A team of international researchers has learned that dose escalation of hydroxyurea treatment for children with sickle cell anemia is more effective than a lower, fixed dose of the same drug, and with no additional toxicities.

The study, known as NOHARM MTD (Novel use Of Hydroxyurea in an African Region with Malaria – Maximum Tolerated Dose), focused on children in Uganda. But the results could impact use of hydroxyurea worldwide, including the United States and Europe. The findings were published in the New England Journal of Medicine (June 25, 2020).

This clinical research milestone removes a major barrier to broadly expanding the use of hydroxyurea in low-resource regions like sub-Saharan Africa, according to the physicians who led the study at Makerere University in Kampala, Uganda; Cincinnati Children’s Hospital Medical Center; and the Indiana University School of Medicine.

For this study, 187 children with sickle cell anemia living in Uganda received hydroxyurea. About half received a fixed dose of 20 mg per kilogram of body weight per day. The other half received an escalating dose, which started at 25 mg per kilogram of body weight per day and increased up to 35 mg per kilogram of body weight per day, if tolerated. Doctors evaluated the children every two to three months for laboratory and clinical benefits, as well as potential side effects.

While the study team was planning to keep the children on these separate treatment arms for two years, an independent data review panel changed the course about 18 months into the study, due to clear benefits of the higher dose.

Implications for Sickle Cell Anemia Care Worldwide 

Sickle cell anemia is a serious global health issue. In the United States, about 2,000 children are born with the disease each year. Worldwide, the number is between 300,000 and 400,000 with more than 80% born in sub-Saharan Africa (and 20,000 in Uganda alone). Yet most therapeutic developments for sickle cell have not been available to children in Africa. That includes hydroxyurea, which effectively reduces the acute and chronic disease manifestations and is approved by the U.S. Food and Drug Administration.

Earlier studies in sub-Saharan Africa showed hydroxyurea to be safe, feasible to use and effective for treating sickle cell anemia, according to Russell Ware, MD, PhD, a pediatric hematologist at Cincinnati Children’s who led those studies and is senior investigator on the current NEJM paper. The drug boosts fetal hemoglobin, which reduces sickling of the red blood cells and improves anemia, lowers pain and other sickle-related events, and reduces clinical interventions such as transfusions and hospitalizations.

Potential Benefits Outweigh Costs 

Previous studies have shown that personalized dosing based on pharmacokinetics is the ideal way to determine an individual patient’s appropriate hydroxyurea dose.

“Children with sickle cell anemia who live in sub-Saharan Africa and other low-resource settings do not routinely have access to hydroxyurea, much less personalized dosing therapy,” Ware says. “The dose escalation algorithms we tested in this study could help public health officials in that region safely and effectively provide hydroxyurea at the appropriate dose to benefit children on a wide scale.”

Expanding hydroxyurea treatment in the Sub-Sahara will require affordable drug costs, education of healthcare providers and an increased drug supply. In addition, newborn screening for sickle cell anemia is needed to help identify those who will benefit from treatment as early as possible. Ware says that the additional costs associated with screening and increasing access to the drug will be more than offset by fewer clinical adverse events, transfusions and hospitalizations.

For more information, contact Russell.Ware@cchmc.org.

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