Individualized, PK-Guided Dosing of Hydroxyurea for Young Children with Sickle Cell Anemia: Final Results from the Hydroxyurea Optimization through Precision Study (HOPS)

Introduction: Hydroxyurea is standard of care for young children with sickle cell anemia (SCA), yet optimal dosing remains uncertain. We prospectively demonstrated that an individualized, pharmacokinetic (PK)-guided initial dosing strategy for children with SCA was feasible, safe, and effective in the single center TREAT trial (NCT02286154). The Hydroxyurea Optimization through Precision Study (HOPS, NCT03789591) was then designed to evaluate PK-guided dosing in a multicenter trial design to directly compare the benefits of PK-guided dosing to a standard weight-based dosing with gradual, stepwise escalation to maximum tolerated dose (MTD).

Methods: Children and adolescents with SCA (aged 6 months - 21 years) were recruited from 14 pediatric sickle cell centers in the U.S. and randomized 1:1 with equal distribution < 2 and ≥ 2 years of age to account for age-related variability in baseline HbF, to receive a starting hydroxyurea dose of either 20 mg/kg/day or a PK-guided dose. PK data were collected using a sparse microsampling approach requiring 10 μL of blood at 3 time-points over 3 hours. A protocol-guided dose adjustment strategy was then used for both arms to achieve moderate myelosuppression with the most relevant toxicity criterion defined as an absolute neutrophil count (ANC) <0.75 x10⁹/L. Doses were adjusted for growth to maintain the intended mg/kg dose. The primary endpoint was HbF after 6 months of treatment testing the hypothesis that PK-guided dosing yields a more robust HbF response than standard weight-based dosing. GEE modeling was used to estimate average HbF between both arms while accounting for age and within-individual autocorrelation.

Results: A total of 127 participants enrolled; 12 withdrew prior to initiating hydroxyurea and 11 prior to month 6. This final analysis includes 104 participants (101 HbSS, 3 HbS/b⁰-thalassemia) who reached month 6, the a priori desired sample size to address the primary endpoint. The median age at enrollment was 9 months (IQR 7 - 23) with 75% ≤ 2 years of age. Baseline HbF was 27.4 ± 11.2%, but most patients had hemolytic anemia with zero participants having baseline Hb > 10.5 g/dL and ARC < 100 x10⁹/L to suggest hereditary persistence of fetal hemoglobin. Baseline ANC was relatively low (3.1 ± 1.9 x 10⁹/L) and 21% of participants had a baseline ANC < 1.5 x 10⁹/L before initiating hydroxyurea.

The PK-guided starting dose was significantly higher compared to weight-based dosing (27.5 ± 5.2 vs 20.2 ± 0.6 mg/kg/day, p<0.001). There was no evidence of increased hematologic toxicities in the PK-guided dosing arm with 43 dose holds (21 PK-guided arm, 22 weight-based arm) in 30 participants due to hematologic toxicity, most commonly transient incidental neutropenia. There were no neutropenic infections or significant bleeding due to thrombocytopenia. Only 5 participants (3 in PK-guided arm 2 in weight-based arm) required a dose decrease in hydroxyurea.

Across the entire cohort, early initiation of hydroxyurea with dose escalation resulted in significant hematologic improvement: Hb increased from 9.0 ± 1.1 to 10.1 ± 1.4 g/dL, p<0.001; ARC 265 ± 123 to 185 ± 110, p<0.001; HbF 27.4 ± 11.2 to 34.3 ± 10.3%, p<0.001. Most (74%) participants achieved HbF ≥ 30% and 31% had HbF ≥ 40% at month 6, compared to 46% and 13%, before treatment initiation.

HbF increase was significantly higher with PK-guided (8.8 ± 1.6) than weight-based dosing across all ages (4.9 ± 1.0%, p=0.04). When accounting for age, PK-guided initial dosing resulted in significantly greater %HbF change compared to weight-based initial dosing for participants ≥ 2 years of age (p = 0.04) but not for participants < 2 years of age (p = 0.59).

Conclusions: HOPS represents the largest cohort of very young children with SCA treated with hydroxyurea to date and demonstrates that early initiated and carefully titrated hydroxyurea results in robust HbF response for most patients. Individualized, PK-guided dosing results in significantly improved hematologic response especially for children ≥ 2 years of age. HOPS supports feasibility of PK-guided dosing across many clinical sites and demonstrates the safety and efficacy of starting hydroxyurea very early in life with careful attention to dose, regardless of starting Hb, HbF, or ANC. Future studies are warranted to determine if HbF response is sustained and how much this strategy ameliorates or prevents clinical complications of SCA.

Heeney:MiNA Therapeutics: Consultancy; Praxis: Current equity holder in publicly-traded company; Pfizer: Consultancy, Current equity holder in publicly-traded company; Blueprint Medicines: Consultancy; Abbvie: Current equity holder in publicly-traded company; Omeros: Consultancy; Amgen: Current equity holder in publicly-traded company; GE Healthcare: Current equity holder in publicly-traded company; Bluebird Bio: Consultancy; CRISPER Therapeutics: Current equity holder in publicly-traded company; Beam Therapeutics: Consultancy, Current equity holder in publicly-traded company; Dianthus Therapeutics: Current equity holder in publicly-traded company; Abbott Labs: Current equity holder in publicly-traded company; Novartis: Consultancy, Current equity holder in publicly-traded company. Niss:Pfizer: Consultancy. Quinn:Aruvant: Research Funding; Hillhurst Biopharmaceuticals: Consultancy; Disc Medicine: Consultancy; Emmaus Medical: Research Funding. Fritch Lilla:Chiesi: Speakers Bureau; Agios: Honoraria; Octapharma: Consultancy; Sobi: Honoraria. Remiker:X4: Speakers Bureau; Horizon Therapeutics: Consultancy; Bluebird Bio: Consultancy. Tang:Novo-Nordisk: Research Funding; Pfizer: Research Funding. McGann:Novartis: Research Funding.