Hydroxyurea provides ‘remarkable clinical benefit’ in hemoglobin SC disease
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Key takeaways:
- Fewer patients assigned hydroxyurea than placebo developed painful vaso-occlusive events.
- Fewer hospitalizations occurred in the hydroxyurea group.
SAN DIEGO — Hydroxyurea conferred benefit to children and adults with hemoglobin SC disease, according to study results presented at ASH Annual Meeting and Exposition.
Patients who received hydroxyurea experienced significantly fewer painful vaso-occlusive events and fewer hospitalizations. The agent also appeared well tolerated, according to investigators.
“There is no disease-modifying drug approved for treatment of hemoglobin SC,” Yvonne Dei-Adomakoh, MBBS, associate professor of hematology and consultant hematologist at University of Ghana, told Healio. “Hydroxyurea is readily available, so we really wanted to find out if it was useful in this setting. These patients have a lot of morbidity and mortality, so we are pleased — but not really surprised — that this drug could potentially help.”
Background
Hemoglobin SC — which accounts for about 25% of sickle cell disease cases in the United States — occurs when a person has one copy of the gene for hemoglobin C disease and one copy of the gene for sickle cell disease.
“There is a general perception that people who have [hemoglobin SC] disease have a mild phenotype, and it is important to dispel this myth among both the public and health care workers,” Dei-Adomakoh said in a press release. “Many people with [hemoglobin SC] disease are not receiving long-term care or disease-modifying treatment for their condition as they are felt not to have the ‘real’ sickle cell disease.”
Hydroxyurea is the standard treatment for people with sickle cell anemia, having been proven to benefit those with hemoglobin SS or sickle beta zero thalassemia.
However, hydroxyurea is not indicated for hemoglobin SC due to limited prospective data and lack of consensus study endpoints, according to study background.
Dei-Adomakoh and colleagues hypothesized that clinical or laboratory variables beyond acute vaso-occlusive events may be appropriate endpoints for hemoglobin SC in a definitive trial.
Methods
Researchers conducted the double-blind, placebo-controlled PIVOT trial in Ghana, where hemoglobin SC accounts for about half of sickle cell disease cases.
The trial enrolled 243 patients — 120 adults and 123 children (age range, 5 to 50 years) — with hemoglobin SC.
Researchers excluded those who recently underwent transfusion, as well as those with cytopenia, those in pregnancy or those receiving current disease-modifying therapy.
All study participants underwent clinical assessments and laboratory tests. Investigators then randomly assigned them to 20 mg/kg hydroxyurea daily or placebo for 1 year.
Study participants initially underwent monthly monitoring and, based on blood counts, could receive up to two 2.5-mg/kg daily dose escalations. After the blinded treatment phase, participants could be offered open-label continuation if deemed safe. Bimonthly monitoring continued through month 12.
Frequency of dose-limiting toxicities in each treatment group — based on a noninferiority design with a 15% threshold — served as the primary endpoint, with specific emphasis on cytopenia and high hemoglobin (< 12 g/dL or 1 g/dL increase).
Secondary endpoints included laboratory changes and clinical adverse events. Assessments included complete blood counts, reticulocytes, hemoglobin quantification, sickle cell-related events, hospitalizations and malaria.
Erythrocyte characteristics — such as whole blood viscosity, ektacytometry and point of sickling — served as exploratory endpoints.
The final analysis included 214 participants. Researchers randomly assigned 107 of them to hydroxyurea at a starting dose of 20 ± 0.4 mg/kg/day. The average dose at month 12 reached 20.3 ± 2.8 mg/kg day. The other 107 received placebo.
Ninety-six patients assigned hydroxyurea and 102 assigned placebo completed 12 months of blinded treatment.
Key findings
A higher percentage of trial participants assigned hydroxyurea experienced dose-limiting toxicities (33% vs. 11%; difference, 22 percentage points; 95% CI, 11-34).
“This absolute difference in percentage points was higher than the 15% noninferiority margin we predicted so, formally, PIVOT did not meet its primary endpoint,” Dei-Adomakoh said.
Researchers observed the higher incidence of dose-limiting toxicities with hydroxyurea among both children (20% vs. 4%) and adults (47% vs. 18%).
Dose-limiting toxicities included thrombocytopenia (19% for hydroxyurea vs. 1% for placebo; difference, 18 percentage points; 95% CI, 9-26), neutropenia (13% vs. 0%; difference, 13 percentage points; 95% CI, 6-20) and high hemoglobin (11% vs. 10%; difference, 2 percentage points; 95% CI, –7 to 11).
One patient assigned hydroxyurea developed reticulocytopenia. No cases of anemia occurred in either group.
Nearly all cytopenias were transient grade 2 neutropenia or thrombocytopenia.
“Although PIVOT was not powered for clinical efficacy, there was a remarkable clinical benefit observed in the hydroxyurea arm,” Dei-Adomakoh said.
Researchers observed fewer clinical adverse events (incidence rate ratio = 0.7; 95% CI, 0.48-0.92), less vaso-occlusive pain (incidence rate ratio = 0.38; 95% CI, 0.28-0.52), fewer hospitalizations (incidence rate ratio = 0.42; 95% CI, 0.22-0.81) and fewer sickle-related complications (incidence rate ratio = 0.39; 95% CI, 0.26-0.59) in the hydroxyurea group.
One adult assigned hydroxyurea died within 24 hours of developing acute chest syndrome.
“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,” Dei-Adomakoh said.
Perspective
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Charles S. Abrams, MD
One-quarter of people with sickle cell disease in the U.S. have hemoglobin SC. It primarily affects people who can trace their heritage to western Africa.
Some people call it a milder form than the more common sickle cell disease, and it is in the sense that people live a decade or two longer, but that’s still much shorter than the general population. So it's better, but it’s still a serious disease.
There was another study a while back by a famous hematology researcher — Russell E. Ware, MD, PhD — who looked at the effects of hydroxyurea treatment for hemoglobin SC and he found there were some effects. This trial was larger than Dr. Ware’s trial but, as Dr. Dei-Adomakoh mentioned, an even larger trial could really show [the potential].
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Dei-Adomakoh Y, et al. Abstract 3. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.
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