Background: Hydroxyurea is well established as the standard of care for children with sickle cell anemia (SCA) in the US, but current dosing schemes and dose responses for individual patients are highly variable. Traditionally, hydroxyurea is started at a low dose of 15-20 mg/kg/day, then slowly escalated to maximum tolerated dose (MTD) based upon hematological parameters to avoid toxicities. Using this approach, the average hydroxyurea MTD is about 25 mg/kg/day and yields an average HbF induction of 20-25%, but the time to achieve MTD is more than 6 months. We developed and prospectively evaluated a population pharmacokinetics (PK)-based dosing model of hydroxyurea for children with SCA, aiming to initiate hydroxyurea at a personalized dose that achieves MTD quickly and achieves a more robust HbF response.

Methods: The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) is a prospective sudy with a primary objective to develop and evaluate a population PK-based model to predict the hydroxyurea MTD through an individualized dosing strategy. The study recruited patients (age 6 months to 18 years) who were initiating hydroxyurea therapy. Prior to starting hydroxyurea, each participant took a single oral dose of 20 mg/kg with subsequent post-dose sampling at 15, 60, and 180 minutes. This sparse sampling strategy was based upon our previously described population PK model that allows accurate estimation of hydroxyurea exposure using only three post-dose blood samples. Plasma hydroxyurea concentrations were measured by HPLC. Published PK data from children who had reached MTD demonstrated that the mean hydroxyurea exposure (AUC) at MTD was 115 mg×h/L. TREAT incorporated individual PK data for each participant using population PK model based Bayesian estimation, to generate a starting hydroxyurea dose that would target this AUC goal in an attempt to start at a dose near or at MTD. Clinical follow-up and dose adjustments were subsequently provider-dependent and based upon institutional clinical guidelines recommending dose escalation to MTD, based on a target ANC of less than 3.0 x10^6/L. The official determination of MTD was declared by two independent hematologists blinded to patient identity; MTD was defined as a stable daily dose without dose escalation, holds, or decreases for at least 8 weeks, along with laboratory values within the target range. The primary outcome of TREAT was to reduce the time to MTD by at least two months from an average of published studies demonstrating a mean (±SD) of 9±4 months.

Results:A total of 38 children enrolled in TREAT had PK studies performed to generate an individualized starting dose. Only three participants (7.9%) had incomplete PK studies that did not allow for an individualized starting dose and were started at 20 mg/kg. The enrolled children were young with an average (mean±SD) age of 3.1±4.3 years. Most participants (26/38=68%) were less than two years of age at enrollment, while half (19/38=50%) were less than one year of age. For participants starting with PK-based dosing (n=35), the average starting hydroxyurea dose was 27.5±4.5 mg/kg/day, with 12/35 children (34%) starting hydroxyurea at doses ≥30 mg/kg/day. Despite the high starting doses, there were very few hematological toxicities, with only 2/35 participants requiring a dose decrease from the starting dose due to moderate neutropenia. The individualized starting dose was the actual MTD for 73% of participants without the need for a single dose escalation. The mean time to MTD was 6.2 months (median 4 months) compared to a historical baseline of 9 months. Even with high starting HbF (24.9±11.6%), response was excellent with all participants who have completed at least 6 months of hydroxyurea demonstrating an increase in HbF from baseline. The mean maximum achieved HbF is 35.5±9.5% with 74% achieving HbF>30% and 35% achieving HbF>40%.

Conclusions: TREAT has demonstrated the feasibility of individualized, PK-guided hydroxyurea therapy and suggests that early initiation of hydroxyurea for young children with SCA is both safe and effective, achieving HbF responses (>30-40%) beyond which has been seen with standard dosing. This precision medicine approach to hydroxyurea therapy suggests that it is possible to exceed the traditional therapeutic goals with individualized dosing and could be transformational for the treatment of young children with SCA.


Quinn: Global Blood Therapeutics: Research Funding. Ware: Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Asterisk with author names denotes non-ASH members.

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