Hydroxyurea Dose Escalation for Children with Sickle Cell An
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Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown.

In a randomized, double-blind trial, researchers compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events.

Results:
-- Children received hydroxyurea at a fixed dose or with dose escalation; the mean doses were 19.2±1.8 mg per kilogram per day and 29.5±3.6 mg per kilogram per day, respectively.
-- The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose.
-- At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group.
-- Children in the dose-escalation group had fewer sickle cell–related adverse events, vaso-occlusive pain crises, cases of acute chest syndrome or pneumonia, transfusions, and hospitalizations.
-- Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia.

Conclusively, Among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety.

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2000146?query=featured_home
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