Maximum Hydroxurea Dose, Annual Screening Could Reduce Sickle Cell Anemia Strokes in Children

Emmanuela E. Ambrose, MD

Screening for stroke via transcranial doppler (TCD) and pursuing maximum tolerated dose (MTD) regimens of hydroxyurea may provide maximized prevention of stroke among children with sickle cell anemia in key populations.

New data presented at the American Society of Hematology (ASH) 2022 Annual Meeting in New Orleans this week showed the multifactorial benefit of the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) trial—a program designed by US and Africa investigators to seek and assess efficacy in stroke risk prevention among children in Tanzania with sickle cell anemia via TCD screening and MTD-regimen hydroxyurea.

The trial, led by Emmanuela E. Ambrose, MD, of the Bugando Medical Center and Catholic University of Health & Allied Sciences, indicate the benefit of timely and informed screening plus absolute utility of the potent, disease-modifying therapy.

Investigators noted that sickle cell anemia, despite being most prevalent in sub-Saharan Africa, is met with limited resources designed to treat both acute and chronic complications associated with the blood disorder.

“Sickle cell anemia-related pediatric strokes are especially devastating, and lack of a reliable, affordable, and safe blood supply prohibit implementation of chronic transfusions,” they wrote. “TCD ultrasound for primary stroke risk assessment coupled with hydroxyurea, escalated to MTD, to decrease stroke risk could be transformative for children with sickle cell anemia in Africa.”

Ambrose and colleagues conducted a prospective phase 2 open-label assessment at the Bugando Medical Centre in Mwanza. The team provided hands-on TCD training to local caregivers. Children with sickle cell anemia aged 2 – 16 years old were enrolled; exclusion criteria included prior stroke, red cell transfusion, and hospitalizations.

Investigators offered hydroxyurea with escalation to MTD to patients with maximum Time-Averaged Mean Velocity (TAMV) scores defined as conditional or abnormal per TCD exams. Patients with normal TAMV scores were rescreened annually. MTD hydroxyurea regimens were initiated at 20 mg/kg/day with 500 mg capsules, then escalated by 5 mg/kg/day every 8 weeks until the maximum of 35 mg/kg/day was reached.

The team sought a primary end point of change in TCD-based velocity after a 12-month hydroxyurea regimen.

The trial included 196 children with sickle cell anemia screened from April 2019 – April 2020. Mean age at enrollment was 6.8 years old; 53% of patients were female, and a majority of children had documented clinical severity including painful vaso-occlusive episodes (93%), malaria (88%), transfusion (68%) and hospitalization (91%).

Mean patient hemoglobin was 7.8 g/dL, hemoglobin F (HbF) was 9.3, and ANC was 5.5 x 109/L. Three-fourths (75%) of patients reported normal TCD exam scores; 24% were elevated and 1% were inadequate exams. Mean TAMV was 138 cm/sec for the 147 children with normal scores, and 182 cm/sec for the 47 children with elevated scores.

Investigators initiated hydroxyurea with 45 patients; 1 withdrew after initiation due to nonadherence. Over 12 months, investigators observed hemoglobin increases to 9.2 g/dL, HbF to 24.1%, and ANC decline to 3.6 x 109/L. In 42 children to provide 12-month TCD scores, mean velocity was 149 cm/sec, with an average decline of 35 cm/sec over that time. Stroke categories were markedly improved; patients moved from 43 condition and 2 abnormal scores at baseline to 35 normal, 6 condition and 1 abnormal at 12 months. No clinical strokes were observed in patients.

Ambrose and colleagues concluded that SPHERE successfully documented 4 key outcomes:

• Building local capacity with clinical training, research infrastructure resources and high-quality TCD execution is feasible in sickle cell anemia-prevalent regions like Tanzania
• Children in Tanzania with sickle cell anemia are at a pronounced baseline risk of stroke
• Hydroxurea escalated from moderate dose to MTD significantly lowers TCD velocities
• Hydroxyurea at MTD reduced primary stroke risk

“As hydroxyurea access expands to more children with sickle cell anemia in Tanzania, the SPHERE results indicate that TCD screening and hydroxyurea treatment at MTD can maximize stroke prevention strategies,” investigators wrote.

The study, “Hydroxyurea with Dose-Escalation to Reduce Primary Stroke Risk in Children with Sickle Cell Anemia in Tanzania: Primary Results of the Sphere Trial,” was presented at ASH 2022.