October 19, 2017
4 min read

Hydroxyurea appears safe for African children with sickle cell anemia

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Russell E. Ware
Chandy John

Hydroxyurea did not increase the risk for malaria infection in children with sickle cell anemia who live in malaria-endemic regions of Uganda, according to the results of a randomized, double-blind clinical trial published in Blood.

“Hydroxyurea has proven laboratory and clinical efficacy for children and adults with sickle cell anemia living in the United States and Europe,” Russell E. Ware, MD, PhD, director of the division of hematology at Cincinnati Children’s Hospital Medical Center, told HemOnc Today. “However, there are virtually no data regarding its safety and toxicities in sub-Saharan Africa, which bears the greatest global burden of disease.”

Sickle cell anemia is a life-threatening inherited disorder characterized by abnormal red blood cells that collect in blood vessels and obstruct blood flow to organs, which may result in severe pain, organ failure, stroke or death. More than 300,000 affected babies are born worldwide each year, mostly in sub-Saharan Africa, where an estimated 50% to 90% of children with sickle cell anemia die by the age of 5 years, often without an established diagnosis.

Hydroxyurea helps reduce the production of sickle hemoglobin, thus increasing the amount of healthy fetal hemoglobin. Approved by the FDA for adults with severe symptoms and by the European Medicines Agency for affected adults and children aged older than 2 years, hydroxyurea has a low incidence of treatment-related toxicity and no serious long-term adverse events. Evidence-based guidelines published by the NHLBI strongly recommend wider usage of hydroxyurea, including offering treatment to infants as young as 9 months.

However, hydroxyurea is not widely prescribed in sub-Saharan Africa, partly because of a lack of data that hydroxyurea would be effective and safe in low-resource regions.

Additionally, research has suggested that hydroxyurea could make people with sickle cell anemia more susceptible to malaria — a serious and sometimes fatal disease spread by mosquitoes — which is common across sub-Saharan Africa.

“There are concerns that hydroxyurea might worsen the severity of malaria in young children with sickle cell anemia, so a clinical trial using hydroxyurea in a malaria endemic region of Africa was warranted,” Chandy John, MD, MS, professor of pediatrics, microbiology and immunology at Indiana University School of Medicine, told HemOnc Today. “Because hydroxyurea provides such positive outcomes for people in high-resource regions, we want to be sure that this drug is safe for children in low-resource, malaria-prone settings.”

To help make that determination, researchers from the United States and Uganda established the year-long randomized, placebo-controlled Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM) trial.


Led by Robert O. Opoka, MMED, professor at Makerere University in Kampala, Uganda, researchers recruited 213 children aged 1 to 4 years receiving care at Mulago Hospital Sickle Cell Clinic in Kampala, Uganda, between Sept. 24, 2014, and Oct. 2, 2015. Five children with severe malnutrition, known chronic medical conditions, or who received a blood transfusion within 30 days were excluded.

Researchers randomly assigned 208 children to either once-daily oral hydroxyurea — 1,000 mg scored tablets and 100 mg dispersible tablets — or a placebo for a full year. All patients also received standard care for sickle cell anemia — including folic acid, penicillin prophylaxis and pneumococcal vaccinations — along with insecticide-treated mosquito nets and antimalaria medication.

After trial completion, all participants could receive open-label hydroxyurea.

Researchers monitored children for clinical malaria and toxicities at 2 weeks and at 1, 2, 3, 4, 6, 8, 10 and 12 months.

Incidence of clinical malaria served as the primary endpoint. Secondary endpoints included sickle cell anemia-related adverse events, clinical adverse events and dose-limiting toxicities.

Three children assigned hydroxyurea experienced a total of five malaria episodes, and seven children receiving placebo had a total of seven malaria episodes. All 10 study participants with malaria recovered.

Malaria incidence did not differ between children prescribed hydroxyurea (0.05 episodes per child per year; 95% CI, 0.02-0.13) vs. placebo (0.07 episodes per child per year; 95% CI, 0.03-0.16). The hydroxyurea-placebo malaria incidence rate ratio was 0.7 (95% CI, 0.2-2.7).

Children receiving hydroxyurea also had lower rates of pain crises and hospitalizations.

Fewer children assigned hydroxyurea experienced a composite of sickle cell anemia-related adverse events that included vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration or blood transfusion (45% vs. 69%; P = .001). Incidence of serious adverse events, sepsis and dose-limiting toxicities was comparable between the arms.

“In this setting, the incidence and severity of malaria was no greater in the hydroxyurea arm, compared to the placebo arm,” Chandy said. “Laboratory and clinical benefits of hydroxyurea were observed, suggesting that hydroxyurea therapy is safe and effective in this low-resource setting.”

Six of the 12 malaria episodes required hospitalization and four episodes had concomitant vaso-occlusive pain crisis (n = 3) or pneumonia (n = 1). Two children in the hydroxyurea arm died, one from presumed sepsis and the other from unknown sudden death. One child in the placebo arm died, presumably of sepsis.


“Because the children prescribed hydroxyurea experienced significantly better outcomes without any increase in malaria risk, we were incredibly encouraged to further explore the drug’s use in sub-Saharan Africa,” Ware said.

Researchers are recruiting additional participants in malaria-prone regions of sub-Saharan Africa to assess how sickle cell anemia-related adverse events and hematological responses compare for children receiving fixed-dose treatment vs. dose-escalation regimens.

“The incidence of malaria in the NOHARM trial was lower than predicted; accordingly, our conclusions of safety for hydroxyurea treatment may not be applicable to regions with higher malaria rates,” Ware said. “Another area for further investigation is the optimal dosing and monitoring scheme for hydroxyurea in sub-Saharan Africa, given the costs of both the drug itself and periodic blood tests in areas with limited resources. Before hydroxyurea can be recommended for wide use across sub-Saharan Africa, partnerships are needed to develop and implement effective, affordable, and sustainable models of treatment delivery.” by Chuck Gormley

Disclosures: Ware reports consultant roles with Global Blood Therapeutics and Nova Laboratories, an advisory role with Agios Pharmaceuticals, research funding from Bristol Myers-Squibb, and a data and safety monitoring board position with the FDA. All other authors report no relevant financial disclosures.