Clinical Pearls & Morning Reports
On a global scale, the incidence of sickle hemoglobinopathies is greatest in sub-Saharan Africa, with more than 300,000 babies with sickle cell disease born annually, representing approximately 1% of births in the region. Tshilolo et al. conducted an international trial, Realizing Effectiveness across Continents with Hydroxyurea (REACH), to investigate the feasibility, safety, and benefits of hydroxyurea treatment for children with sickle cell anemia living in sub-Saharan Africa. Read the latest NEJM original article here.
Q: What are the benefits of hydroxyurea for patients with sickle cell anemia?
A: Hydroxyurea was first shown to induce fetal hemoglobin production more than 30 years ago and is now a Food and Drug Administration–approved treatment for sickle cell anemia in both children and adults. By means of the induction of fetal hemoglobin and other beneficial changes, including mild myelosuppression, hydroxyurea therapy has been shown to have clinical efficacy in reducing the incidence of acute vaso-occlusive events, ameliorating chronic organ damage, and prolonging survival. Evidence-based guidelines from the National Heart, Lung, and Blood Institute recommend offering hydroxyurea treatment to persons with sickle cell anemia as early as 9 months of age.
Q: Why perform a trial to assess hydroxyurea treatment for children with sickle cell anemia living in Africa?
A: Whether hydroxyurea will be safe and effective in Africa is unclear. Coexisting conditions such as malaria, other infectious diseases that are endemic to the area, and malnutrition may increase the incidence of toxic effects and limit treatment responses.
A: With full enrollment, high rates of adherence to trial visits and medication use, and a retention rate of nearly 95% in the trial over a period of 3 years, the REACH trial showed that hydroxyurea treatment was both feasible and safe in sub-Saharan Africa. Hematologic dose-limiting toxic effects during the first 3 months of treatment (the primary safety end point) occurred in only a small number of participants, and the hydroxyurea dose was then safely escalated toward a maximum tolerated dose, similar to treatment protocols in the United States. Expected hematologic benefits occurred, with significant increases in the hemoglobin and fetal hemoglobin levels. Significant reductions were observed in the incidence rates of sickle cell–related clinical events, including vaso-occlusive pain, and major clinical events including infection, transfusion, and death. No serious adverse events or deaths were considered by the investigators to be related to hydroxyurea treatment.
A: The benefits of hydroxyurea therapy with regard to malaria infections were significant — with a rate reduction of more than 50% — and were not predicted before the trial, despite the lack of malaria chemoprophylaxis programs at all the clinical sites. This benefit was especially notable after 12 months of treatment, so it may reflect known inhibitory effects of fetal hemoglobin, more than direct effects by hydroxyurea, on parasite growth. The importance of this effect should be evident for sub-Saharan Africa, where Plasmodium falciparum malaria is a major killer of children and is especially lethal in those with sickle cell anemia. In a finding that perhaps reflects the decrease in the incidence of malaria, there was a significant reduction in the incidence of transfusions, which is important because of the general lack of safe blood supply across Africa.