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2619 Optimizing Hydroxyurea Therapy with Reduced Laboratory Monitoring for Children with Sickle Cell Anemia in Sub-Saharan Africa: The Reach Experience

Program: Oral and Poster Abstracts
Session: 114. Hemoglobinopathies, Excluding Thalassemia—Clinical: Poster III
Hematology Disease Topics & Pathways:
sickle cell disease, Biological, Diseases, Non-Biological, Therapies, Pediatric, Hemoglobinopathies, Study Population, Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Banu Aygun, MD1,2, George A. Tomlinson, PhD, BSc, MSc3*, Patrick T. McGann, MD4,5, Leon Tshilolo, MD PhD6*, Thomas N. Williams, MD PhD7*, Peter Olupot-Olupot, MD PhD8*, Brigida Santos, MD9*, Susan E. Stuber, MA10*, Adam Lane, PhD11*, Teresa Latham, MA10* and Russell E. Ware, MD, PhD5,12

1Pediatric Hematology Oncology and Stem Cell Transplantation, Cohen Children's Medical Center, New Hyde Park, NY
2Cohen Children's Medical Center of New York, New Hyde Park, NY
3Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
4Cincinnati Children's Hospital Medical Center, Division of Hematology, Cincinnati, OH
5Global Health Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
6Centre Hospitalier Monkole, Kinshasa, Congo (The Democratic Republic of the)
7KEMRI-Wellcome Trust Programme, Kilifi, Kenya
8Mbale Clinical Research Institute, Mbale, Uganda
9Hospital Pediatrico David Bernardino, Luanda, Angola
10Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
11Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
12Cincinnati Children's Hospital Medical Center, Children's Hospital Medical Center, Cincinnati, OH

Introduction: Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is an open-label study of hydroxyurea for children with sickle cell anemia (SCA) in sub-Saharan Africa (Angola, DR Congo, Kenya, and Uganda). Initial results documented the feasibility, safety, and benefits of hydroxyurea for SCA in sub-Saharan Africa but guidance for optimizing hydroxyurea therapy is needed. We describe 5 years of hydroxyurea dosing and monitoring in the largest prospective cohort of children with SCA receiving hydroxyurea to date.

Methods: Children 1-10 years of age with SCA were enrolled. The hydroxyurea dose was fixed at 15-20 mg/kg/day for the first 6 months with monthly complete blood counts (CBCs) to ensure safety. From month 6-24, the dose was escalated (5 mg/kg every 8 weeks) to maximum tolerated dose (MTD), defined as mild myelosuppression with absolute neutrophil count (ANC) <4.0 x 109/L on 2 consecutive CBCs without hematological toxicities. CBCs were performed monthly until MTD or a stable dose was achieved, then subsequently every 3 months. Dose limiting toxicities (DLT) requiring a temporary treatment hold were defined as 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. Known genetic modifiers of SCA, including G6PD deficiency and α-thalassemia trait, were determined for all participants.

Results: A total of 606 children initiated hydroxyurea and currently 555 (92%) remain on treatment, with average treatment duration of 48 ± 12 months and a total of 2,441 patient-years of hydroxyurea treatment. Over 85% achieved MTD with 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 increases over time, the most recent average dose is 23.9 ± 5.4 mg/kg/day (site range 22.9-24.6 mg/kg/day). Lab benefits have been sustained; Hb increased from 7.3 g/dL at baseline to 8.4 g/dL at MTD and remains 8.3 g/dL at Month 60. Similarly, the average HbF increased from 11% baseline to 25% at MTD and remains 23% at Month 60. The average ANC decreased from 6.8 x 109/L at baseline to 3.2 x 109/L at MTD and remains 3.5 x 109/L at Month 60. Lab toxicities are infrequent, transient, and mostly incidental. Of 19,730 CBCs obtained during the treatment phase, 421 (2.1%) in 225 participants included a DLT. The most common DLT was thrombocytopenia (33%), with only 4 platelet counts <20 x 109/L and no bleeding. Anemia was the second most common DLT (26%), most commonly associated with a high reticulocyte count and malarial infection, unrelated to hydroxyurea. Severe neutropenia (ANC <0.5 x 109/L) was rare (5 events) with no neutropenic infections. Over 2/3 of DLT events were identified incidentally during a scheduled visit when the study participant was asymptomatic, including all 5 severe neutropenic episodes. Weight-for-age and height-for-age Z-scores were not associated with higher rates of DLT during hydroxyurea treatment. Children with two-gene deletional α-thalassemia trait tolerated significantly lower hydroxyurea doses than the normal genotype (MTD dose 20.0 vs. 24.0 mg/kg/day, p <0.001) and had significantly different treatment responses at Month 60 including lower HbF (19.5 vs 24.3%, p <0.0001) and MCV (72 vs 99 fL, p<0.001) but higher hemoglobin (8.5 vs 8.1 g/dL, p=0.016). DLT frequency was unaffected by α-thalassemia status. Males with G6PD A- deficiency did not demonstrate significant differences in dosing, response, or toxicity.

Conclusions: Hydroxyurea is safe, well-tolerated, and effective for children with SCA living in sub-Saharan Africa. Treatment responses are robust and sustained in REACH across all 4 clinical sites and unaffected by baseline Z-score. Hydroxyurea optimization requires periodic dose escalation for weight gain and titration to mild myelosuppression. Deletional α-thalassemia trait significantly influences the hydroxyurea dose and treatment responses, but the lab benefits with optimized dosing are still robust regardless of the α-globin genotype. Lab toxicities from hydroxyurea are uncommon and typically asymptomatic, suggesting that routine CBC monitoring is needed only at 3-month intervals once a stable dose is achieved, more to optimize the dose than to identify incidental toxicities. This approach to optimizing hydroxyurea therapy will allow more widespread utilization in low-resource settings with limited laboratory monitoring.

Disclosures: Aygun: National Heart, Lung, and Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; Patient-Centered Outsomes Research Institute: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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