source: American Society of Hematology

year: 2017

authors: Patrick T. McGann, Omar Niss, Min Dong, Anu Marahatta, Kathryn L McElhinney, Thad A. Howard, Tomoyuki Mizuno, Theodosia A. Kalfa, Karen Kalinyak, Punam Malik, Charles T. Quinn, Russell E. Ware, Alexander A. Vinks

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.

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%.

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