https://orcid.org/0009-0000-5447-252X
Key Points
Neurocognitive gains from hydroxyurea therapy were found among Ugandan children with sickle cell anemia at month 18 versus enrollment.
Strongest predictor of improvement was baseline score, reinforcing importance of early initiation of treatment to reduce risk of decline.
Children with sickle cell anemia (SCA) frequently develop progressive neurocognitive impairment. We aimed to determine effects of hydroxyurea therapy on neurocognitive function in Ugandan children with SCA by comparing levels at enrollment to a planned 18-month interim assessment. Ugandan children (N=264) ages 3-9 years were enrolled from a SCA clinic and treated in a 30-month single-arm open-label trial with escalation to maximum tolerated dose (MTD). Primary outcome was the effects of hydroxyurea on cognition, attention and executive function, along with transcranial doppler ultrasound (TCD) blood flow velocity. Sibling controls (N=110) without SCA underwent neurocognitive testing in parallel to establish age-normalized z-scores for comparison. Participant enrollment mean age was 5.6±1.2 years, with comparable socio-economic status (SES) and caregiver education versus controls. At enrollment, SCA participants had lower mean cognitive z-scores than controls; 8.7% had cognitive impairment versus 1.6% controls. Month 18 mean dose 25.4mg/kg, with participants significantly improved z-scores versus baseline in all three domains: cognition: -0.54±1.10 vs. -0.07±1.16, p<0.001; attention: -0.07±1.01 vs. 0.27±0.84, p<0.001; and executive function: -0.06±0.62 vs. 0.08 ±0.72, p=0.010. No measure differed from controls. Proportion with SCA and cognitive impairment declined to 4.0%, with decreased mean TCD velocity. Higher neurocognitive treatment z-scores were primarily associated with higher baseline, also with better SES, hydroxyurea-induced TCD and hematological effects. Despite improvement, unadjusted cognitive scores remained negatively associated with age. Hydroxyurea therapy improved SCA neurocognitive function in sub-Saharan children, potentially aided by practice effects. Early treatment is needed for optimal effect. Our ongoing trial will assess impact from longer-term therapy. This trial was registered at www.clinicaltrials.gov as NCT04750707.
