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SAN DIEGO -- Treatment with hydroxyurea led to more hematologic dose-limiting toxicities (DLTs) compared with placebo in patients with hemoglobin SC, a milder form of sickle cell disease (SCD), a Ghanaian randomized phase II trial showed.

Hematologic DLTs -- mostly mild and transient -- occurred in 33% of patients taking hydroxyurea compared with 11% of patients taking placebo -- a difference of 22 percentage points (95% CI 11-34), which exceeded the predefined 15-percentage point noninferiority margin, reported Yvonne Dei-Adomakoh, MBBS, of the University of Ghana Medical School in Accra, at the American Society of Hematology annual meeting and in .

However, hydroxyurea was associated with fewer vaso-occlusive pain events (57.0 vs 149.6 events per 100 person-years; incidence rate ratio [IRR] 0.38, 95% CI 0.28-0.52), and fewer hospitalizations (12.9 vs 30.6 per 100 person-years; IRR 0.42, 95% CI 0.22-0.81).

In addition, a composite of all sickle-related clinical complications occurred in 37 participants on hydroxyurea versus 69 participants on placebo (IRR 0.39, 95% CI 0.26-0.59), a difference observed in both children and adults.

"We think hydroxyurea may provide effective disease-modifying therapy for hemoglobin SC patients," said Dei-Adomakoh. "We need to do a definitive phase III trial to confirm our findings."

"In hemoglobin SC, the erythrocytes are smaller and denser, causing mild hemolytic anemia," she explained. "However, the cells can sickle, and so many clinical manifestations are the same as hemoglobin SS. To date, there is no effective disease-modifying treatment available for hemoglobin SC patients."

Hemoglobin SC is the second most common sickle cell disease genotype, behind hemoglobin SS in prevalence and severity, and is particularly prevalent in West Africa due to the origin of the HbC mutation that provides protection against malaria.

In Ghana, screening identifies hemoglobin SC in about 50% of affected newborns, while in the U.S., over 30,000 children and adults have hemoglobin SC, representing 30% of the total population with sickle cell disease.

While hemoglobin SC is often characterized as a mild disease, Venee Tubman, MD, of Texas Children's Hospital in Houston, noted that several reports have described it as a disease that -- while not as equal in severity to hemoglobin SS -- "certainly is not mild for patients who are affected."

For example, a reported a high incidence of avascular necrosis, priapism, renal disease, retinopathy, and chronic pain in patients with hemoglobin SC.

"For many patients with hemoglobin SS, hydroxyurea is the mainstay of therapy for many of these complications, but that is not so for SC disease," Tubman said, adding that the benefit/risk is less clear for patients with hemoglobin SC.

"The risk-to-benefit ratio for hydroxyurea for persons with hemoglobin SS disease has been demonstrated in multiple large randomized controlled trials of adults and children around the world," she noted. "The majority of these trials actively did not include persons with SC disease."

Several studies have been published on hydroxyurea for hemoglobin SC, "but none have rivalled the statistical power of the foundational trials for hydroxyurea in SS disease," she added.

The prospective, double-blind, noninferiority PIVOT trial included patients with hemoglobin SC ages 5 to 50 who were receiving care at a center in Accra. Exclusion criteria included recent blood transfusion, cytopenia, pregnancy, or current disease-modifying therapy.

Of the 212 eligible patients (107 in the hydroxyurea arm and 105 in the placebo arm), mean age was 21.5 years, and 44% were female.

Patients were randomized to 12 months of treatment with hydroxyurea 20 mg/kg daily or placebo. They were initially monitored monthly with two possible 2.5-mg/kg dose escalations based on blood counts, followed by bimonthly monitoring until month 12 with repeat assessments.

The most common DLTs were thrombocytopenia and neutropenia, both occurring more frequently in adults. Older age, lower platelet count, and larger spleen volume were risk factors for developing a DLT while taking hydroxyurea.

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