Sickle-cell anaemia—keeping alive Wethers' legacy

Abstract

The beginning of 2019 witnessed mixed news for the sickle-cell anaemia community. On Jan 10, the results on the first trial of hydroxyurea—the recognised standard of care for patients with sickle-cell disease based on evidence from high-income countries—done in Sub-Saharan Africa were published. Realising Effectiveness Across Continents with Hydroxyurea (REACH), a phase 1–2, open-label, international trial, showed the safety, activity, and feasibility of treating young children with sickle-cell disease with hydroxyurea in this endemic region where the condition is worsened by coexisting malaria and malnutrition. This positive outcome was followed by the death, on Jan 28, of Dr Doris L Wethers, an American paediatrician renowned for her research and advocacy leading to mandatory sickle-cell anaemia testing of all newborns, a measure that helped to greatly increase the life expectancy of patients with sickle-cell disease worldwide. Over the course of Wethers' life, the average life expectancy of children born with sickle-cell anaemia rose from about 18 years to 50 years in the USA. Today, recent advances in gene therapy promise to eradicate this debilitating haematological condition affecting approximately 300 000 babies per year globally. On Dec 3, 2018, preliminary data on gene addition therapy to reverse disease symptoms was presented at the American Society of Hematology's (ASH) annual meeting. Two patients with sickle-cell disease, part of a pilot trial at the Cincinnati Children's Hospital Medical Center (Cincinnati, OH, USA), reported a substantial improvement in their quality of life due to a reduction in disease symptoms, including reductions in chronic pain, sickling events, and anaemia after receiving RVT-1801, an investigational gene therapy for sickle-cell disease and β-thalassaemia, which delivers a modified copy of the fetal haemoglobin gene with anti-sickling properties. This leading-edge therapy could rapidly improve the lives of patients with sickle-cell disease, however, will it reach where it is most needed? Sickle-cell disease is most prevalent in sub-Saharan Africa, where heterozygosity for the sickle-cell mutation provides patients with disease protection against severe malaria, too few large-scale newborn screening programmes have been launched, and, as previously emphasised in this journal, malnutrition remains an important challenge. Currently, the absence of a basic health-care infrastructure in these sub-Saharan regions makes delivering chronic blood transfusions and bone marrow transplants for these patients extremely difficult. Thus, the possibility of treating sickle-cell disease in Africa with promising, but also costly and difficult to deliver, gene therapy in the near future seems improbable. Given the health status and comorbidities unique to patients with sickle-cell disease in low-income and middle-income countries, we cannot assume that interventions developed in high-income countries will be safe and efficacious, or even deliverable, in these settings. Therefore, the results of REACH showing the benefits of hydroxyurea in young children with sickle-cell disease and relative malnutrition, recruited from areas with a high incidence of malaria—Angola, DR Congo, Kenya, and Uganda—not only provides reassuring evidence to safely treat young patients in this endemic area, but also highlights the importance of international collaborations to improve the lives of patients with sickle-cell disease. The treatment protocol implemented in REACH confirms that early interventions for young children with sickle-cell disease exacerbated by malaria and malnutrition can immediately improve quality of life and reduce all-cause mortality. Evidence has also shown that in Sub-Saharan Africa regions where programmes for newborn screening—those that Wethers advocated for during her lifetime—had been introduced, mortality was drastically reduced. To keep Wethers' legacy alive and achieve the ambitious goal of further reducing mortality from sickle haemoglobinopathies, global partnerships of health professionals working in sickle-cell referral centres should focus on equity in access to care by expanding screening programmes and access to WHO-listed essential medicines in low-income and middle-income countries. Several commendable international efforts, such as the Global Sickle Cell Disease Network, and the ASH Research Collaborative (ASH RC) Sickle-Cell Disease Clinical Trials Network being launched this year, have a mission of improving outcomes for patients with sickle-cell disease, particularly for those patients in resource-constraint settings. In this context, REACH should serve as an exemplar to encourage future trials in patients with sickle-cell disease to be done where they are most needed. Sickle-cell anaemia needs more food?Sickle-cell disease results from a genetic substitution that increases the tendency of haemoglobin to polymerise and deform red blood cells, leading to the characteristic sickle shape. Repeated cycles of sickling and unsickling of the erythrocyte increases their fragility, leading to an increased tendency for haemolysis and, thus, to haemolytic anaemia, resulting in a rapid turnover of red blood cells. The lifespan of red blood cells in patients with sickle-cell anaemia is 8–25 days, as opposed to 100–120 days in individuals without sickle-cell disease. Full-Text PDF Open Access