Dose-escalated hydroxyurea has superior clinical efficacy but an equivalent safety profile compared with standard fixed-dose hydroxyurea among children with sickle cell anemia in sub-Saharan Africa, according to findings published in The New England Journal of Medicine.

To determine hydroxyurea dosing standards for children with sickle cell anemia in sub-Saharan Africa, where access to medical care and routine laboratory monitoring is limited, the investigators conducted an extension study of the Novel Use of Hydroxyurea in an African Region with Malaria study (NOHARM; Identifier: NCT01976416), which had established the safety of standard fixed-dose hydroxyurea.

The extension study, NOHARM Maximum Tolerated Dose (MTD; Identifier: NCT03128515), was a randomized, double-blind trial that included 187 children with sickle cell anemia in Uganda. Participants were randomly assigned to 2 treatment groups: hydroxyurea at the standard fixed dose (approximately 20 mg/kg/day) or with dose escalation to the maximum safe dose, defined as the highest dose that would not necessitate close monitoring or interim doctor visits (approximately 30 mg/kg/day). The primary outcome was a hemoglobin level of ≥9.0 g/dL or a fetal hemoglobin level of ≥20% after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events.

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In the fixed-dose arm, 94 children (mean [±SD] age, 4.6±1.0 years) received a mean dose of 19.2 (±1.8) mg/kg per day. In the dose-escalation arm, 93 children (mean age, 4.8±0.9 years) received a mean dose of 29.5 (±3.6) mg/kg per day.

At 18 months, 86% of the children in the dose-escalation group had reached the primary outcome, compared with 37% of the children in the fixed-dose group (P <.001). Due to the clear benefit of dose escalation, the data and safety monitoring board stopped the trial early.

At trial closure, the numbers of clinical events were significantly less among children in the dose-escalation group than among those in the fixed-dose group: clinical sickle cell–related adverse events (incidence rate ratio [IRR], 0.43; 95% CI, 0.34-0.54; P <.001), vaso-occlusive pain crises (IRR, 0.43; 95% CI, 0.34-0.56; P <.001), cases of acute chest syndrome or pneumonia (IRR, 0.27; 95% CI, 0.11-0.56; P =.001), transfusions (IRR, 0.30; 95% CI, 0.20-0.43; P <.001), and hospitalizations (IRR, 0.21; 95% CI, 0.13-0.34; P <.001).

The benefits of dose escalation were also confirmed with laboratory studies. Children in the dose-escalation group had increased hemoglobin levels (mean, 8.7 g/dL vs 8.3 g/dL), increased fetal hemoglobin levels (mean, 30.5% vs 18.2%), decreased reticulocyte counts (mean, 157×109/L vs 261×109/L), and decreased neutrophils (mean, 3.3×109/L vs 5.1×109/L), without an increase in the rate of infections, relative to the fixed-dose group.

The laboratory-confirmed dose-limiting toxic effects were similar in the 2 groups, and no episodes of severe neutropenia or thrombocytopenia occurred.

In rural and low-resource areas, the ideal approach of personalized dosing based on pharmacokinetics is typically not possible. Therefore, the authors suggested the development of stepwise hydroxyurea dose escalation algorithms that factor in individual laboratory values, weight, and the child’s most recent dose as the next step to bringing universal hydroxyurea treatment to all African children with sickle cell anemia.

“With direct comparison of fixed-dose hydroxyurea with dose escalation, our data provide strong evidence that dose escalation is safe and provides considerably greater clinical benefits than standard dosing,” wrote the authors.


John CC, Opoka RO, Latham TS, et al. Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa. N Engl J Med. 2020;382(26):2524-2533. doi: 10.1056/NEJMoa2000146