Sickle cell disease (SCD) affects approximately eight million individuals globally, with its highest prevalence observed in sub-Saharan Africa, affecting around 5.5 million people. The overall prevalence of SCD stands at 382 cases per 100,000 live births, whereas in the United States, it affects approximately one in 100,000 individuals, primarily among the African American and Hispanic populations.
SCD is linked to significant morbidity and mortality, characterized by complications such as vaso-occlusive pain crises, acute chest syndrome, heart failure, avascular necrosis, and stroke — all of which significantly affect patients' quality of life (QoL).
Recent advancements in drug development for SCD have notably improved overall QoL while reducing morbidity and mortality rates, particularly in countries with access to standard-of-care treatments, like the United States. However, these benefits might not extend universally, especially in developing nations, where access to advanced treatments is limited.
Despite the substantial disease burden in these regions, there remains a dearth of information regarding the efficacy, safety, and accessibility of commonly used drugs in the United States. Furthermore, major clinical trials often suffer from limited or negligible participation from these regions, raising questions about the generalizability and effectiveness of these interventions in all areas of the world.
The Plenary Scientific Session at #ASH23 featured a presentation by Banu Aygun, MD, who provided an eight-year update from the REACH trial, which has answered several important questions about treating children with SCD living in sub-Saharan Africa with hydroxyurea. We had the chance to talk with Dr. Aygun’s team, namely Russell E. Ware, MD, PhD, senior author on the abstract. Insights gained from the trial, which featured four clinical sites (Angola, Democratic Republic of Congo, Uganda, and Kenya), include the optimal dose, feasibility, and safety of treatment — especially in those with concurrent conditions like malaria, endemic infectious diseases, and malnutrition, which could potentially increase the risk of adverse effects and limit drug effectiveness. The original REACH study demonstrated early safety, feasibility, and benefits, supporting broader access to hydroxyurea.1
The trial initially enrolled 635 children with SCD, and currently, a staggering 87% of these children remain under treatment after eight years. These rates are several-fold higher than those achieved in the United States. “The incredibly high retention and adherence rates in REACH speak to the remarkable effects of hydroxyurea as a disease-modifying treatment,” affirmed Dr. Ware. Beyond sustained treatment adherence, the ability to further optimize dosage has been highly effective. “With dose optimization, the average daily dose is now 25-30 mg/kg/day, which is very similar to US-based studies,” he said. Dosage adjustment correlated with notable improvements in important laboratory parameters. In addition to these improvements, when comparing event rates per 100 patient-years from the screening to dose-optimization phases, the authors observed notable reductions in vaso-occlusive episodes, acute chest syndrome, splenic sequestration, and stroke. Additionally, transfusion rates, malaria and non-malarial infections decreased as well as overall mortality, which declined from 3.6 to 1.0 per 100 patient-years.
In an aggregate view, the occurrence of all sickle-related clinical events decreased as the dosage of treatment increased. “Comparing MTD [maximum tolerated dose] to fixed-dose hydroxyurea, higher doses confer significantly better clinical outcomes,” Dr. Ware said. Remarkably, hydroxyurea showcased not only efficacy but also good tolerability, with 2.6% of children experiencing dose-limiting toxicities, maintaining consistent rates across various phases of dose optimization. “Extended hydroxyurea treatment is both safe and effective in these low-resource African settings,” he concluded.
The REACH trial sure did just that, “reaching” some promising milestones. When asked about the success of this study, Dr. Ware said, “REACH has worked extremely well because we found exceptional in-country partners who led each clinical site and assembled great local teams.” He emphasized how “multi-site studies require teamwork and a common goal, with frequent communication, training, and support.” He added that “high-quality research can be conducted in low-resource settings but requires careful planning and must be conducted in full partnership with high ethical standards, ideally with long-term commitment to the treated patients.”
This success story also highlights pressing needs: universal newborn screening programs need to have a global presence. Access and uptake of therapy heavily rely on timely diagnosis so that the right treatments reach the right patients at the right time. The focus is not just on developing new drugs to increase survival rates; it's crucial to invest in scientific research and delivery in all regions. Ultimately, reaching these global health equity goals requires everyone’s commitment, and Dr. Ware certainly acknowledged the ASH-led CONSA project for ramping up newborn screening. “The implications of REACH are that every child with sickle cell anemia (HbSS) in Africa should be offered hydroxyurea,” he said.
Reference
1 Tshilolo L, Tomlinson G, Williams T, et al. Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa. NEJM. 2019;380:121-131.
Drs. Rafae and Al Hadidi indicated no relevant conflicts of interest.
