who were asymptomatic at baseline were

compared, those children in the hydroxyurea group had significantly decreased episodes of dactylitis, hospitalizations, and transfusions (Table 4).
Other adverse events

Twelve (13%) children in the hydroxyurea group and 11 (11%) on

placebo had eczema (P .80). Overall, 15 (8%) children had a
diagnosis of asthma by the end of the study, 9 (9%) children in the
hydroxyurea group, and 6 (6%) children in the placebo group
(P .44). No child developed a malignancy.

Discussion
Further analysis of data from the BABY HUG trial and continued
follow-up of participants provide critical information for clinicians
considering hydroxyurea prescription for young children with
SCA. Overall, young children taking hydroxyurea in the BABY
HUG trial had significantly fewer acute sickle cellrelated complications than those taking placebo. The lower rates of complications
were associated with fewer hospitalizations and transfusions. There
were no clinically important AEs or SAEs that were related to
hydroxyurea.
Hydroxyurea treatment was associated with a 2.2-fold lower
rate of pain and 5.2-fold lower rate of dactylitis. Children taking
hydroxyurea were less likely to have multiple episodes of pain or
dactylitis, and all patients with 4 episodes were in the placebo
group. This reduction in pain rate with hydroxyurea was similar to
that seen in the Multicenter Study of Hydroxyurea (MSH),
indicating that the salutary effects of hydroxyurea on painful
vaso-occlusive events can be observed at all ages.10 The proportion
of patients hospitalized for pain was substantially lower in those
taking hydroxyurea than those taking placebo; there was no
difference in their length of stay, which was approximately 4 days
and similar to other reports.11-13 In the hydroxyurea group, none of
the baseline parameters was associated with the occurrence of
multiple pain events, perhaps because there were so few children in
the hydroxyurea group with multiple pain events. Subjects who
were asymptomatic at study enrollment had lower rates of dactylitis, as well as fewer transfusions and hospitalizations (Table 4).
Further study is needed to determine whether hydroxyurea impacts
pain severity, intensity of outpatient and inpatient analgesic treatment, and time missed from school, and if clinical response can be
accurately predicted in clinical practice. Lowered rates of pain and
dactylitis should have a substantial long-term impact with regard to
lowering the medical costs of outpatient and inpatient management14 and improving quality of life.15
Hydroxyurea was also associated with a 3.5-fold lower rate of
ACS and a lower rate of recurrent ACS. A smaller percentage of
children in the hydroxyurea group were transfused for ACS
compared with the placebo group; however, this difference was not
statistically significant. ACS in children receiving placebo was
associated with lower HbF. The overall rate of ACS in BABY HUG
was lower than reported in the CSSCD. We believe this was

BLOOD, 22 NOVEMBER 2012 VOLUME 120, NUMBER 22

partially attributable to improved immunization against S pneumoniae and Hemophilus influenzae, and uniform use of penicillin
prophylaxis; in one CSSCD study, 14% of infants, age 0-2 years,
with ACS were bacteremic, mostly with S pneumoniae.16 Prevention of ACS has prognostic importance because early ACS is
associated with recurrent episodes later in childhood17 and pulmonary disease and mortality later in life.18
Despite the beneficial hematologic effects of hydroxyurea, we did
not identify a significant difference in gallbladder disease during our
2 years of follow-up; although hemolysis was reduced in the subjects in
the hydroxyurea group, it was not completely eliminated. Rates of
splenic sequestration and transfusion for these events were similar
between the 2 groups. The median time to the first event was 39 weeks
for 8 hydroxyurea-treated subjects, and 53 weeks for 9 placebo-treated
subjects (P .79).1 In the subjects who were asymptomatic at baseline,
there was a trend toward a lower rate of splenic sequestration in the
hydroxyurea group, suggesting that children may need to start hydroxyurea before symptoms to realize some of its protective effects.
Fever was the most common AE during the study, accounting
for approximately one-third of all events. While over 50% of
children with fever were admitted to the hospital only 5% of the febrile
episodes were associated with bacteremia/sepsis, meningitis, osteomyelitis, or ACS. The small percentage of children with invasive infections is
likely attributable to the introduction of penicillin prophylaxis and
pneumococcal and meningococcal vaccines.19,20 Unfortunately, risk of
infection still exists because of the emergence of nontypeable and
nonvaccine strains of pneumococcus.21,22
In the BABY HUG trial, all 3 S pneumoniae infections occurred
in children not taking hydroxyurea. Follow-up studies of children
on hydroxyurea will be needed to determine whether indeed
hydroxyurea has any protective effects against pneumococcal
bacteremia/sepsis in children with SCA. Recent evidence from a
mouse model indicates that hydroxyurea could have a protective
effect against invasive pneumococcal disease.23
Unexpectedly, gastroenteritis was significantly less frequent in
children taking hydroxyurea; this effect has not been previously
reported in other adult or pediatric hydroxyurea studies. It is
tempting to speculate that hydroxyureas ability to replenish nitric
oxide (NO)24,25 may be related to this finding. NO improves gut
motility26; however, as described for priapism,27 chronic NO
depletion may change the sensitivity of smooth muscle to NO and
disrupt normal protective feedback mechanisms, resulting in a
robust response to a modest increase in NO because of infection/
inflammation. In addition, NO is bacteriostatic for several organisms, including Escherichia coli,28 and bactericidal for some.29 It
may be that alteration in bowel flora by hydroxyurea somehow
reduced the incidence of gastroenteritis.
As previously reported, mild to moderate myelosuppression
occurred more frequently in the hydroxyurea group; however, mild
to moderate neutropenia is an expected treatment effect and severe
neutropenia was rare.1 All subjects initially received hydroxyurea
at 20 mg/kg/d, but 9 (9%) had dose reductions (typically to
17.5 mg/kg/d) during the treatment phase because of excessive
myelosuppression. Currently, the standard clinical practice is to
hold or reduce the dose of hydroxyurea in the setting of moderate
hematologic toxicities, particularly neutropenia below
1.0-1.5 109/L.30 However, this may not be necessary because
myelosuppression was not associated with infections or other
cytopenias. Although the BABY HUG trial protocol did not include
dose escalation to maximum tolerated dose, based on previously
published studies31-34 and results from the BABY HUG Follow-up

From www.bloodjournal.org by guest on June 7, 2015. For personal use only.

BLOOD, 22 NOVEMBER 2012 VOLUME 120, NUMBER 22

Study I (NCT00890396), we expect that these subjects will tolerate dose

escalation to MTD as they get older.
Our study was potentially limited by identification of many
clinical events by self-report. However, particularly for painful
events, self-report is required to identify the extent of disease.35,36
Study coordinators were diligent in documenting clinical events at
each monthly study visit, records were obtained from pediatricians
and outside hospitals/emergency departments to document events,
and the MCC reviewed source data for 100% of events.
In conclusion, hydroxyurea significantly reduced the frequency
of painful events, ACS, and associated transfusions and hospitalizations, without significant hydroxyurea-related AEs. Importantly,
hydroxyurea was not associated with an increased rate of infection
in this very young population. Reduction of sickle cellrelated
complications in early childhood should translate to long-term
benefits. As previously reported, disease severity was not a
criterion for enrollment into the trial, and family perception of
disease severity was not a primary reason for enrollment in the
trial.37 Fifty-four percent of children in the hydroxyurea group were
clinically asymptomatic at enrollment, and they also had significant
reductions in sickle cellrelated events. Therefore, beneficial
effects of hydroxyurea occur in both asymptomatic and symptomatic young children with SCA.
Follow-up studies analogous to the recently published adult
MSH follow-up18 will evaluate the long-term safety and effectiveness of hydroxyurea and its potential for improved longevity and
quality of life. Continued collection of clinical event and safety data
are being performed in the current BABY HUG Follow-up Study
(NCT00890396) that has been extended through 2016. Because of the
benefit of hydroxyurea in decreasing acute sickle cellrelated complications, clinicians should consider shifting their practice to prescribe

BABY HUG EVENTS

4309

hydroxyurea therapy for all very young children with SCA, rather than
treating only those most severely affected.38

Acknowledgments
The authors acknowledge the efforts of the BABY HUG subjects
and their families, the contributions of all who participated in
BABY HUG (http://www.c-tasc.com/cms/StudySites/babyhug.htm).
The authors especially thank Dr Bea Files and Dr Michael Jeng, the
medical consultants assigned to reviewing AEs.
This work was supported by NHLBI/National Institutes of
Health Contracts N01-HB-07150 through N01-HB-07160, with
additional support from the Best Pharmaceuticals for Children Act
and the NICHD.

Authorship
Contribution: C.D.T., B.A.F., Z.L., S.T.M., B.T., R.E.W., and
W.C.W. designed the analysis; C.D.T. and Z.L. analyzed the data;
and C.D.T., B.A.F., Z.L., S.T.M., R.K., R.I., P.S., J.L., O.A.,
R.E.W., and W.C.W. wrote the manuscript; and all authors approved the manuscript submission.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
A complete list of the BABY HUG Investigators appears online at
http://www.c-tasc.com/sites/default/files/StudySites/babyhug.html.
Correspondence: Courtney D. Thornburg, MD, MS, Duke
University Medical Center, DUMC Box 102382 Durham, NC
27710; e-mail: courtney.thornburg@dm.duke.edu.

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2012 120: 4304-4310

doi:10.1182/blood-2012-03-419879 originally published
online August 22, 2012

Impact of hydroxyurea on clinical events in the BABY HUG trial

Courtney D. Thornburg, Beatrice A. Files, Zhaoyu Luo, Scott T. Miller, Ram Kalpatthi, Rathi Iyer,
Phillip Seaman, Jeffrey Lebensburger, Ofelia Alvarez, Bruce Thompson, Russell E. Ware and
Winfred C. Wang

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