Realizing Effectiveness across Continents with Hydroxyurea (REACH): A Prospective Multi-National Trial of Hydroxyurea for Sickle Cell Anemia in Sub-Saharan Africa

Abstract

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 <4.0x109/L or absolute reticulocyte count <150x109/L. A total of 515 participants (85%) achieved MTD at an average dose of 22.5±4.9 mg/kg/day (IQR 18.5-26.1, range 11.8-34.0 mg/kg/day); the average time to MTD was 11 months from treatment initiation. The primary safety endpoint was hematological dose limiting toxicities (DLT) in the first 133 children at each site. Only 4.9% of REACH participants had DLT during the first 3 months of treatment, favorable to the predicted 20-30% based on smaller US pediatric studies with fewer patient-years of observation including HUG-KIDS, HUSOFT, and BABY HUG. Overall, hydroxyurea was well-tolerated with no excess lab toxicities, with 0.18 recorded toxicities/year during 111 patient-years of screening and 0.22 toxicities/year during 1438 patient-years of treatment. Lab benefits of hydroxyurea included clinically significant increases in hemoglobin concentration, mean corpuscular volume, and fetal hemoglobin, plus significant decreases in white blood cell count, neutrophils, and reticulocytes. Clinical benefits were also observed, as rates of vaso-occlusive pain, acute chest syndrome, and transfusions all decreased ~50% during the treatment phase. Unexpectedly, the rate and severity of malaria also decreased; malaria declined from 47.8 to 22.3 events per 100 patient-years, while clinically severe malaria (Grade 3 or above) fell from 9.9 to 2.5 events per 100 patient-years during treatment. Effects on all-cause mortality were also pronounced, with 3.6 deaths per 100 patient-years during screening decreasing to 1.1 deaths per 100 patient-years on hydroxyurea.The NHLBI-funded multi-national REACH trial provides the first prospective data on hydroxyurea treatment for children with SCA in sub-Saharan Africa. These results document the feasibility, safety, and benefits of daily oral hydroxyurea in the area of greatest global burden. With evidence that hydroxyurea can reduce sickle-related clinical events, transfusions, malaria, and even death, wider access to hydroxyurea in Africa can be planned to provide treatment where it is most needed. DisclosuresWare:Nova Laboratories: Consultancy; Addmedica: Research Funding; Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Other: advisory board; Global Blood Therapeutics: Other: advisory board.