Session: 114. Hemoglobinopathies, Excluding Thalassemia—Clinical: Poster III
Hematology Disease Topics & Pathways:
sickle cell disease, Diseases, Non-Biological, Therapies, Pediatric, Hemoglobinopathies, Study Population, Clinically relevant, imaging
Methods: The SPHERE trial (NCT03948867) is a single center prospective phase 2 open-label screening and treatment pilot study at Bugando Medical Centre, a teaching and referral hospital in Mwanza, Tanzania. Children 2-16 years old with SCA consented to TCD screening by locally trained and certified examiners; recent febrile illness, red cell transfusion, or hospitalization were temporary exclusions. Study participants with maximum Time-Averaged Mean Velocity (TAMV) on TCD exam categorized as conditional (170-199 cm/sec) or abnormal (≥200 cm/sec) are offered hydroxyurea with escalation to MTD, while those with normal TCD screening exams will be rescreened annually. Hydroxyurea is initiated at ~20 mg/kg/day using 500 mg capsules and a weekly dosing calculator, then escalated every 8 weeks by 5 mg/kg/day up to 35 mg/kg/day. Children on hydroxyurea are seen monthly during dose escalation and every 3 months after reaching MTD. The primary endpoint is change in TCD velocity after 12 months of hydroxyurea therapy. Secondary endpoints include changes in splenic volume and filtrative function; change in renal function; incidence of infection, especially malaria; hydroxyurea pharmacokinetics; and genetic modifiers of disease including pharmacogenomics.
Results: From April 2019 to April 2020, a total of 202 children underwent TCD screening, exceeding the projected enrollment pace and goal (Figure). The average age (mean ± SD) at enrollment was 6.8 ± 3.5 years, and 53% were female. A majority had previous dactylitis (75%), painful vaso-occlusive episode (93%), blood transfusion (68%), and malaria (89%). Recurrent hospitalization was common with 30% having >5 previous hospitalizations. Only 4% had previously used hydroxyurea. Baseline labs included hemoglobin = 7.8 ± 1.3 g/dL, HbF = 9.3 ± 5.4 %, and ANC = 5.5 ± 2.4 x 109/L. Baseline assessment revealed a palpable spleen in 46 children (23%), and most of these (29) were ≥5 cm below the costal margin. Abdominal ultrasonography documented splenic tissue in 91% of children with an average volume of 101 ± 123 mL (range 8-1045). TCD examinations were performed in all children at enrollment with average TAMV of 148 ± 27 cm/sec [median 144, IQR 130-169 cm/sec] with 76% normal, 21% conditional, 2% abnormal, and 1% inadequate exams. Of 47 children eligible for hydroxyurea for elevated TCD velocities, 45 successfully initiated treatment, while 1 lived too far away for regular visits, and 1 had low blood counts from acute splenic sequestration and died before initiating study treatment.
Conclusion: Children with SCA in Tanzania have a high risk for primary stroke. Identification of elevated TCD velocities through screening by local trained certified examiners, coupled with initiation of hydroxyurea treatment with dose escalation to MTD, offers a feasible and affordable means by which to lower TCD velocities and reduce primary stroke risk. Now fully enrolled, SPHERE has built local clinical capacity, research infrastructure and high-quality TCD screening, and will prospectively determine the benefits of hydroxyurea for stroke prevention, as a prelude for expanding hydroxyurea access for children with SCA in Tanzania.
Disclosures: No relevant conflicts of interest to declare.
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