Children living in sub-Saharan Africa with sickle cell anemia (SCA) who receive the maximum tolerated dose (MTD) of hydroxyurea appear to be at a decreased risk of infection with malaria, according to research published in Blood. The underlying mechanisms for this decreased risk are, however, not completely understood, though absolute neutrophil counts (ANCs) appear to be an effective predictor.

The phase 1/2 prospective REACH trial (Realizing Effectiveness Across Continents With Hydroxyurea; Identifier: NCT01966731) was designed to evaluate the safety and efficacy of hydroxyurea among children with SCA living in 1 of 4 clinical sites in Angola, the Democratic Republic of Congo, Kenya, and Uganda. Researchers enrolled 606 participants to receive dose escalation up to MTD; the primary results from REACH indicated higher hemoglobin concentration as well as lower ANCs.

At the study’s outset, there was a concern that the MTD of hydroxyurea would increase the participants’ risk of contracting malaria. Yet across the 4 study sites, malaria risk decreased by approximately 50%, which was a welcome, albeit surprising, finding from REACH. For this longitudinal analysis using data from patients enrolled to REACH, researchers aimed to identify factors that predicted lower malaria risk among children with SCA.

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Overall, of the 606 patients enrolled; 218 patients contracted malaria whereas 388 did not. At baseline, in the malaria vs no malaria group, the mean age was 5.5 vs 5.4 years, 53.7% vs 49.7% of participants were male sex, and spleen status was nonpalpable in 80.8% vs 83.9%, respectively.

Univariate analysis showed that ANC was a significant predictor of ANC, as were splenomegaly, hemoglobin levels, and reaching MTD. Participant age, malaria season, MTD dose, fetal hemoglobin, alpha-thalassemia, and glucose-6-phosphate dehydrogenase deficiency were, however, not predictors.

Multivariable analysis suggested that ANC values of less than 3 109/L conferred a lower chance of contracting malaria. Patients with 1- to 4-cm splenomegaly, however, had a higher risk of contracting malaria compared with nonpalpable spleen (hazard ratio, 2.01; P =.0001).

“Because malaria is documented to cause frequent and severe anemia in children with SCA, understanding the clinically significant association between hydroxyurea and lower malaria incidence represents an important research goal while expanding hydroxyurea treatment across Africa,” the authors wrote in their report.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 


Olupot-Olupot P, Tomlinson G, Williams TN, et al. Hydroxyurea treatment is associated with lower malaria incidence in children with sickle cell anemia in sub-Saharan Africa. Blood. 2023;141(12):1402-1410. doi:10.1182/blood.2022017051