Disclosures Introduction: Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is an open-label multi-country prospective trial of hydroxyurea for children with sickle cell anemia (SCA) in sub-Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). Initial results documented the feasibility, safety, and benefits of hydroxyurea treatment with dose escalation to maximum tolerated dose (MTD), but further hydroxyurea dose optimization data are needed to assess long-term benefits and risks. We now report the REACH experience with up to 8 years of hydroxyurea treatment, describing laboratory responses, clinical outcomes, and dose-related toxicities (DLT). Methods: Children 1-10 years of age with SCA were enrolled. After screening, the hydroxyurea dose was fixed at 15-20 mg/kg/day for 6 months with monthly complete blood counts (CBC) to ensure safety. From Month 6-24, the dose was escalated (5 mg/kg every 8 weeks) to MTD, defined as mild myelosuppression with absolute neutrophil count (ANC) <4.0 x 109/L on 2 consecutive CBC. Beyond Month 24, dosing was optimized for weight gain and increased based on CBC results. With a low DLT rate using the original MTD criteria (ANC <1.0 x 109/L, Hb <4.0 g/dL, reticulocyte count <80 x 109/L unless Hb >7.0 g/dL, or platelets <80 x 109/L), dose optimization criteria were modified toward a target ANC of 3.0 x 109/L. The hydroxyurea dose was increased if ANC >3.0 x 109/L, Hb >5.0 g/dL, reticulocytes >100 x 109/L and platelets >100 x 109/L. Laboratory responses, clinical responses, and DLT rates were compared across the four dosing phases (Screening, Fixed Dose, Dose Escalation, and Dose Optimization). Results: A total of 635 children enrolled in REACH and began screening; 606 initiated hydroxyurea and currently 527 (87%) remain in the trial, with an average treatment duration of 83 months (range 76-105 months) and total of 4,199 patient-years of hydroxyurea treatment. Over 85% achieved MTD initially at an average hydroxyurea dose of 22.5 ± 5.0 mg/kg/day, ranging from 19.0 mg/kg/day in Angola to 25.4 mg/kg/day in Uganda. With dose optimization, doses have increased and the most recent average is 28.1 ± 5.1 mg/kg/day, ranging from 27.1 mg/kg/day in Congo to 28.8 mg/kg/day in Uganda. Across the four dosing phases, key laboratory responses (Hb, HbF, and ANC) have improved over time: the average Hb increased from 7.3 g/dL at baseline to 8.4 g/dL at MTD and is currently 8.7 g/dL; average HbF increased from 11% at baseline to 25% at MTD and is now 27%; and average ANC decreased from 6.8 x 109/L at baseline to 4.2 x 109/L at MTD and is currently 3.6 x 109/L. Comparing event rates per 100 patient-years between Screening to Dose Optimization, vaso-occlusive episodes decreased from 104.5 to 43.9, acute chest syndrome decreased from 9.0 to 2.1, splenic sequestration decreased from 1.8 to 0.7 and stroke decreased from 1.8 to 0.3. Transfusion rates decreased from 48.6 to 11.2, malaria from 46.8 to 19.1, non-malarial infections from 111.7 to 52.9, and death has decreased from 3.6 to 1.0 per 100 pt-years. As a composite, all sickle-related clinical events including vaso-occlusive pain, acute chest syndrome, stroke, and all serious adverse events have decreased as the dose increased (Fig 1). Lab toxicities have been infrequent and transient, with 2/3 identified incidentally during a scheduled visit without illness. Among 25,730 total CBCs obtained in REACH, only 421 (2.6%) in 225 participants had a DLT, and the incidence rate has not increased across dosing phases from Screening (0.22 events per pt-year) through Dose Optimization (0.21 events per pt-year). During COVID, 549 children had labs checked at 6-month intervals without any increase in the DLT rate or clinical events. Many DLT are unrelated to hydroxyurea including thrombocytopenia (33%) with splenomegaly, followed by anemia (26%) with malaria. Severe neutropenia (ANC <0.5 x 109/L) was very rare (5 events) with no neutropenic infections. Conclusions: Hydroxyurea is safe, well-tolerated, and effective for children in REACH. Hydroxyurea escalation to MTD with further dose optimization is associated with improved laboratory and clinical responses, but no increased toxicity. Routine CBC monitoring at 3-month intervals is sufficient and extension to longer intervals may be appropriate. Hydroxyurea dosing at 25-30 mg/kg/day is feasible and safe in sub-Saharan Africa and provides optimal treatment benefits. Aygun: GBT: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Latham:Emmaus Medical: Research Funding. Ware:Addmedica: Research Funding; Emmaus Medical: Research Funding. Figure 1