Received: 9 August 2021 Revised: 29 September 2021 Accepted: 10 October 2021

DOI: 10.1002/pbc.29423 Pediatric

Blood &
Cancer The American Society of
Pediatric Hematology/Oncology
C O M M E N TA R Y

A call to start hydroxyurea by 6 months of age and before the

advent of sickle cell disease complications

Narcisse Elenga1 Simon Kayemba-Kay’s2 Mathieu Nacher3 Natasha Archer4

1
Sickle Cell Disease Center, Centre Hospitalier de Cayenne, French Guiana, Cayenne, France
2
Service de Pédiatrie, Centre Hospitalier de Chartres, Le Coudray, France
3
INSERM U1424, Centre Hospitalier de Cayenne, French Guiana, Cayenne, France
4
Pediatric Hematology and Oncology, Boston Children’s Hospital, Boston, Massachusetts, USA

Correspondence
Narcisse Elenga, Pediatric Medicine and Surgery, Cayenne Hospital, Rue des Flamboyants, BP 6006, 97306 Cayenne cedex, French Guiana, France.
Email: elengafr@gmail.com

Sickle cell disease (SCD), a group of inherited hemoglobin disorders
characterized by the presence of sickle hemoglobin (HbS), can cause
significant organ damage and death in both children and adults.1
Where it is available, universal newborn screening allows for early
diagnosis and management shortly after birth, thereby reducing the
incidence of serious complications.2 While three disease-modifying
therapies, crizanlizumab, voxelotor, and L-glutamine, have recently
been approved for the treatment of SCD, the most accessible and effec-
tive treatment is still hydroxyurea (HU).3 In children with severe sickle
cell anemia (SCA), HU has been shown to increase fetal hemoglobin
(HbF) levels and reduce pain and hospitalizations.3,4 Here, we discuss
the rationale of starting HU treatment at 6 months of age and before
the occurrence of any disease-specific complications such as severe
anemia, dactilytis, and/or splenic sequestration.
HU, a direct but reversible ribonucleotide reductase inhibitor, inter-
feres with the synthesis of deoxyribonucleic acid (DNA) by the reduc-
tion of deoxyribuncleotide triphosphate pools. While HU’s mecha-
nisms of action remain poorly understood, the cytotoxic effects of HU
cause an increase in the recruitment of HbF-rich erythroid progenitors,
reduction in reticulocytes, white blood cells, and platelets, and increase
in the bioavailability of nitric oxide all of which contribute to the many
clinical benefits observed with its use.5 Benefits range from decreased
emergency department visits, hospital admission rates, blood transfu-
sion requirements, organ dysfunction, and death.
Abbreviations: SCD, alpha-fetoprotein; Sickle cell disease, HbS; HU, Hydroxyurea; SCA,
Sickle cell anemia; Hb F, Fetal hemoglobin; DNA, Deoxyribonucleic acid; TREAT, Therapeutic
Response Evaluation and; PK, Adherence Trial; MTD, Pharmacokinetic; AMH, Maximum
tolerated dose; TCD, Anti Mullerian Hormone; ANCs, Transcranial Dopplerabsolute
neutrophil counts.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC
Newborns with SCD are asymptomatic because of the high value
of HbF present at birth. The hemoglobin switch, largely orchestrated
by the BCL11A gene, leads to a decrease in gamma globin produc-
tion and increase in beta-like globin production. HbF falls rapidly dur-
ing the first 24 months of life, but this fall is greatest during the first
6 months of life.6,7 By 6 months of age, most infants with SCA have
between 30% and 40% HbF and those values will only drop further
without treatment. In the absence of HU, the onset of symptoms can
and is likely to occur once HbF levels fall below 30%, given uncontrolled
sickle hemoglobin polymerization, further justifying the start of HU by
6 months of age.
National guidelines recommend starting HU anywhere from
9 months to 2 years of age. In the United States, the American Soci-
ety of Hematology recommends starting those with SCA on HU at
9 months of age, while the United Kingdom’s national guidelines rec-
ommend the use of HU in children with SCA younger than 12 months.8
In France and Italy, HU is indicated for patients with SCA from the age
of 2 years onward.9,10 However, the optimal age of HU initiation has
not yet been established.
The idea of starting HU early in infants is not novel. Initially, the
HUSOFT study11,12 involved infants aged 6–24 months and reported
no major safety issues. Approximately 2 years ago, a retrospective
study by Schuchard et al. demonstrated improved HbF induction and
decreased hospitalizations, pain, and transfusions in children started
on HU between 0 and 1 year of age compared to children started from
1–2 and 2–5 years of age.13 This study and the accompanying edito-
rial by Ware et al. reinforced this concept.14 In addition, data from the
Therapeutic Response Evaluation and Adherence Trial (TREAT) study
and recent data on pharmacokinetic (PK)-guided HU dosing in children

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https://doi.org/10.1002/pbc.29423
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at 6 months of age show that infants started earlier on HU have higher,
sustained values of HbF.15
The design of the BABY HUG trial4 called for recruitment between
9 and 18 months of age, which is the rationale for the recommended
starting age of 9 months in the United States. However, complications
of SCD can develop much earlier. If we want to achieve the goal of
treating our patients before they develop chronic, inexorable, and ulti-
mately fatal organ damage, the ideal age to start HU is before the
advent of symptoms. As many children have laboratory and clinical
manifestations of SCA by 6 months of age, early initiation of therapy
at that age will be beneficial.
The fear of mutagenesis and infertility has largely contributed to
a reluctance on the part of providers and families to start HU,16,17
despite preclinical and clinical studies that demonstrate HU as nei-
ther mutagenic nor carcinogenic to people with SCD.18,19 A fear that
HU may cause cancer is still cited as a concern. Unfortunately, most
of the information available regarding infertility is from small cohort
studies. Studies in women have demonstrated no statistically signif-
icant difference in mean anti-Mullerian hormone (AMH) in women
with SCA treated with HU compared to those not treated with HU,
although a larger number of patients treated with HU were in the less
than fifth percentile.20 In men with SCA, while HU has been shown
to worsen already existing testicular dysfunction,21 other studies have
shown no difference in sperm parameters in HU-exposed versus HU
nonexposed patients.22 Given the lack of definitive data on infertility
and real-life reports of pregnancy in women on HU and in partners of
men on HU,19 HU remains the drug for SCA with the best risk/benefit
profile.18
In practice, it may be simpler to start this treatment at the same time
as penicillin, that is when the diagnosis is made. However, this may not
allow for sufficient time for comprehensive counseling and, while rare,
the potential for an allergic reaction secondary to one of the medica-
tions may result in the discontinuation of two life-saving medications
and feelings of mistrust between families and their medical team. In
addition, baseline white blood cell count values are generally lower in
the young infants because the chronic inflammatory state of SCA is
not yet established, which may result in lower than desired absolute
neutrophil counts (ANCs) in early life. Lastly, a higher glomerular fil-
tration rate means a faster clearance of the drug, so higher doses may
be required than in older children. If treatment should be started due
to symptoms, as early as 2 months of age, having some time between
penicillin initiation is ideal and PK-guided dosing, as suggested by Dong
et al.23 may be useful.
With PK-guided dosing, children have fewer toxicities and blood
draws,8,24,25 making the drug more appealing for even young infants.
Previously, HU dosing was based solely on weight, with a gradual
increase to the maximum tolerated dose (MTD). This strategy achieves
predictable clinical and laboratory benefits, but often takes longer than
6 months to achieve. To achieve this more quickly, trials have been con-
ducted to enable personalized, PK-guided HU dosing strategy.24–26 PK-
guided dosing makes dosing easier and also more effective.
The clinical manifestations of SCD can appear as early as 3 months
of age and can be potentially severe. Hand-foot syndrome or dactylitis,
characterized by painful swelling of the feet and/or hands, is one of the
ELENGA ET AL .
first manifestations of the disease. It may be more common and severe
in early childhood.27,28 Early use of HU has been shown to decrease
pain and dactylitis, with minimal toxicity.3,29,30
HU, in addition to reducing the frequency of acute complications,
may also prevent the development of chronic end-organ damage. One
study has shown that hyperfiltration of the kidney was present in chil-
dren 9 months to 1 year of age prior to any treatment.31 HU is asso-
ciated with a decrease in hyperfiltration in young children with SCA32
and is also associated with better urine concentrating ability and less
renal enlargement.33 HU also reduces the severity of anemia, and ane-
mia in childhood is associated with poor brain development. Beyond
reducing transcranial Doppler (TCD) velocities in children with SCA
and primary stroke,34 HU may also prevent irreversible changes that
impact cognitive function.35,36 While most studies have not been per-
formed in very young children, the effects of HU on the brains of
school-age children is evident.
In resource-limited countries, HU has been shown to reduce the
incidence of vaso-occlusive events, infections, malaria, transfusions,
and deaths, which argues for wider access to this treatment. This rec-
ommendation to start HU as early as 6 months of age may be even more
powerful in these low-resource settings, where the mortality rate due
to SCA is very high, especially in the first years of life.30 The insufficient
blood supply37 as well as the lack of rapid access to care for many indi-
viduals with SCA in resource-limited countries may be directly com-
bated by the less likely risk of acute anemia and increased splenic func-
tion with the use of HU.38
More than 25 years after its introduction in the management of SCA,
HU is recognized as an effective drug without serious acute toxicity,
especially when the benefit/risk ratio is considered. Determining the
appropriate age to initiate HU is critical, as it could result in a new gen-
eration of children with significantly less acute and chronic complica-
tions. Based on the data available in the literature, we suggest the pre-
scription of HU as early as 6 months of age and before the onset of SCD
complications.
ACKNOWLEDGMENTS
Not applicable.
AUTHOR CONTRIBUTIONS
Narcisse Elenga and Natasha Archer analyzed the data and drafted the
manuscript. Simon Kayemba-Kay’s and Mathieu Nacher provided crit-
ical comments on the manuscript. All authors read and approved the
final version of the manuscript.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
ORCID
Narcisse Elenga https://orcid.org/0000-0003-0624-4180
Natasha Archer https://orcid.org/0000-0002-6460-5872
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How to cite this article: Elenga N, Kayemba-Kay’s S, Nacher
M, Archer N. A call to start hydroxyurea by 6 months of age
and before the advent of sickle cell disease complications.
Pediatr Blood Cancer. 2021;e29423
https://doi.org/10.1002/pbc.29423.