Ghana stands as a focal point in the global burden of sickle cell disease (SCD), with one of the highest carrier rates and thousands of infants born with the condition each year. For decades, limited access to care, delayed diagnoses, and entrenched stigma have left patients grappling with severe complications.1,2 In a globally significant “PIVOT,” Ghana's Korle Bu Teaching Hospital, Africa’s mecca for sickle cell research established in 1923, took center stage at yesterday’s plenary lineup, which included the presentation of findings from the Prospective Identification of Variables as Outcomes for Treatment (PIVOT) trial. The study shifted focus from hemoglobin SS (HbSS) to hemoglobin SC (HbSC) disease. This double-blind, placebo-controlled, randomized trial evaluates the safety and efficacy of hydroxyurea for individuals with HbSC disease — a largely underserved subset of the SCD population.
HbSC is a significant but under-researched form of SCD, particularly prevalent in sub-Saharan Africa. Although it is often described as less severe than HbSS, individuals with HbSC frequently suffer from acute vaso-occlusive episodes (VOEs), chronic anemia, and complications such as avascular necrosis and retinopathy. Hydroxyurea, a cornerstone of therapy for HbSS, has not been widely studied or approved for HbSC. The PIVOT trial addresses this gap, aiming to evaluate hydroxyurea’s potential as a disease-modifying therapy for HbSC and identify endpoints for future definitive trials.
The PIVOT trial enrolled 243 participants aged 5 to 50 years. After rigorous screening, 214 individuals were randomized, with 107 receiving hydroxyurea (Siklos®) and 105 on placebo. Participants were monitored over 12 months with a 20 mg/kg/day starting dose, adjusted as needed. The study’s primary endpoint was the frequency of dose-limiting toxicities (DLT), while secondary endpoints examined laboratory changes, clinical outcomes, and quality of life. Exploratory assessments included advanced tests of blood viscosity and erythrocyte deformability.
Baseline data highlighted the substantial disease burden faced by participants, with average hemoglobin levels of 11.0 ± 1.2 g/dL and a high prevalence of prior VOEs and hospitalizations. Over the study period, hydroxyurea demonstrated clear clinical and hematological benefits. Participants treated with hydroxyurea experienced significantly fewer painful VOEs (incidence rate ratio [IRR] = 0.38, p<0.0001) and hospitalizations (IRR=0.42, p=0.012) compared to placebo. Laboratory improvements included increased fetal hemoglobin by 7.6% and mean corpuscular volume by 17 fL, alongside modest reductions in absolute neutrophil and reticulocyte counts. Importantly, hydroxyurea’s DLT profile was manageable, with transient grade 2 cytopenias accounting for most adverse events.
One of the most striking outcomes was the significant reduction in a composite endpoint encompassing acute sickle-related complications, which occurred in only 37 hydroxyurea-treated participants compared to 69 in the placebo group (p<0.0001). These results strongly suggest that hydroxyurea can provide meaningful disease modification for HbSC, challenging the long-held perception that the condition requires less aggressive management than HbSS.
The PIVOT trial underscores hydroxyurea’s potential benefit for HbSC and establishes a framework for future research. By demonstrating that standard clinical endpoints such as VOEs are suitable for evaluating treatment efficacy, this study sets the stage for more extensive, multicenter phase III trials. Including exploratory measures like blood viscosity and erythrocyte deformability offers additional insights into the pathophysiology of HbSC and may inform novel therapeutic strategies.
The work of lead abstract author Yvonne Dei-Adomakoh, MBBS, and her international team is a testament to the growing recognition of the need for equitable research in global health. With its focus on an African cohort, the PIVOT trial highlights the importance of addressing regional and global disparities in health care and research. The findings can potentially transform the management of HbSC disease, providing a new standard of care for a historically underserved population.
With this evidence establishing hydroxyurea as an effective treatment, the hematology community can now make a confident PIVOT towards hydroxyurea for HbSC. The significance of this trial's importance isn't just its potential to spark discussions within the ASH conference halls but its capacity to transform care for patients with a debilitating understudied disease on a global scale.
- Minniti C, Brugnara C, Steinberg MH. HbSC disease: a time for progress. Am J Hematol. 2022;97(11):1390-1393.
- Asare EV, Wilson I, Benneh-Akwasi Kuma AA, et al. Burden of sickle cell disease in Ghana: the Korle-Bu experience. Adv Hematol. 2018;2018(1):6161270.
