Escalating Doses Of Hydroxyurea In Very Young Children With Sickle Cell Anemia

In the HUSOFT and BABY HUG trials (Wang, et al., J. Pediat, 2001 and Lancet, 2011), very young children (6-24 and 9-18 months old at entry, respectively) with sickle cell anemia (SCA) initiated hydroxyurea (HU) at a fixed dose of 20 mg/kg/day, which improved hematologic parameters, provided substantial clinical benefits, and had an excellent safety profile. These results encouraged parental acceptance of HU treatment in very young children with SCA and in some parents promoted an expectation of early therapy. At our institution, select children as young as 6 months of age have initiated HU upon parental request. As in HUSOFT and BABY HUG, these children have begun at a dose of ∼20 mg/kg/day but then had dose escalation, based on hematologic parameters, toward a maximal tolerated dose (Ware, et al., Blood, 2010). Because the impact of dose escalation in this population is unknown, we have retrospectively reviewed our experience.

Children with homozygous sickle cell anemia (HbSS) who began HU therapy prior to 18 months of age between June 2010 and October 2012 were retrospectively identified following IRB approval. Demographic data, dosage information, and laboratory results pre-HU and at last clinical follow-up were analyzed. Descriptive data are presented below as means (±SD) unless otherwise noted. Statistical comparisons were performed with the Exact Wilcoxon Signed Rank test.

Participants (n=6; female=3) were begun on HU because of recurrent dactylitis (n=2) or parental request (n=4). The mean initial dose of HU was 19.1 (±1.6) mg/kg/d, which subsequently was escalated to 25.4 (±4.4) mg/kg/d over an average of 14.8 (±10.5; range, 4.9-32.1) months. HU therapy was interrupted briefly in 2 participants for neutropenia and reticulocytopenia, respectively. Both incidents were felt related to viral suppression and both participants resumed HU at their previous dosage without further toxicities. Hematologic response is summarized in the following table along with hematologic response data reported in the HUSOFT and BABY HUG trials in subjects of comparable age.

Six patients with HbSS who were begun on treatment at a mean age of 12 months had their dose of hydroxyurea escalated over an average follow-up period of 15 months. Hematologic responses included marked increases in Hb level, HbF, and MCV and a decrease in ARC, along with relatively stable neutrophil and platelet counts. When compared with subjects of approximately the same age in the BABY HUG and HUSOFT trials, all of whom were treated at doses of ≤20 mg/kg/d, our patients may have demonstrated more robust changes in their Hb, HbF, MCV and ARC levels, possibly related to their higher hydroxyurea dosing. The ongoing BABY HUG follow-up studies should provide complementary information for subjects who are ≥3 years of age, since they are having dose escalation toward maximum tolerated dose (MTD) and will be evaluated over an extended period of time. Overall, our current data suggest that increasing hydroxyurea dosage starting at a very early age is safe and hematologically efficacious and warrants further exploration with the goal of maximizing clinical benefit.

Off Label Use: Hydroxurea therapy in children with sickle cell disease.