In children with sickle cell anemia in Africa, the maximum tolerated dose (MTD) of hydroxyurea (HU) is associated with a lower incidence of malaria, according to study results published in Blood. The incidence of malaria was found to decline when the absolute neutrophil count (ANC) was below a certain level.
HU at the MTD is associated with lower malaria incidence in sickle cell anemia “through incompletely defined mechanisms,” according to lead author Peter Olupot-Olupot, MD, PhD, of Mbale Clinical Research Institute in Uganda, and colleagues. “Treatment-associated mild myelosuppression with [ANC] below 3.0 × 109/L is salutary.”
While the incidence of malaria is unaltered in children with sickle cell anemia, the risk of death is higher. However, early diagnosis and treatment can be lifesaving. In the phase I/II prospective study, dubbed REACH, researchers aimed to determine the safety, feasibility, and benefits of HU at the MTD for children with sickle cell anemia living in sub-Saharan Africa. The initial trial results showed a 50% decrease in the incidence of malaria over the first 30 months of treatment, a finding that was most pronounced after achieving the MTD.
This longitudinal analysis of all malaria events in the REACH study to date focused on a variety of baseline demographic, laboratory, clinical, and genetic factors. Between September 2014 and January 2022, malaria infections were recorded at four clinical sites in Angola, the Democratic Republic of Congo, Kenya, and Uganda. A total of 606 children (mean age 5.5 years) were treated with HU at a fixed dose of 17.5 mg/kg/day for six months, followed by dose escalation to the MTD, defined as mild myelosuppression with an ANC of 2.0-4.0 × 109/L. A total of 717 clinical malaria episodes occurred in 336 participants over 3,387 patient-years of HU treatment.
Malaria risk was significantly associated with ANC, splenomegaly, hemoglobin, and achieving the MTD. However, age, malaria season, MTD, fetal hemoglobin, alpha-thalassemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency had no effect.
Further analysis of confirmed infections showed that ANC was significant (hazard ratio [HR] = 1.37 per doubled value, 95% CI 1.10-1.70; p=0.0052) and ANC values of 3.0 × 109/L were associated with lower malaria incidence.
“This observation has relevance for [HU] treatment, since dose escalation to MTD is designed to cause mild myelosuppression with an optimal ANC of 1.0-3.0 × 109/L,” the authors said. “Higher [HU] doses can therefore maximize fetal hemoglobin induction and are associated with lower malaria incidence.”
Spleen status was also an important predictor of malaria risk, with less than 5 cm palpable splenomegaly associated with an increased incidence (HR=2.01, 95% CI 1.41-2.85; p=0.0001), a finding that the authors said was unexplained and not seen with moderate to massive splenomegaly. The authors noted that the use of palpation to assess splenomegaly was a limitation of the study and suggested further studies should use ultrasounds to measure spleen size and volume.
“Now with [more than] 3,300 patient years of [HU] treatment, the incidence of confirmed malaria on [HU] treatment is 11.2 infections per 100 patient-years, documenting a substantial and sustained greater than 50% reduction in the infection incidence rate,” the authors said. They noted that because participants were 5.5 years at the time of enrollment and the decrease in the malaria rate occurred within the first year of treatment, the decline is unlikely a result of increasing age.
“Potential mechanisms of action between [HU] and malaria remain incompletely defined, but treatment effects in children with [sickle cell anemia] related to myelosuppression, reduced inflammation, iron chelation, and antimalarial activity, in addition to general health improvement through higher [hemoglobin] and [fetal hemoglobin] could be important,” the authors concluded.
Any conflicts of interest declared by the authors can be found in the original article.
Olupot-Olupot P, Tomlinson G, Williams TN, et al. Hydroxyurea is associated with lower malaria incidence in children with sickle cell anemia in sub-Saharan Africa [published online ahead of print, 2022 Nov 14]. Blood. doi:10.1182/blood.2022017051.