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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Hydroxyurea for sickle cell disease in children and for prevention
of cerebrovascular events: the Belgian experience
Béatrice Gulbis, David Haberman, Dominique Dufour, Catherine Christophe, Christiane Vermylen, Faustin Kagambega, Francis Corazza,
Christine Devalck, Marie-Françoise Dresse, Kathleen Hunninck, Axel Klein, Phu Quoc Le, Miche`le Loop, Philip Maes, Pierre Philippet,
Eric Sariban, Chris Van Geet, and Alina Ferster
Hydroxyurea (HU) is considered to be the
most successful drug therapy for severe
sickle cell disease (SCD). Nevertheless,
questions remain regarding its benefits in
very young children and its role in the
prevention of cerebrovascular events.
There were 127 SCD patients treated with
no attempt to reach maximal tolerated
doses who entered the Belgian Registry:
109 for standard criteria and 18 who were
at risk of stroke only. During 426 patient-
years of follow-up for patients with stan-
dard criteria, 3.3 acute chest syndromes,
1.3 cerebrovascular events, and 1.1 osteo-
necrosis per 100 patient-years were ob-
served. A subgroup of 32 patients fol-
lowed for 6 years experienced significant
benefit over this period. In each subgroup
of children (younger than 2 years, 2-5,
6-9, and 10-19 years) followed for 2 years,
clinical and biologic changes were simi-
lar, except for children younger than 2
years who had no total hemoglobin in-
crease and remained at risk of severe
anemia. In 72 patients evaluated by trans-
cranial Doppler studies (TCD), 34 patients
were at risk of primary stroke and only 1
had a cerebrovascular event after a fol-
low-up of 96 patient-years. These results
confirm the benefit of HU, even in very
young children, and its possible role in
primary stroke prevention. (Blood. 2005;
105:2685-2690)
© 2005 by The American Society of Hematology
Introduction
Since the first results of the Multicenter Study of Hydroxyurea
(MSH) in adult sickle cell anemia patients published by Charache
et al,
1
hydroxyurea (HU) has been successfully used in patients
with sickle cell disease (SCD) who have recurrent painful crisis
and/or acute chest syndrome (ACS)
2,3
as well as in patients with
beta-thalassemia major.
4
In addition to its myelosuppressive effect
and ability to induce fetal hemoglobin (HbF) synthesis, HU has
been shown to reduce the adhesion of sickle erythrocytes to
endothelial cells and to modulate endothelial cell activation and
nitric oxide generation.
5
Whereas HU clinical benefits in severely affected adult SCD
patients were confirmed by a randomized controlled trial in 1995
(MSH),
1,6
its role in very young children requires further
studies.
2,7-10
Unanswered questions remain about its sustained efficacy and
long-term safety, especially in children who might be exposed to
HU for decades. Since our publication in 2001,
2
inclusion of
patients in the Belgian Registry of SCD patients treated by HU has
been ongoing. It has allowed a reassessment of the efficacy and
safety of HU, especially in pediatric patients, and the evaluation of
its possible role in the prevention of primary stroke or stroke
recurrence.
Patients, materials, and methods
Patients enrolled
The Belgian Registry including SCD patients treated by HU was opened in
1993.Approval was obtained from the Pediatric Department of the Children
University Hospital Reine Fabiola review board for this registry. Informed
consent was provided according to the Declaration of Helsinki. Entry
criteria in this registry, clinical monitoring, and laboratory measurements
have been described in detail previously.
2
Briefly, to be eligible, patients
had to have reported the year before entry at least 2 or more painful
vaso-occlusive crises (VOCs) per year requiring hospitalization; one
episode of acute chest syndrome (ACS), defined as acute chest pain with
new lung infiltration and PaO
2
less than 75 mmHg; overt stroke or transient
ischemic attack (TIA), defined as transient neurologic deficit (or seizures)
and confirmed by a neurologist after electroencephalography and imaging;
priapism, defined as persistent painful erection not associated with erotic
stimulation; or the development of ischemic bone necrosis, defined as hip or
shoulder pain with functional impairment and abnormal bone scintigraphy,
magnetic resonance imaging, or radiography.
In one center, routine transcranial Doppler studies (TCDs) were
proposed in all patients and performed according to the technique described
in the Stroke Prevention Trial (STOP) study.
11,12
Velocities higher than 200
cm/s were considered abnormal. Magnetic resonance imaging (MRI) and
angiography (MRA) were performed in the case of abnormal TCD result or
From the Departments of Hematology/Oncology and Radiology, Hôpital
Universitaire des Enfants, Brussels, Belgium; the Department of Hematology,
Hôpital Universitaire Brugmann, Brussels, Belgium; the Department of Clinical
Chemistry, Hôpital Universitaire Erasme, Brussels, Belgium; the Department of
Pediatric Hematology, Cliniques Universitaire Saint-Luc, Brussels, Belgium;
Clinique de l’Espérance, Montegnée, Belgium; Hôpital de la Citadelle,
Lie`ge, Belgium; UZ Gent, Gent, Belgium; Paolakinderziekenhuis,
Antwerpen, Belgium; and UZ Gasthuisberg, Leuven, Belgium.
Submitted July 16, 2004; accepted December 3, 2004. Prepublished online as Blood
First Edition Paper, December 16, 2004; DOI 10.1182/blood-2004-07-2704.
Supported by Fond National de la Recherche Scientifique grants 7.4510.99,
7.4561.01, and 7.4515.03.
Reprints: Alina Ferster, Hemato-Oncology Unit, Hôpital Universitaire des Enfants,
Av. J. J. Crocq, 15, B-1020 Brussels, Belgium; e-mail: aferster@ulb.ac.be.
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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if judged appropriate by the clinician. Patients only at risk of stroke with at
least 2 consecutive transcranial Doppler studies (TCDs) demonstrating a
blood-flow velocity of 200 cm/s or higher in the median cerebral arteries
were also enrolled.
Hydroxyurea therapy
The HU dose was given orally once a day, initially at 20 mg/kg. It was
escalated by 5 mg/kg if judged appropriate by the treating physician and
tolerated by the patient. This was not a centralized treatment protocol: dose
escalation, as well as the attempt to reach the maximum tolerated dose
(MTD) was not defined by guidelines. Noncompliance with HU therapy
could not be assessed by pharmacologic data or by drug dispensing data.
Parents, legal guardians, and/or patients were informed of the potential
risks, benefits, and side effects relative to HU. Sexually active adolescents
were aware of the need of efficient contraception.
Annual data collection
Initial and annual clinical monitoring evaluation included status of the
patient (dead or alive), the number of hospitalizations and duration per year,
major SCD-related events, number of transfusions, presence of myelotoxic-
ity, presence of an opportunistic infection, development of a malignant
disease, or any other serious adverse event. Baseline and annual laboratory
investigations included total hemoglobin level, fetal hemoglobin (HbF), the
mean corpuscular volume (MCV), and absolute neutrophil count (ANC).
Values within 3 months after a blood transfusion were excluded. The
hematologic toxicity was reported in case of white blood cell (WBC) count
less than 3
10
9
/L and platelet count less than 100 000
10
9
/L. The mean
HU dose per kilo was calculated each year.
Statistical methods
Statistical analyses were performed using the Wilcoxon signed rank test to
assess significant differences between clinical events or hematologic
parameters, before and during HU treatment.
Results
Patient characteristics, treatment, and compliance
Between 1993 and 2002, 127 patients were enrolled in the Belgian
Registry: 109 for conventional criteria (99 for 2 or more VOCs, 21
for an acute chest syndrome, 7 for stroke, and 1 for transient
ischemic attack) and 18 for abnormal TCD only. Of the patients,
119 had a diagnosis of HbSS, 4 of HbS °-thalassemia, 3 of
HbSC, and 1 of HbSD. The -globin genotype was unknown for
most of the patients. Median age at entry was 6 years (range, 8
months to 19 years), and mean follow-up was 47 months (range,
1-8 years).
Daily hydroxyurea doses reported each year are shown in Table
1. Of the 109 patients included for severe clinical events, 2 (1.8%)
received hydroxyurea doses higher than 30 mg/kg per day (Table
1). The 18 patients enrolled for an abnormal TCD received similar
doses, and none of them had hydroxyurea doses higher than 30
mg/kg per day.
HU was interrupted definitely for 12 patients: 7 underwent
allogeneic bone marrow transplantation, 1 failed to respond after 2
years of treatment, 1 with HbSC because of a total Hb level higher
than 13 g/dL, 2 refused to pursue the treatment after 1 and 2 years,
and 1 patient developed malignancy. Hydroxyurea was also
transiently stopped in 3 cases, 2 for pregnancy and 1 for systemic
lupus syndrome, diagnosed one year after the beginning of
treatment. Due to relocation, 11 patients were lost to follow-up in
the registry.
In some adolescents, poor compliance was evident. Neverthe-
less, they were encouraged to continue the follow-up in the registry,
with the exception of those who refused explicitly.
Adverse event
The mean number of hospitalizations and duration dropped
significantly during the 8 years of HU treatment (P
.05 when
compared with baseline values, Table 1). Of patients meeting
clinical event inclusion criteria, 92 (87%) of 106 were free of
major events requiring hospitalization at 1 year, while at 7 and
8 years after initiation of treatment, 6 (25%) of 24 and 5 (36%)
of 14 patients, respectively, remained so. For these 109 patients
included for standard criteria, sickle cell–related event rates
are presented in Table 2. This represents 426 patient-years
of follow-up.
Despite a sustained increase in HbF level and an increase in
hydroxyurea doses to 30 mg/kg per day, a girl aged 13 months at
inclusion, with previous history of splenic sequestration, was
hospitalized 20 times during these 2 years of HU therapy and
continued to present multiple vaso-occlusive crises and dactylitis
during the first year of HU. She died during the second year of
therapy from acute severe anemia during an episode of splenic
sequestration. Acute promyelocytic leukemia was diagnosed in a
21-year-old female after 8 years of HU therapy. This patient has
been treated with all trans-retinoic acid and polychemotherapy and
has now been in remission for 20 months. In 6 cases, transient
hematologic toxicity was reported. There were 2 patients who
Table 1. Clinical outcome in SCD patients included for standard criteria before and during therapy
Duration of hydroxyurea therapy
Before
1 y
2 y
3 y
4 y
5 y
6 y
7 y
8 y
No. of evaluable patients
109
106
88
70
54
39
32
24
14
Hospitalizations per patient per year
3.2
2.7
1.3
2.2*
1.6
2.9*
1.1
1.5*
1.3
1.9*
1.3
1.5*
1.6
1.7†
1.0
1.3*
0.6
1.2†
Days in hospital per patient per year
20
17
6.8
14*
7.1
12*
5.7
8.5*
7.9
11†
7.7
9.6†
10
13†
6.7
8.3†
3.7
7.0†
Mean hydroxyurea dose, mg/kg daily,
no.‡
Less than 20
NA
52
47
40
30
23
19
10
8
Between 20 to 25
NA
49
33
21
18
12
7
11
4
Between 25 to 30
NA
2
8
7
4
3
5
2
1
More than 30
NA
1
1
1
2
1
1
1
0
Results are mean
1 SD.
*Statistically significant change from baseline, defined by P
.001.
†Statistically significant change from baseline, defined by P
.05.
‡Data missing for 4 patient-years.
NA indicates not applicable.
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became pregnant on HU and gave birth to healthy babies. No
opportunistic infection occurred.
Long-term effects of hydroxyurea therapy
Adverse events and laboratory values of a cohort of 32 patients (15
females and 17 males) maintained over 6 years on HU were
analyzed (Tables 3-4). All of them were diagnosed as homozygous
for HbS. Median age at entry was 6 years (range, 8 months to 19
years). Hospitalizations, VOCs, and ACS were more frequently
observed after 3 years of treatment than during the first 3 years.
Recurrent stroke was observed once in an 8-year-old girl, 6 years
after the initial event. No strokes or TIAs occurred in the 31
patients without a history of previous stroke or TIA. During the 6
years of HU therapy, 8 (25%) of 32 patients remained free from any
sickle cell disease–related event requiring hospitalization. With
time, a larger proportion of patients received an HU dose of less
than 20 mg/kg per day: 36 (38%) of 96 during the years 1 to 3 and
52 (54%) of 96 during the fourth to sixth years. Nevertheless,
hematologic response to HU was sustained, and no significant
difference could be observed between the hematologic values in the
third year and those obtained at years 4, 5, and 6.
Risk of cerebrovascular events
There were 8 patients followed for a median of 6 years (range, 3-9
years), with 44 cumulative patient-years of follow-up, at risk of
secondary stroke. Median age at entry was 7 years (range, 8 months
to 19 years), and one patient received hydroxyurea doses higher
than 30 mg/kg per day. At entry, 3 patients were no longer
transfused because of poor compliance, parents’ refusal, or alloim-
munization, while 5 patients were still under a chronic transfusion
program for 3 (n
2) and 4 (n
3) months. Recurrent stroke
occurred in one patient after 6 years of follow-up despite evidence
of good compliance with therapy as assessed by hematologic
response to HU.
Among the 101 patients included for standard criteria and no
previous stroke or TIA, 54 were evaluated by TCD before and/or
during HU treatment. Of the patients, 16 presented with velocities
more than 200 cm/sec (mean, 229
13 cm/sec). In 11 of 16 who
had measurements performed before the start of HU, similar values
were obtained (230
14 cm/sec). MRI/MRA was performed in 12
and considered abnormal in 4 patients.
Among the 18 patients included in the registry on the basis of an
abnormal TCD alone, baseline TCD velocities were of 228
19
cm/sec. Of the patients, 11 have been prospectively followed by
TCD and 2 of them had TCD velocities that returned to normal/
conditional value on HU. The mean TCD velocities in this group of
11 patients decreased from 235
25 cm/sec to 204
27 cm/sec
(P
.01). Among these 18 patients, 14 underwent MRI/MRA
studies, which were interpreted as abnormal in 3 patients. In this
group of 18 patients, the median age at entry was 5 years (range,
1-17 years), and median duration of follow-up was 3 years
(range, 1-6 years). Mean daily doses of HU as well as
hematologic response to HU were similar to that of the whole
cohort (data not shown).
As a whole, 34 patients were considered at risk of primary
stroke on the basis of abnormal TCD, and 7 of the 21 explored by
MRI/MRA had moderate/severe arterial stenosis. Only 1 of these
34 patients presented a cerebrovascular event (seizures) after an
evaluation of 96 patient-years. Neuropsychologic evaluation was
not performed in this cohort.
Follow-up of patients younger than 2 years
Included in the registry were 14 patients younger than 2 years, and
10 of them had a minimum follow-up of 2 years of HU therapy.
Their clinical events and hematologic values during therapy were
compared with those observed in older patients with the same
follow-up of 2 years and aged of 2 to 5, 6 to 9, and 10 to 19 years
(Tables 5-6). Reduction of hospitalizations and VOCs on HU was
significant in all 4 age groups, when compared with baseline data.
The rate of sickle cell–related events as well as the number of
hospitalizations on HU were similar in all age groups, but the
hospitalization durations were longer in the younger group. One
patient who died was described previously. The 10 infants initially
received a dose of less than 20 mg/kg per day, which was increased
Table 3. Cumulative event numbers and rates
during a 6-year follow-up of 32 patients
Type of event
Years of HU therapy
1 to 3
4 to 6
Hospitalizations, no.
No.
82
142
Rate/100 patients-years
85
148
Hospitalizations, d
No.
446
855
Rate/100 patients-years
465
890
Vaso-occlusive crisis, 2 or more than 2/y
No.
15
22
Rate/100 patients-years
16
23
Acute chest syndrome
No.
0
3
Rate/100 patients-years
0
3.1
Cerebrovascular event
No.
0
1
Rate/100 patients-years
0
1
Bone necrosis/dactylitis
No.
1
0
Rate/100 patients-years
1
0
Severe anemia
No.
3
3
Rate/100 patients-years
3.1
3.1
Mean hydroxyurea dose, mg/kg daily, no.
Less than 20
36
52
Between 20 to 25
47
26
More than 25
13
20
Table 2. Cumulative event numbers and rates during an 8-year
follow-up for 109 patients enrolled for standard criteria
during 426 patient-years
Type of event
Adverse
events, n
Rate/100
patient-years*
Hospitalizations, no.
587
138
Hospitalization, d
4400
1033
Vaso-occlusive crisis requiring hospitalization,
2 or more than 2/y
93
22
Acute chest syndrome
14
3.3
Cerebrovascular event
6*
1.3
Osteonecrosis
5
1.1
Priapism
1
0.23
Opportunistic infection
0
0
Transient hematologic toxicity
6
1.4
Death
1
0.23
Malignancy
1
0.23
*There was 1 stroke and 5 TIAs. The patient who had stroke on HU had had initial
stroke. The 5 TIA occurred in patients without any previous central nervous system
(CNS) symptoms.
HYDROXYUREA FOR SCD IN CHILDREN AND CNS EVENTS
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for 2 of them. The infant who died was treated with 30 mg/kg per
day of HU but without significant leuco- or thrombocytopenia.
Toxicities of HU were reported with 2 transient episodes of
thrombocytopenia (2 infants) that required temporary discontinua-
tion of therapy. There were 5 episodes observed of severe anemia
(Hb,
6 g/dL) that required transfusion (4 infants). Aplastic crisis
associated with a Parvovirus infection was documented in one
patient.
Discussion
The ongoing experience with the prospective Belgian Registry for
severe sickle cell disease patients treated with HU confirms our
previous results
2
that long-term HU therapy is feasible and is
associated with a clinical improvement (reduction of hospitaliza-
tion numbers and duration). As found in our previous study,
2
the
majority of patients no longer experienced VOCs requiring hospi-
talization during the first year of HU treatment. In the cohort of 32
patients treated for 6 years, clinical improvement persisted through-
out this period with significant reduction of the number of
hospitalizations and duration compared with baseline data. Never-
theless, more events were reported during years 4 to 6 than 1 to 3,
possibly due to observed reduced treatment intensity during the
latter period. This reduced treatment intensity could be explained
by the absence of strict guidelines for HU dose modification and by
the tailoring of therapy by the treating physician based on the
biologic response of each patient. Biologic improvement was
maintained throughout the period of therapy, except for the ANC,
which diminished, but not significantly, during years 4 to 6.
Recently, Zimmerman et al
13
have shown that additional changes
are obtained when HU is used at MTD. In their pediatric cohort at
the Duke Medical Center, a significant increase in Hb, HbF, and
MCV was obtained when compared with the Belgian cohort
without a significant increase in toxicity. The Belgian and the Duke
patients are similar in terms of number, mean treatment duration,
and follow-up. Nevertheless, in the Belgian cohort, patients were
younger (median age, 6 years compared with 11 years in the Duke
series) and HU was used at lower doses: of the 426 evaluable
patient-years, 229 received less than 20 mg/kg per day and only 7
(1.6%), more than 30 mg/kg per day, while in the Duke series 21
patients (17%) received more than 30 mg/kg per day. The
additional clinical benefit of HU used at MTD in terms of VOC rate
remains to be proved in children.
Regarding specific events while on HU, the incidence of ACS
on HU is 3.3 episodes for 100 patient-years, whereas the expected
incidence of ACS in a pediatric cohort of untreated patients is 25.3
episodes per 100 patient-years in children of 2 to 4 years of age, and
this decreases gradually with age to reach an incidence of 9.3 in
children of 10 to 19 years.
14
This lower-than-expected incidence of
ACS with HU treatment confirms our previous data. In the MSH
study,
1
299 adults were randomized to receive HU or placebo for a
period of approximately 2 years. During the trial period, 75 ACS
events occurred and were 2 times more frequent in the placebo arm
(51 events) than in the HU arm (25 events). While the MSH study
aimed to escalate the dose up to the highest possible dose without
myelosuppression, our data confirm that HU is efficient at prevent-
ing ACS without reaching the maximum tolerated dose.
The overall incidence of cerebrovascular accident (CVA) in our
population is notably higher (1.3 for 100 patient-years) than
described in a large cohort of more than 3000 children by
Ohene-Frempong et al,
15
who reported a prevalence of 4% and an
incidence of 0.61 per 100 patient-years. This discrepancy of
observations may be related to the population of the Belgian
Registry, which is composed of severely affected patients and does
not represent a population of unselected SCD patients. More
interesting are the data on patients at risk of secondary stroke.
Recurrence rate of CVA in our patients with stroke or TIA (1/8) is
Table 4. Biologic outcome during a 6-year follow-up of 32 patients
Hydroxyurea therapy
Before
1 year
2 years
3 years
4 years
5 years
6 years
Hemoglobin level, g/dL
8.2 (6.7-10)
8.7 (6.7-12)†
9.0 (6.2-12)*
8.7 (6.8-13)†
8.6 (6.6-14)†
8.8 (6.7-14)†
8.8 (6.9-11)†
HbF level, g/dL
0.3 (0.01-0.8)
1.4 (0.01-5.1)*
1.4 (0.12-4.3)*
1.4 (0.17-3.8)*
1.3 (0.16-3.2)*
1.0 (0.10-2.8)*
1.1 (0.08-2.5)*
MCV, fL
83 (68-113)
93 (69-117)*
93 (75-118)*
91 (70-118)
93 (74-119)
91 (70-121)
92 (67-120)
ANC,
10
9
/L
5.2 (2.8-9.3)
3.4 (1.4-6.6)*
4.5 (1.3-12)
4.2 (2.2-11)
4.3 (0.8-10)
4.8 (1.5-11)
4.6 (2.0-15)
No statistically significant change at 4, 5, and 6 years respectively for all parameters when compared with 3 years.
Results are expressed as median (range).
*Statistically significant change from baseline, defined by P
.001.
†Statistically significant change from baseline, defined by P
.05.
Table 5. Cumulative event numbers and rates during a 2-year
patient follow-up of 4 age groups
Type of event
Age at inclusion, y
Younger than
2 (n
10)
2 to 5
(n
28)
6 to 9
(n
28)
10 to 19
(n
26)
Hospitalizations, no.
No.
32
63
113
47
Rate/100 patients-years
160
112
226
90
Hospitalizations, d
No.
224*
296
406
261
Rate/100 patients-years
1120
529
812
502
Vaso-occlusive crisis, 2
or more than 2/y
No.
2
10
9
10
Rate/100 patients-years
10
18
18
19
Acute chest syndrome
No.
0
1
2
0
Rate/100 patients-years
0
1.8
4
0
Cerebrovascular event
No.
1
0
0
0
Rate/100 patients-years
5
0
0
0
Bone necrosis/dactylitis
No.
1
0
0
1
Rate/100 patients-years
5
0
0
1.9
Death
No.
1
0
0
0
Rate/100 patients-years
5
0
0
0
Severe anemia
No.
5
2
0
0
Rate/100 patients-years
25
3.6
0
0
*One child with recurrent splenic sequestrations accounted for 156 days.
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low compared with the 50% expected rate of recurrence of CVA in
untransfused patients.
15,16
In transfused patients, the prevalence of
recurrent stroke has been reported at 13% to 22% (with one
recurrence for each 24-41 patient-years) and the prevalence of TIA
is 19%.
16,17
A similar recurrence rate on HU was observed in our 8
untransfused patients with 44 patient-years of follow-up. Ware et
al
3
have reported a cohort of 16 children with previous stroke or
TIAin whom chronic transfusion was stopped and replaced by HU.
After a median follow-up of 22 months, 3 patients had recurrence
of stroke, but recurrences happened shortly after cessation of
transfusion, when the increase of HbF was not optimal. These
preliminary data have been confirmed in a cohort of 35 children on
HU for a median time of 42 months: the stroke recurrence rate was
5.7 per 100 patient-years but 3.6 per 100 patient-years in children
who continued transfusions for a few months.
18
In 5 of our patients,
chronic transfusion has been continued for at least 3 months after
the start of HU, and this might explain why they did not experience
early recurrence. In another cohort of 5 patients,
19
HU was
effective at preventing recurrent stroke. Our results, as well as
those described by Ware et al
18
and Sumoza et al,
19
suggest that
chronic transfusion might be safely stopped after the start of HU
therapy and that HU may prevent stroke recurrence when chronic
transfusion is not possible.
Several prospective series have shown that elevated blood flow
velocities measured by TCD predict stroke,
11,12
and when velocities
are higher than 200 cm/s, the risk is above 10% to 13% per year.
The randomized STOP study
20
clearly demonstrated that stroke
was prevented by chronic transfusions, as one event occurred in the
transfusion group, whereas 11 occurred in the standard care group,
after a median follow-up of 22 months, leading to early closure of
the study. Nevertheless, adherence to a prophylactic chronic
transfusion program by patients, parents, and doctors is low, due to
risks, costs, and side effects. In particular, the Belgian experience
with chronic transfusion is very disappointing because of a high
rate of severe alloimmunization, mainly explained by the absence
of blood donors of African origin. The limited experience in the 34
patients at risk of primary stroke (18 without any other classical
severity criteria and 16 with standard criteria) and treated with HU
is very encouraging. It suggests that HU might be an alternative to a
chronic transfusion program in this subset of patients, since only
one event (seizures) occurred with an experience of 96 patient-
years. More interestingly, these patients are comparable with those
of the STOP study, with similar baseline TCD velocities and almost
the same proportion of moderate/severe stenosis on MRA (7/26
versus 25/100 in STOP study).
21
Slight total hemoglobin increase,
inversely correlated to cerebral blood flow velocity, the significant
lowering of ANC, as well as reduced neutrophil activation
22
and
adherence molecules expression with HU
23
might have contributed
to the stabilization of the pathologic process at this level. In our
small series, TCD velocities were improved in a group of 11
patients prospectively followed but returned to normal/conditional
value in only 2, while in the STOP study improvement/
normalization of blood flow velocities was achieved mostly after
transfusions in 26 of 38 patients without severe MRA abnormali-
ties.
21
The possible equivalence between HU and a conventional
transfusion program for primary and secondary stroke prevention
should be assessed by a prospective randomized study. Further-
more, we question if, for optimal stroke prevention, the use of
MTD would not be beneficial since in the Duke experience no new
cerebrovascular event occurred in a similar cohort of patients.
13
The use of HU instead of transfusion for stroke prevention will
avoid the risk of iron overload and the need of iron chelation.
18
It
will also reduce the development of multiple red cell alloantibodies
and the risk of viral transmission in areas where the use of blood is
not safe.
The overall HU tolerance was good with neither prolonged
myelosuppression nor opportunistic infections. The extremely low
rate of reported hematologic toxicity might be due to methodologic
bias (registry with annual report and not a prospective trial).
Nevertheless, this also may be explained by the nonattempt to
reach MTD with the majority of patients receiving a dose of less
than 20 mg/kg per day. Furthermore, the definition of myelotoxicity
differs slightly from the Duke series, and adolescents with poor
compliance were not excluded from the analysis. Long-term
treatment was not associated with increased toxicity, while reduc-
tion in ANC and elevation in total Hb and HbF remained stable
throughout the years, suggesting that marrow exhaustion does not
occur after such a follow-up.
The development of acute promyelocytic leukemia in one
21-year-old woman after receiving HU for 8 years
24
is of concern
and raised the question of possible SCD or HU-related malignan-
cies. Patients with long-term exposure to HU showed no increase
of number of acquired DNA mutations.
25
Increase of illegitimate
variable-diversity-joining region (VDJ) recombination in chil-
dren on HU has previously been suspected.
25
However, in the
prospective follow-up of the Duke series, no significant increase
of illegitimate VDJ recombination after 5 years on HU was
found.
13
This suggests that long-term continuous follow-up and
prospective registration of patients is the only way to evaluate
the risk and should be mandatory.
Repeated vaso-occlusive crises are sometimes present from
infancy and early childhood. Furthermore, dactylitis, anemia, and
Table 6. Biologic outcome in 4 patient age groups during treatment with HU
Group age at inclusion, y (n)
Younger than 2 (10)
2 to 5 (28)
6 to 9 (25)
10 to 19 (26)
At inclusion
Hemoglobin level, g/dL
8.2 (6.5-12)
8.1 (6.3-10)
7.9 (6.4-10)
8.7 (7.0-10)
HbF leve, g/dL
0.66 (0.52-2.4)
0.59 (0.15-2.2)
0.46 (0.03-2.8)
0.41 (0.15-2.5)
MCV, fL
79 (73-93)
82 (68-113)
85 (67-95)
88 (70-101)
ANC,
10
9
/L
6.5 (2.4-8.4)
5.6 (2.4-12)
5.7 (2.7-17)
5.7 (2.8-11)
Second-year HU
Hemoglobin level, g/dL
7.6 (2.3-10)
8.9† (6.2-12)
8.6† (6.5-12)
8.9 (7.1-12)
HbF leve, g/dL
1.6* (0.35-2.4)
1.5† (0.24-4.3)
1.3* (0.12-4.5)
1.3* (0.15-3.8)
MCV, fL
94* (74-109)
91* (81-102)
92* (80-117)
96* (70-110)
ANC,
10
9
/L
4.2 (1.4-7.3)
5.0 (2.5-10)
4.1* (1.3-12)
3.9* (1.3-9.5)
Results are expressed as median (range).
*Statistically significant change from baseline, defined by P
.001.
†Statistically significant change from baseline, defined by P
.05.
HYDROXYUREA FOR SCD IN CHILDREN AND CNS EVENTS
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Page 6

high WBC counts in infancy predict a severe outcome, and this
could trigger an early start of HU in these patients.
7,26
We wondered
if the biologic and clinical responses to HU and toxicity were
different in very young children when compared with older ones.
Wang et al
7
have shown that treatment with HU is feasible in very
young children and might delay functional asplenia. Nevertheless,
efficacy among different age groups has never been prospectively
studied and compared until now. Followed prospectively for 2
years, 4 age groups of children (younger than 2 years, 2-5 years,
6-9 years and 10-19 years) had similar biologic values at inclusion,
except for HbF that was, as expected, significantly higher in
children younger than 2 years. Fetal hemoglobin and MCV values
changed similarly with treatment in all age groups, but Hb levels
did not rise significantly in the younger group. Children younger
than 2 years had clinical response similar to older patients, except
for days in the hospital. Clinically, reduction of the number of
hospitalizations and duration each year on HU was significant in all
4 age groups, when compared with baseline value, and did not
differ statistically among the 4 groups, demonstrating that similar
improvement is obtained regardless of age. Of interest, 4 of the
children included in the registry at younger than 2 years developed
episodes of severe acute anemia. Unfortunately, detailed data on
each case are not available and information on splenic size or
Parvovirus infection was missing for some patients in the database,
making further discussion hazardous. However, the patient who
died from severe anemia during splenic sequestration is compa-
rable with the one described by Wang et al.
7
In their experience,
among 28 enrolled children who were younger than 2 years, only
21 completed 2 years of treatment. One patient died of a fatal
episode of splenic sequestration before completing 2 years of
treatment. These 2 patients raise the question of HU benefit and
safety in very young patients at risk of severe anemia and/or splenic
sequestration. At this moment, these 2 deaths should not be
interpreted as toxic death, but rather as a lack of efficacy of HU in
this specific situation. Our data do not support the use of HU for
very young children to limit the severity of anemia, since Hb level
did not increase significantly in this group, but the ongoing
BABY-HUG trial will answer this question.
The ongoing experience of the Belgian Registry confirms the
clinical benefit of treatment with HU, even in very young children.
The effectiveness of HU for primary or secondary stroke preven-
tion is possible, and this should continue to be assessed prospec-
tively, ideally by means of randomized trials. The use of HU at
MTD may bring additional benefit. The Belgian Registry continues
to provide us with a useful instrument to measure safety and
efficacy of HU treatment.
Acknowledgment
We would like to thank Dr L. Hookey for his substantial editorial
assistance.
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