February 28, 2017
3 min read

Earlier initiation of hydroxyurea benefits children with sickle cell anemia

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SAN DIEGO — The maximal tolerated dose of hydroxyurea appears safe and effective among younger children with sickle cell anemia, according to findings presented at the ASH Annual Meeting and Exposition.

Further, initiating treatment with hydroxyurea at a younger age appears to have “a short-term additive effect” on baseline levels of fetal hemoglobin, although the impact is not sustained.

“In older children (> 5 years), hydroxyurea is safe and provides similar laboratory benefits as in adults when escalated to a mean maximal tolerated dose of 25.6 ± 6.2 mg/kg per day,” Christina Abrams, MD, pediatric resident at Le Bonheur Children’s Hospital at the University of Tennessee, and colleagues wrote. “In infants, a fixed dose of 20 mg/kg per day is safe, improves hematologic parameters and provides substantial clinical benefits. However, the hematologic benefits of intensifying hydroxyurea to [the] maximal tolerated dose in young children have not been evaluated.”

In the Hydroxyurea Study of Long-Term Effects, Abrams and colleagues examined the initial and long-term hematologic changes induced by earlier initiation of hydroxyurea and escalation to the maximal tolerated dose in young children aged less than 5 years of age who had not yet experienced a physiologic decline in fetal hemoglobin. Treatment with hydroxyurea was increased to the maximal tolerated dose in all children after enrollment, defined by an absolute neutrophil count goal of 2,000 x 106/L to 4,000 x 106/L or other hematologic toxicity. Medication possession ratios were calculated as the number of days the medication was in the family’s possession divided by the number of days the medication was prescribed for and multiplied by 100. Medication possession ratios greater than 80% were used as a substitute marker of good adherence.

The researchers compared the results of children who began hydroxyurea before age 5 with those who began treatment at 5 years of age and older at three points in the study: baseline, or before beginning treatment with hydroxyurea; the point at which the maximal tolerated dose was achieved; and five years after the maximal tolerated dose was achieved.

Researchers collected data for 151 children, which amounted to almost 700 patient-years of follow-up. The mean medication possession ratio was 106% (median, 100%; interquartile range, 84.8 to 107.1).

Younger patients (< 5 years; n = 49) began treatment with hydroxyurea at a mean age of 2.6 years (standard deviation, 1.1 years); mean age for initiation among the older patients (≥ 5 years; n =102) was 11.1 years (standard deviation, 3.7 years; P < .001). Treatment was increased over a greater length of time in younger patients (13.6 months vs. 10.6 months; P = .04); younger patients also reached, on average, a higher maximal tolerated dose (28.8 mg/kg per day vs. 24.7 mg/kg per day; P < .001).

Younger patients had higher mean fetal hemoglobin levels (14.9% vs. 7.5%; P < .001), absolute reticulocyte count (300 vs. 270 x 103; P = .02) and white blood cell count (15.6 vs. 12.6 x 103/μL; P < .001) at baseline.

Comparable relationships were noted when the maximal tolerated dose was reached, and there were no differences between the age groups in “the direction or magnitude of changes after escalation of hydroxyurea.” For example, fetal hemoglobin increased an average of 13.3% in the younger age group compared with 13.4% in older patients.

The mean age of patients in the younger group was 9.1 years (standard deviation, 1.0 years) after five years of therapy at the maximal tolerated dose compared with 15.7 years in the older age group (standard deviation, 3.7 years). At this point, patients in the older age group had slightly increased levels of hemoglobin compared with younger patients, but fetal hemoglobin levels decreased with age at comparable levels between the two groups.

Increasing hydroxyurea to the maximal tolerated dose among young children with sickle cell anemia appeared safe and effective, and resulted in consistent, enduring improvements across many hematologic parameters. Hydroxyurea had “a short-term additive effect” on elevated baseline fetal hemoglobin in this age group, but the impact was not maintained.

“Initiating hydroxyurea at an early age does not prevent the normal physiological decline of fetal hemoglobin,” the researchers wrote. “The clinical impact of intensifying hydroxyurea to the maximal tolerated dose in very young children warrants further exploration.” – by Julia Ernst, MS


Abrams C, et al. Abstract 125. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Disclosures: Abrams reports no relevant financial disclosures. Please see the full study for a list of all other relevant financial disclosures.