Hydroxyurea Shows Clinical Benefit in HbSC, Misses the Mark on Safety

Yvonne Dei-Adomakoh, MBBS

Credit: University of Ghana

Hydroxyurea had a manageable safety profile and reduced painful vaso-occlusive events (VOCs) and hospitalizations in people with hemoglobin sickle cell (HbSC) disease. Although a phase 2 trial did not meet its primary endpoint of dose-limiting toxicities, a phase 3 trial may further reinforce its clinical benefit in this population.¹

“Hydroxyurea was well tolerated by most patients with HbSC, with hematologic dose-limiting toxicities that were typically mild and transient. We also observed laboratory and clinical benefits, including fewer VOCs and hospitalizations,” lead investigator Yvonne Dei-Adomakoh, MBBS, hematologist at the University of Ghana Medical School Korle Bu Teaching Hospital in Accra, Ghana, said in a statement.² “Since our phase II study was focused primarily on safety and dosing, it is now essential to carry out a phase III trial to look specifically at clinical efficacy.”

The Prospective Identification of Variables as Outcomes for Treatment (PIVOT) Phase 2, double-blind, placebo-controlled trial was conducted in Ghana. Dei-Adomakoh presented its findings at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California.

The trial did not meet its primary endpoint of comparable dose-limiting toxicities (DLTs) in each treatment arm, although the investigators stated that the trial provides important information about the morbidity of HbSC disease and hydroxyurea’s potential disease-modifying potential for this population.1

Dei-Adomakoh and colleagues found that more participants assigned to the hydroxyurea treatment arm had DLTs than the placebo arm (32.7% vs 10.5%, P <.001) but almost all cytopenias were transient Grade 2 neutropenia or thrombocytopenia. Twelve participants in the hydroxyurea group experienced 20 DLT events of elevated hemoglobin compared to 11 events in 10 participants in the placebo group. The hydroxyurea group also had increased mean corpuscular volume (+17 fL) and fetal hemoglobin (+7.6%), plus modest decreases in absolute neutrophil count (-1.1 x 109/L) and absolute reticulocyte count (-30 x 109/L), but no significant change in hemoglobin (-0.1 g/dL).¹

“There is a general perception that people who have HbSC disease have a mild phenotype, and it important to dispel this myth among both the public and health care workers,” Dei-Adomakoh said.² “Many people with HbSC disease are not receiving long-term care or disease-modifying treatment for their condition as they are felt not to have the ‘real’ SCD. Hydroxyurea is the current standard of care for people with HbSS, and we thought that it’s possible that patients with HbSC may also benefit from hydroxyurea, but there have been very few prospective studies so far.”

The investigators did find clinical benefits with hydroxyurea, including 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). The hydroxyurea group also had fewer malaria events, but the difference was not significant (IRR, 0.80 [95% CI, 0.47-1.35]; P <.30). Both children and adults had decreased VOC rates. A protocol-specified composite endpoint of any acute sickle-related complication occurred in 37 participants in the hydroxyurea arm and 69 in the placebo arm (χ2 = 20.4, P <.0001).¹

“Hydroxyurea comes at a low cost; in Ghana it’s on our national health insurance,” Dei-Adomakoh added.² “If we see safety and efficacy in a multicenter phase III trial, I think that countries should push for it to be on their national health insurance and be readily available at very low cost to patients with SCD.”

REFERENCES

1. Dei-Adomakoh Y, Segbefia CI, Latham TS, et al. Double-Blind, Placebo-Controlled Randomized Controlled Trial of Hydroxyurea for HbSC: Results of the Prospective Identification of Variables As Outcomes for Treatment (PIVOT) Trial. Presented at: ASH Annual meeting; December 7-10; San Diego, California. Abstract 3.

2. Researchers Report New Opportunities to Improve Quality of Life for People with Non-Malignant Blood Disorders. Press release. ASH. December 7, 2024.