ALBERT

Description: Introduction. Based on sparse historical data, Tanzania ranks fourth globally for the estimated number of annual births with sickle cell disease. Northwest Tanzania is projected to have an especially high burden of sickle cell disease, but no contemporary surveillance data exist to verify this projection. We designed a large prospective study to determine the prevalence of both sickle cell trait and sickle cell disease in northwest Tanzania. Additional objectives included an analysis of two known genetic modifiers of sickle cell disease [alpha thalassemia trait and glucose-6-phosphate dehydrogenase (G6PD) deficiency], as well as genetic variants affecting fetal hemoglobin (HbF) expression and characterization of hemoglobin variants. Methods. The Tanzania Sickle Surveillance Study (TS3) is a prospective cross-sectional study to determine the prevalence of sickle cell trait and disease in an area projected to be at high risk. Dried blood spots (DBS) from all children born to HIV-infected mothers in the 9 regions across northwest Tanzania were collected by the HIV Early Infant Diagnosis (EID) program and transported to a central laboratory at Bugando Medical Centre, a teaching and consultancy hospital in Mwanza. DBS were tested by isoelectric focusing and scored as normal, trait, disease, or variant. Samples scored as disease or variant were retested for confirmation, and then frozen for subsequent genetic analysis. In the US, genomic DNA was extracted from each DBS, and sickle cell disease status was confirmed by PCR and TaqMan genotyping. All confirmed samples were then analyzed for alpha thalassemia trait (rightward -3.7 gene deletion) using quantitative real time PCR, and for G6PD deficiency using three real time PCR probes to distinguish A and B G6PD isoforms, to identify the G6PD A- variant, and to confirm the sex, respectively. Single nucleotide polymorphisms within 3 quantitative trait loci [BCL11A, the HBS1L-MYB intergenic polymorphism (HMIP) region, and the gamma-globin promoter XmnI site] that modify baseline HbF were analyzed using TaqMan genotyping. DBS with hemoglobin variants were investigated for the presence of common variants found in East Africa. Results. Between February 2017 and May 2018, a total of 232 IEF gels were completed by local staff in Tanzania. Among EID samples from children

Description: Introduction. Hydroxyurea treatment has proven safety, feasibility, and efficacy for children with sickle cell anemia living in sub-Saharan Africa. Even in malaria endemic regions, hydroxyurea is safe and has been shown to reduce vaso-occlusive events and lower mortality. The optimal dosing regimen is not known, however, and specifically whether a fixed dose at 15-20 mg/kg/day is better than escalation to maximum tolerated dose (MTD) at 25-30 mg/kg/day. Particularly in low-resource settings, additional drug-related toxicities and monitoring costs associated with dose escalation could outweigh potential laboratory and clinical benefits. Methods. Children with sickle cell anemia previously enrolled in NOHARM (NCT01976416) received hydroxyurea at ~20 mg/kg/day during the open-label portion of that trial, after which they transitioned to commercial supply at that same daily dose. All were then offered enrollment in the NOHARM MTD trial (NCT03128515), a double-blinded trial with 1:1 randomization between continuing fixed-dose oral hydroxyurea (20 ± 2.5 mg/kg/day) versus dose-escalation to MTD (30 ± 2.5 mg/kg/day), using hydroxyurea tablets donated by Addmedica. The primary study outcome was the proportion of study participants who achieved either hemoglobin ≥9.0 g/dL or fetal hemoglobin ≥20% after 24 months of treatment. Secondary outcomes included sickle-related clinical adverse events, malaria events, and laboratory toxicities. We now present the main results of the NOHARM MTD trial. Results. A total of 187 children enrolled and began study treatment: 94 children (4.8 ± 0.9 years, 55 males) received hydroxyurea at fixed dose versus 93 who received hydroxyurea with dose escalation (4.6 ± 1.0 years, 47 males). At Month 6 of study treatment the average doses were 19.3 ± 1.7 mg/kg/day and 29.0 ± 3.5 mg/kg/day, respectively, and these dose differences were continued through Month 12 and Month 18. The trial was terminated prematurely by the independent Data Safety Monitoring Board after 146 children had reached Month 18, when the clinical complications and interventions were significantly fewer among children randomized to MTD compared to fixed-dose. The incidence rate ratio (IRR) with 95% confidence intervals (CI) included the following: all sickle-related Adverse Events [IRR = 0.43, CI = (0.34, 0.56), P

Description: Hydroxyurea is a potent and safe disease-modifying therapy for sickle cell anemia (SCA), with available data proving laboratory and clinical efficacy for both children and adults. Although the global burden of SCA is greatest within sub-Saharan Africa, almost all studies with hydroxyurea to date have been conducted in the US and Europe. Since additional comorbidities may affect children with SCA in low-resource settings, including malnutrition, malaria, and other infections, prospective research is needed to develop locally appropriate guidelines for hydroxyurea use. To assess the feasibility, safety, and benefits of hydroxyurea for SCA in sub-Saharan Africa, we designed the prospective multi-center REACH trial (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731). Four sites with high scientific and organizational capacity and geographical diversity (Luanda, Angola; Kinshasa, Democratic Republic of Congo; Kilifi, Kenya; and Mbale, Uganda) were selected to treat 600 children aged 1-10 years, using hydroxyurea capsules donated by Bristol-Myers Squibb. Open-label treatment at 15-20 mg/kg/day continued for six months unless hematological toxicity occurred, followed by escalation using weight and pre-defined laboratory criteria to maximum tolerated dose (MTD). Primary study endpoints included feasibility (enrollment, retention, adherence); safety (hematological toxicities, infections, MTD), and benefits (lab parameters, sickle-related clinical events, transfusions, death). We now present the main results of the REACH trial. Between July 2014 and December 2016, a total of 635 children with SCA were enrolled. The median age at enrollment was 5.4 years (IQR 3.4-7.4 years). During a two-month screening period, 29 children withdrew due to ineligibility (11), non-adherence (8), relocation (3), withdrawal of consent (3), or death (4). A total of 606 children initiated hydroxyurea at an average dose of 17.5±1.8 mg/kg/day. Study retention was excellent during treatment, with 5% overall drop-out due to study withdrawal or death. Study adherence was outstanding with 97% completed scheduled visits and 94% collected lab studies. After Month 6, the dose was escalated by 2.5-5.0 mg/kg/day every 8 weeks until mild marrow suppression, typically absolute neutrophil count

Description: Key Points Compared with placebo, hydroxyurea did not increase the incidence or severity of malaria events in Ugandan children with SCA. Hydroxyurea provided significant clinical and laboratory benefits, suggesting it will be safe and effective across sub-Saharan Africa.

Description: Introduction. Children with sickle cell anemia enrolled in Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) received open-label hydroxyurea at maximum tolerated dose (MTD) in four countries within sub-Saharan Africa (Tshilolo et al, NEJM 2019;380:121-131). Unlike children in the United States or Europe, a substantial proportion of REACH participants had splenomegaly at enrollment, and more developed splenomegaly while receiving hydroxyurea. Splenic enlargement in association with hydroxyurea treatment in sub-Saharan Africa is previously unrecognized, and its causes and consequences remain unclear. Methods. Palpable splenomegaly was evaluated at both the mid-clavicular and mid-axillary lines at each scheduled and unscheduled sick visit. The size of the spleen, defined as the greatest distance (cm) below the subcostal margin, was recorded in the REDCap trial database at all four clinical sites. Cross-sectional analysis was performed at baseline enrollment using four spleen categories (Not Palpable, 1-4 cm, ≥5 cm, or Splenectomy) with correlations for age, sex, site, growth parameters, alpha-thalassemia trait and G6PD deficiency. This analysis was repeated using the largest spleen size over the first two years on hydroxyurea, but examining two-year laboratory values and also the hydroxyurea dose at MTD, time to MTD, dose-limiting toxicities, and clinical outcomes including acute splenic sequestration, malaria infections, and sepsis. Results. A total of 606 children started hydroxyurea study treatment, including 6 (1.0%) with previous splenectomy, 59 (9.7%) with previous splenic sequestration, and 99 (16.3%) with palpable splenomegaly at enrollment (52 children with 1-4 cm and 47 with ≥5 cm). Large spleens (≥5 cm) were commonly observed at baseline at all clinical sites except Uganda, which identified only 1 child. Compared to those with no palpable spleen, children with large spleens at baseline had similar age and growth parameters, but were significantly more likely to have alpha-thalassemia (78.7% versus 56.2%, P=0.004) and also G6PD deficiency among males (28.0% versus 17.6%, P=0.32). Children with large spleens at enrollment also had a lower hemoglobin (Hb = 6.5 versus 7.3 g/dL, P

Description: Incident stroke, both primary and recurrent are common in children with sickle cell anemia (SCA) in Jamaica with incidences of 7.8% by 14 years of age and 29/100 person-years respectively. Cerebral vasculopathy manifested by elevated transcranial doppler (TCD) velocity (〉170 cm/sec) is the major risk factor for both with a prevalence of 19.8% among Jamaican children with SCA. Chronic blood transfusion is the standard of care to reduce stroke risk and recurrence in children with SCA in high income countries, but in low-resource settings where blood availability, safety and local acceptance are limited, hydroxyurea (HU) is emerging as a viable alternative. However, the efficacy of HU for incident stroke prevention in children with newly diagnosed severe cerebrovascular disease without the use of transfusions in a low resource setting like Jamaica is unclear. The EXpanding Treatment for Existing Neurological Disease (EXTEND) trial (ClinicalTrials.gov NCT02556099) was designed to investigate the effects of open label HU on TCD velocities after 18 months of treatment, compared to the pre-treatment value. Secondary aims included the effects of HU on the incidence of neurological events including magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) changes, non-neurological events, hematological responses and toxicity. We enrolled 43 children with SCA, 2 to 17 years of age , between Nov 2014 and April 2016, stratified into 3 groups: Low Risk Group (LRG) - On Hydroxyurea with TCD ≥170 cm/sec, N=12; Medium Risk Group (MRG) - HU naive with TCD ≥170 cm/sec, N=21; and High Risk Group (HRG) - Previous Stroke, N=10. All children received HU initially at 20 mg/kg/day followed by two monthly dose escalation using weight and pre-defined laboratory criteria to maximum tolerated dose (MTD) and thereafter 3 monthly visits. The average HU dose at MTD (mean±1SD) was 25.3±0.4 mg/kg. TCD was performed every 6 months according to the Stroke Prevention in Sickle Cell Anemia (STOP) protocol. The average age at enrollment was 7.7±2.6 years, with MRG significantly younger than HRG (6.7±2.0 years vs 9.2±3.7 years; p

Description: Introduction. The burden of sickle cell anemia (SCA) is high across the Caribbean, including the Dominican Republic where the morbidity of SCA is substantial due to limited resources. Approximately 10% of affected children will develop primary stroke, with serious medical and neurocognitive sequelae. In the US, transcranial Doppler (TCD) ultrasonography is an effective screening tool to identify children at risk for primary stroke, which then allows preventive therapy with either hydroxyurea or blood transfusions. To date, however, no routine TCD screening and treatment program for stroke prevention has been established in the Dominican Republic. We designed a prospective screening and treatment study (SACRED, NCT02769845) for prevention of primary stroke in children with SCA using open-label hydroxyurea at maximum tolerated dose (MTD). Methods. Children with SCA between age 3-15 years and receiving medical care at Robert Reid Cabral Children's Hospital in Santo Domingo, Dominican Republic were recruited over a 12-month period. Treatment depended on the baseline TCD examination: children with abnormal time-averaged mean velocities (≥200 cm/sec, high stroke risk) were recommended to receive monthly transfusions for primary stroke prevention, as per standard treatment preferences at the Robert Reid Hospital; those with conditional velocities (170-199 cm/sec, moderate stroke risk) were offered hydroxyurea study treatment unless they were currently receiving chronic transfusions for other clinical indications. Oral open-label hydroxyurea using 500mg capsules was prescribed at fixed-dose (20 mg/kg/day) for 6 months, followed by dose escalation to MTD. TCD examinations were repeated every 6 months, with the main study endpoints being changes in laboratory parameters and TCD velocities after 18 months of study treatment. Results. A total of 283 children were enrolled with the following baseline TCD velocities: 200 (70.7%) normal, 63 (22.3%) conditional, 11 (3.9%) abnormal, and 9 (3.1%) inadequate velocities. Among 50 children eligible for hydroxyurea study treatment, the average age was 6.8 ± 2.8 years and included 27 males/23 females with evidence of substantial SCA-related morbidity (88% with previous transfusions, 60% with 〉5 hospitalizations). A total of 48 children initiated hydroxyurea at 20.2 ± 1.2 mg/kg/day, which was maintained for 6 months followed by dose escalation, reaching MTD at 24.1 ± 6.0 mg/kg/day. Laboratory changes from baseline to Month 18 included significant increases in hemoglobin (7.5 ± 0.9 to 8.9 ± 1.3 g/dL, P

Description: Introduction. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is a prospective multicenter open-label trial that has already demonstrated hydroxyurea treatment at maximum tolerated dose (MTD) is safe, feasible, and offers major benefits for children with sickle cell anemia living in sub-Saharan Africa (Tshilolo et al, NEJM 2019;380:121-131). One unexpected benefit was a significant reduction in the number of malaria infections, including those with Grade 3 severity or above, across four trial sites in varied epidemiological settings. The overall rate of symptomatic malaria infections decreased from 46.9 events per 100 patient-years during screening to 22.9 events per 100 patient-years on treatment, an incidence rate ratio of 0.49 (95% confidence intervals [CI] = 0.37-0.66). This decreased rate of malaria was observed during the first 12 months of treatment, but declined further between Months 12-36, after the children had dose escalation to achieve hydroxyurea MTD at 22.5 mg/kg/day. Potential mechanisms of malaria protection remain unknown at this time, but could relate to both patient characteristics as well as treatment-related laboratory changes in hemoglobin (Hb), mean corpuscular volume (MCV), absolute neutrophil count (ANC), or fetal hemoglobin (HbF). Methods. Malaria infections were recorded in the REACH REDCap electronic database. Using several methods for recurrent events, with time-varying predictors as well as landmark analysis, associations with infections recorded during study treatment were assessed for multiple variables including trial site, high or low malaria season, age, gender, spleen status, hydroxyurea dose, MTD status, latest laboratory values (Hb, MCV, ANC, and HbF, all measured at least 15 days prior to the onset of the infection), as well as genetic modifiers alpha-thalassemia and G6PD deficiency. Univariate relationships were assessed using the Anderson-Gill model, followed by multiple regression to estimate Hazard Ratios (HR) with 95% CI's. Additional analyses were performed using a gap-time model that resets the clock after each infection, as well as using only the first infection in each participant; the subset of 200 acute blood-smear proven malaria infections was also analyzed separately. Results. A total of 635 children were enrolled in REACH and eligible for analysis, of whom 606 started hydroxyurea treatment. There were 333 malaria infections recorded during 1580 patient-years of observation, including 50 during screening and 283 on treatment, of which 200 had documented positive blood smears at the clinical site. Significant associations for malaria risk were identified with higher ANC (HR = 1.06 per 1 x 109 neutrophils/L, CI = 1.02-1.10, P=0.005), higher MCV (HR = 1.01 per fL, CI = 1.00-1.02), and palpable splenomegaly (HR 1-4cm = 1.73, CI = 1.22-2.45, P= 0.002, HR ≥5cm = 1.52, CI = 1.04-2.21, P=0.03). In multiple regression, the latest ANC and MCV, as well as splenomegaly remained significant but higher HbF was also associated with more malaria (HR = 1.02 per %HbF, CI = 1.00-1.03, P=0.03). These trends were consistent when using the landmark, gap-time and first infection analytical approaches. Analysis of only documented blood-smear positive malaria infections again identified higher ANC, MCV, and splenomegaly as risk factors, but found no association with HbF. Achieving MTD was found to confer significant protection against documented malaria infections (HR = 0.62, CI=0.39-1.00, P=0.048). Conclusion. Hydroxyurea treatment in children with sickle cell anemia living in sub-Saharan Africa is associated with a decreased risk of malaria infections, particularly after achieving MTD. The mechanisms by which hydroxyurea protects against malaria are likely multi-factorial, but do not appear to be related to HbF induction, as higher HbF values were not protective and in some analyses were a risk factor. However, a higher ANC was significantly associated with malaria risk in all models and analyses; since hydroxyurea treatment lowers the ANC, dose escalation to MTD may confer protection against malaria infection by reducing inflammation. Spleen status is also crucial and the role of splenomegaly as a risk factor for malaria requires further investigation. Disclosures Ware: Novartis: Other: DSMB; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Addmedica: Other: Research Drug Donation; Bristol Myers Squibb: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Description: Tanzania ranks third in Africa for the estimated number of annual births with sickle cell disease, but these estimates are based on sparse data from small studies reported over the past 50 years. A recently completed surveillance study from Uganda documented substantial variation in the prevalence of sickle cell trait and disease across the country. Tanzania lacks a national newborn screening program, and no contemporary multi-regional screening of infants has been undertaken. We designed and conducted a prospective study to determine the prevalence of sickle cell trait and disease by region and district in northwest Tanzania, where the prevalence of sickle cell is thought to be highest. The study used existing public health infrastructure while building local capacity for accurate diagnosis of sickle cell disease. Secondary objectives included characterization of hemoglobin variants and exploration of associations between sickle cell trait, sickle cell disease, malaria, and HIV. The Tanzania Sickle Surveillance Study (TS3) is a prospective cross-sectional study of HIV-exposed infants born in 9 regions across the Lake Zone of northwest Tanzania. In Tanzania, the HIV early infant diagnosis (EID) program collects dried blood spots (DBS) from all children born to HIV-infected mothers. DBS are transported to a central laboratory for prompt detection of HIV vertical transmission. In northwest Tanzania, the DBS are transported to Bugando Medical Centre, a teaching and consultancy hospital in Mwanza, where they are tested for HIV and then stored on-site, and thus available for further testing. Isoelectric focusing (IEF) equipment was donated to Bugando Medical Centre along with reagents and supplies. Two laboratory staff were trained by a board certified hematologist, and then attended a two day seminar by the IEF manufacturer. One pediatrician completed a 2-month observership at Cincinnati Children's Hospital. All DBS samples were tested by IEF using appropriate controls. Completed gels were scored independently by two Tanzanian staff members as normal, disease, trait, variant, or uninterpretable. DBS samples scored as disease or variant were repeated for confirmation and preserved for later genotyping. Regular Skype calls were convened with US-based collaborators to improve quality and interpretation. HIV test results were obtained from the local EID program. Between February 2017 and May 2018, 232 IEF gels were completed by the local staff. After children 〉24 months of age were excluded to obtain a more accurate newborn prevalence, the median age of children tested was 52 days (IQR 41-93 days), and a total of 17,278 unique DBS samples were scored. The quality of laboratory testing was extremely high with only 20 samples scored as uninterpretable and 54 with missing results, and the primary analysis was performed on the 17,204 remaining samples. The overall prevalence of sickle cell trait and disease in the entire cohort was 20.3% and 1.2%, respectively, with a 0.1% prevalence of hemoglobin variants. This corresponds to an allelic frequency of 0.114 for the sickle gene mutation and demonstrates perfect Hardy-Weinberg equilibrium. No HbC or other common beta-globin variants were identified. Geospatial mapping revealed some variation across regions, with sickle trait ranging from 16.6% to 22.5% and disease ranging from 0.5% to 1.5%. Analysis of individual districts with 〉100 samples revealed wider geographic variability, with sickle trait ranging from 15.2% to 27.8% and disease ranging from 0.0% to 4.3%. Co-morbidity between HIV and sickle cell disease was analyzed to compare it with the effect on mortality previously observed in Uganda. The prevalence of sickle cell disease was the same among HIV-infected and HIV-negative children (1.2%), suggesting no difference in mortality. The prevalence of sickle cell trait and disease among infants born in northwest Tanzania is very high, exceeding 20% trait and 1.2% disease. All regions in the Lake Zone are affected possibly due to lack of immigration to the area and similar environmental exposures. Targeted newborn screening can be started in high prevalence districts, using existing public health infrastructure with minimal start-up cost and training. Future work will evaluate the correlation between historical malaria prevalence and sickle cell prevalence, and identify hemoglobin variants. Disclosures Ware: Addmedica: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Agios: Other: advisory board; Global Blood Therapeutics: Other: advisory board; Biomedomics: Research Funding; Nova Laboratories: Consultancy.

Description: Introduction: Sickle cell anemia (SCA) is highly prevalent in sub-Saharan Africa with 〉300,000 annual births, and substantial morbidity and mortality due to limited resources. The burden of stroke in this population is of particular concern, given the devastating clinical and neurocognitive sequelae of these events. Hydroxyurea, a potent disease modifying therapy for SCA, is safe and feasible for low-resource and malarial endemic countries within sub-Saharan Africa and when used at maximum tolerated dose (MTD), decreases the incidence of acute painful vaso-occlusive events, infections, malaria, transfusions, hospitalizations, and death. Whether hydroxyurea can prevent primary stroke in SCA within Africa has not yet been determined, due in part to lack of stroke screening programs using transcranial Doppler (TCD) ultrasonography. If effective, hydroxyurea would have even more therapeutic benefits for children with SCA, particularly in settings where blood is not available, affordable, or safe. We designed the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) trial to determine the stroke risk among Tanzanian children using TCD screening and to investigate the effects of hydroxyurea to reduce that risk. 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. Figure Disclosures No relevant conflicts of interest to declare.