Hydroxyurea for Sickle cell disease in children: Current status

The children with sickle cell disease have an abnormal hemoglobin which leads to sickling,
hemolysis and vaso-occlusive events that cause pain and tissue injury.

Treatment of sickle cell disease is largely supportive. Hydroxyurea (hydroxycarbamide) is a

drug that is commonly used worldwide to modify the disease course. The effect of
hydroxyurea is through increase in the fetal hemoglobin (HbF) concentrations; fetal
hemoglobin (HbF) levels are inversely associated with vaso-oclussive crisis (VOC) and severe
anemia. This increase in HbF leads to decrease in the sickling events and consequently
decrease in hospitalization, painful crises and tissue injury. All of these improve the quality
of life.

Current state of evidence: There have been systematic reviews and guidelines that strongly
support the administration of hydroxyurea in children with sickle cell disease. An expert
panel was convened in 2009 by the National Heart, Lung, and Blood Institute (NHLBI),
United States; in its report published in 2014; the panel issued a strong recommendation
that treatment with hydroxyurea be offered regardless of clinical severity to reduce
complications (e.g., pain, dactylitis, Acute chest syndrome, anemia) related to sickle cell
disease in infants 9 mo of age or older, in children, and in adolescents with sickle cell anemia
[1]. The panel had issued these recommendations based on high quality of evidence for
children 9- 42 months age and of moderate quality of evidence for children older than 42
months and adolescents.

Another systematic review published in 2013 specifically summarised the available evidence
on the efficacy, effectiveness and safety of hydroxyurea in the management of SCD in
children below 5 years of age to support guideline development in Kenya, a LMIC [2]. This
study suggested that hydroxyurea used in children, if adequately adhered to by patients and
appropriately monitored, may be associated with reduced rates of hospitalisation and
reduced frequency of painful vaso-occlusive crises.

The drug is also listed in the World Health Organization (WHO) Model List of Essential
Medicines for Children in section 10.3 (hydroxycarbamide) (April 2015) [3]. An expert review
of the WHO supported the use of hydroxyurea as a disease modifier in sickle cell anemia [4].

Further studies are being planned to scale the use of hydroxyurea in low and middle income
countries; one such study is planned in sub-Saharan Africa [5].

Current usage at state level in India: The state of Gujarat has included hydroxyurea in its
sickle cell anemia program [6].
Safety: Hydroxyurea is relatively nontoxic, with myelosuppression as the major dose-limiting
toxicity. In various studies in children and ones including infants, the occurrence of severe
cytopenias has been uncommon. Short term toxicities of hydroxyurea are mainly those
associated with myelosuppression (e.g., neutropenia, anemia, thrombocytopenia). These
are generally rapidly reversible by holding the dose temporarily (e.g., for about two weeks)
and restarting at a lower dose. There is certainly a need for regular monitoring including the
hematological parameters to detect any abnormality in white cell counts anytime during the
continuation of treatment[1, 2].

Based on the available evidence, it is reasonable to recommend use of

hydroxyurea in children diagnosed to have sickle cell disease.

Indications for use of hydroxyurea in children with sickle cell disease: All infants 9 mo of
age or older, children, and adolescents with sickle cell anemia

Dose: The starting dose 10-15 mg/kg per day. The dose can be increased in increments of 5
mg/kg/d increments every 8 weeks till maximally tolerated dose is reached NOT exceeding
25- 30 mg/kg/day [1].

Suggested protocol for use of hydroxyurea [1]:

Who can initiate treatment?
The care of individuals with sickle cell anemia/ disease needs a comprehensive protocol of
which treatment with hydroxyurea is an important component. Given the burden of the
disease, and the need to reach out to every affected individual, it is suggested that the
treatment with hydroxyurea and other medicines be started by any paediatrician/ physician
or any other medical officer who has received specific training in the management of Sickle
cell disease organized by State Health Services. These individuals need regular follow up to
ensure compliance and monitor them. The program should institute necessary steps to
ensure the implementation of protocols developed and make the treatment available till the
last mile. Within the State health services, appropriate facilities should be available at
medical colleges, District hospitals and CHC.

Recommended Laboratory Tests Before Starting Therapy

Complete blood cell (CBC) count with white blood cell (WBC) differential,
reticulocyte count, platelet count, and red blood cell (RBC) mean corpuscular volume
(MCV)
Quantitative measurement of fetal hemoglobin if available (e.g., hemoglobin
electrophoresis, high-performance liquid chromatography)
 Renal and liver function tests ( ALT and serum creatinine)
Pregnancy test for adolescent girls

Initiating and Monitoring of Hydroxyurea Therapy

Baseline elevation of fetal hemoglobin should not affect the decision to initiate
hydroxyurea therapy
Starting dosage for infants and children: 10-15 mg/kg/d
Monitoring
Monitor CBC count with WBC differential and reticulocyte count at least every 4 wk
when adjusting dosage.
3
Aim for a target absolute neutrophil count 2000/mm ; however, younger persons
with lower baseline counts may safely tolerate absolute neutrophil counts down to
1250/mm3
3
Maintain platelet count 80,000/mm
If dose escalation is warranted based on clinical and laboratory findings, proceed as
follows:
Increase by 5-mg/kg/d increments every 8 wk
Give until mild myelosuppression (absolute neutrophil count of 2000-
4000/mm3) is achieved, up to a maximum of 35 mg/kg/d

The usual practice is to increase the dose in suggested increments every 8 weeks to a
target of approximately 25 mg/kg daily as long as there is no major toxicity.
Once a stable dose is established, laboratory safety monitoring should include CBC
count with WBC differential, and platelet count every 2-3 months and patients
should be provided with 2-3 months of medicines.
Family should be reminded that the effectiveness of hydroxyurea depends on their
adherence to daily dosing; they should be counselled not to double up doses if a
dose is missed
A clinical response to treatment with hydroxyurea may take 3-6 months; therefore, a
6-month trial on the maximum tolerated dose is required prior to considering
discontinuation due to treatment failure (whether due to lack of adherence or failure
to respond to therapy)
Monitor RBC MCV or fetal hemoglobin levels for evidence of consistent or
progressive laboratory response
A lack of increase in MCV, fetal hemoglobin, or both, is not an indication to
discontinue therapy
For the patient who has a clinical response, long-term hydroxyurea therapy is
indicated
Hydroxyurea therapy should be continued during hospitalizations or illness; the
complete blood counts should be monitored.
 When one is starting hydroxyurea in late adolescent period among girls, it is likely
that these girls may get married in the next few years and get pregnant. Thus it
should be specifically discussed upfront when starting hydroxyurea in them that
once they are married and are planning pregnancy in the absence of use of any
contraceptives, then they have to stop hydroxyurea for atleast 3 months and
continue folic acid.

In case of occurrence of neutropenia or thrombocytopenia less than 80000/mm3:

o Temporarily stop hydroxyurea dosing, for upto a week or two.
o Monitor CBC count with WBC differential weekly
o When blood counts have recovered, reinstitute hydroxyurea at a dose of 5 mg/kg/d
lower than the dose given before onset of cytopenia. Most often this happens within 2
weeks. And most often this does not recur.

References:

1. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease:
summary of the 2014 evidence-based report by expert panel members. JAMA. 2014
Sep 10;312(10):1033-48.
2. Mulaku M, Opiyo N, Karumbi J, et al. Evidence review of hydroxyurea for the
prevention of sickle cell complications in low-income countries. Arch Dis Child. 2013
Nov;98(11):908-14.
3. WHO Model List of Essential Medicines for Children (April 2015). Available from
http://www.who.int/medicines/publications/essentialmedicines/EMLc2015_8-May-
15.pdf
4. Neville KA, Panepinto JA. Pharmacotherapy of Sickle Cell Disease 18th Expert
Committee on the Selection and Use of Essential Medicines(21 to 25 March 2011).
Available from:
http://www.who.int/selection_medicines/committees/expert/18/applications/Sickle
cell.pdf
5. McGann PT, Tshilolo L, Santos B, et al. Hydroxyurea Therapy for Children With Sickle
Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial. Pediatr
Blood Cancer. 2016 Jan;63(1):98-104.
6. Sickle Cell Anemia Program Manual. Available from:
https://nrhm.gujarat.gov.in/Images/pdf/SickleCellAnemiaManual.pdf