Hydroxyurea Shows Promise for Hemoglobin SC Disease Despite Safety Concerns
Key Insights
A phase 2 trial (PIVOT) reveals that hydroxyurea reduces painful vaso-occlusive events and hospitalizations in individuals with hemoglobin SC (HbSC) disease.
The trial did not meet its primary endpoint regarding dose-limiting toxicities, but the observed toxicities were generally mild and transient.
Clinical benefits, including fewer vaso-occlusive crises and hospitalizations, suggest hydroxyurea's potential as a disease-modifying treatment for HbSC.
Hydroxyurea demonstrates clinical benefits for individuals with hemoglobin SC (HbSC) disease by reducing painful vaso-occlusive events (VOCs) and hospitalizations, according to a phase 2 trial conducted in Ghana. While the trial did not meet its primary endpoint concerning dose-limiting toxicities (DLTs), the findings suggest that hydroxyurea could serve as a valuable treatment option for this population. The study, known as the Prospective Identification of Variables as Outcomes for Treatment (PIVOT) trial, was presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition.
PIVOT Trial Details
The PIVOT trial was a double-blind, placebo-controlled study conducted in Ghana, where HbSC accounts for approximately 50% of sickle cell disease (search) cases. The trial enrolled 243 participants, including 120 adults and 123 children aged 5 to 50 years, diagnosed with HbSC. Participants were randomized to receive either hydroxyurea at a starting dose of 20 mg/kg daily or a placebo for one year. The primary endpoint was the frequency of dose-limiting toxicities in each treatment group.
Safety Profile and Clinical Benefits
Although the trial did not meet its primary endpoint of comparable dose-limiting toxicities (DLTs) in each treatment arm (32.7% in the hydroxyurea arm vs 10.5% in the placebo arm, P <.001), investigators noted that most cytopenias were transient Grade 2 neutropenia or thrombocytopenia. The hydroxyurea group also experienced increased mean corpuscular volume (+17 fL) and fetal hemoglobin (+7.6%).
Despite the higher incidence of DLTs, the study revealed significant clinical benefits with hydroxyurea treatment. Participants in the hydroxyurea arm experienced significantly fewer VOC painful events (incidence rate ratio, 0.38 [95% CI, 0.28-0.52]; P <.0001) and fewer hospitalizations (IRR, 0.42 [95% CI, 0.22-0.81]; P = .012). There was also a reduction in malaria events, but the difference was not statistically significant (IRR, 0.80 [95% CI, 0.47-1.35]; P <.30).
Expert Commentary
Yvonne Dei-Adomakoh, MBBS, hematologist at the University of Ghana Medical School Korle Bu Teaching Hospital (search) in Accra, Ghana, emphasized the importance of dispelling the myth that HbSC is a mild condition. "There is a general perception that people who have HbSC disease have a mild phenotype, and it is important to dispel this myth among both the public and health care workers," Dei-Adomakoh stated. She added that many individuals with HbSC do not receive long-term care or disease-modifying treatment due to the misconception that they do not have 'real' sickle cell disease (search).
Implications and Future Directions
The findings from the PIVOT trial suggest that hydroxyurea, the current standard of care for HbSS, may also benefit patients with HbSC. Dei-Adomakoh advocated for a multicenter phase 3 trial to specifically assess clinical efficacy. "Since our phase 2 study was focused primarily on safety and dosing, it is now essential to carry out a phase 3 trial to look specifically at clinical efficacy," she said. Given the low cost and availability of hydroxyurea in Ghana, Dei-Adomakoh hopes that a phase 3 trial demonstrating safety and efficacy will encourage countries to include it in their national health insurance plans, making it readily accessible to patients with SCD.