Escalated hydroxyurea dosing more effective for Ugandan children with sickle cell disease
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Escalated dosing of hydroxyurea had greater clinical efficacy than fixed dosing of the drug for children with sickle cell disease in sub-Saharan Africa, according to randomized study results published in The New England Journal of Medicine.
The regimens exhibited a similar safety profile, researchers noted.
“We are fortunate here in the United States because we can screen and identify new babies with sickle cell anemia right away, but many countries in Africa have health care systems that are challenged and cannot do that,” Russell E. Ware, MD, PhD, director of the division of hematology and Global Health Center, co-director of the Cancer and Blood Diseases Institute, and Marjory J. Johnson chair of hematology translational research at Cincinnati Children’s Hospital, as well as professor in the department of pediatrics at University of Cincinnati, told Healio. “Hydroxyurea has been an effective drug for years [for sickle cell disease] and is widely available and affordable. New therapies in the United States are not widely available in many of these countries in Africa so, in this trial, we looked at the best possible dose of hydroxyurea that may be more effective for these patients.”
Hydroxyurea has been shown to be an effective, safe and feasible treatment option for children with sickle cell disease in sub-Saharan Africa, reducing incidence of vaso-occlusive events and mortality among this population. Dosing standards, however, remain undetermined.
In the NOHARM MTD trial, Ware and colleagues sought to compare the benefits and risks of a fixed dose vs. escalated dosing of hydroxyurea among 187 children with sickle cell disease in Uganda. The researchers randomly assigned 94 children (mean age, 4.6 ± 1 years) to a fixed dose (mean, 19.2 ± 1.8 mg/kg per day) and 93 children (mean age, 4.8 ± 0.9 years) to an escalating dose that started at 25 mg/kg per day and increased to as much as 35 mg/kg per day if tolerable (mean, 29.5 ± 3.6 mg/kg per day).
A hemoglobin level of 9 g/dL or more or a fetal hemoglobin level of 20% or more after 24 months served as the primary outcome. Incidences of malaria, vaso-occlusive crises and serious adverse events served as secondary outcomes.
Results showed 86% of children in the dose-escalation group achieved the primary outcome thresholds compared with 37% in the fixed-dose group (P < .001).
Children in the dose-escalation group experienced fewer sickle cell-related adverse events (incidence rate ratio [IRR] = 0.43; 95% CI, 0.34-0.54), vaso-occlusive pain crises (IRR = 0.43; 95% CI, 0.34-0.56) and cases of acute chest syndrome or pneumonia (IRR = 0.27; 95% CI, 0.11-0.56). They also had fewer transfusions (IRR = 0.3; 95% CI, 0.2-0.43) and hospitalizations (IRR = 0.21; 95% CI, 0.13-0.34). Laboratory-confirmed dose-limiting toxic effects were similar in both groups. Researchers observed no cases of severe neutropenia or thrombocytopenia.
The clear benefits of the escalated dosing strategy prompted the data and safety monitoring board to recommend halting the trial and offering all children hydroxyurea with dose escalation.
“This drug isn’t for an acute crisis because it builds up fetal hemoglobin over time,” Ware said. “In some patients, it may take a few weeks to build up. However, we are hopeful that these results will lead to meaningful changes for patients living in these parts of Africa and throughout the world.”
For more information:
Russell E. Ware, MD, PhD, can be reached at Cincinnati Children’s Hospital Medical Center, 3333 Burnett Ave., Cincinnati, OH 45229; email: russell.ware@cchmc.org.
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