Greater Hydroxyurea Doses, Adherence Linked to Improved Pediatric Sickle Cell Anemia Outcomes

Susan E. Creary, MD

Greater daily exposure to hydroxyurea in sickle cell disease pediatric is associated with improved hematologic outcomes including hemoglobin count and mean corpuscular volume, according to new findings.

In new data from a US-based group of investigators, greater rates of hydroxyurea exposure—per parameters including higher doses and treatment adherence—were linked to positive clinical outcomes in pediatric patients. The findings highlight the significance of fully interpreting absolute exposure to hydroxyurea, the first-line therapy for sickle cell anemia—particularly in young, vulnerable patients who can benefit greatly from its effect.

Led by Susan E. Creary, MD, of the Research Institute at Nationwide Children’s Hospital in Columbus, OH, investigators sought to quantify combined hydroxyurea doses and patient therapy adherence, and such exposure’s link to hematologic outcomes that may inform hydroxyurea treatment strategies in children with sickle cell anemia. The team hypothesized that greater hydroxyurea exposure, per >20 mg/kg daily, would be associated with improved patient outcomes.

“Compared to most previously published studies that only report the prescribed dose of hydroxyurea, this analysis incorporated hydroxyurea adherence to better describe actual hydroxyurea exposure,” they wrote.

The team conducted a secondary analysis of data from a pair of prospective trials assessing the benefit of electronic pill bills on increased hydroxyurea adherence among pediatric patients with sickle cell disease at Midwestern care centers. In the first, conducted at Nationwide, patients were ≤19 years old, prescribed the first-line treatment for ≥180 days, were not receiving chronic transfusion therapy, and had daily smartphone access for directly-observed therapy.

In the second trial, investigators assessed electronically monitored pill bottle openings for patients aged 8-21 years old at the Ann & Robert H. Lurie Children’s Hospital of Chicago over 12 months.

Creary and colleagues also collected both trials’ patient demographics, hydroxyurea prescription, and clinical and laboratory data—as well as hemoglobin (Hb), mean corpuscular volume (MCV), absolute neutrophil count (ANC), and fetal hemoglobin level (HbF) at baseline and within 50 days of the trial’s end.

Their final assessment included 45 patients with sickle cell, 29 (64.4%) from the first trial and 16 (35.6%) from the second trial. Median participant age was 12 years old (range, 2 – 19); 25 (55.6%) were male and 44 (97.8%) were Black. Patients were primarily insured publicly or by Medicaid (18 [40.0%]), and more than two-thirds (32 [71.1%]) were on hydroxyurea for sickle cell anemia >12 months prior to the trial.

Investigators observed 23 patients with sickle cell administered higher hydroxyurea exposure, with an average prescribed dose of 27.2 kg/mg daily and median 189 doses administered during the intervention periods. Comparatively, patients with lower exposure (n = 22) reported an average 24.4 mg/kg daily (P = .002) and 157 median doses administered (P = .02).

While mean HbF was >20% for both treatment arms, it was significantly greater in the higher hydroxyurea exposure group. Investigators additionally observed significantly greater MCV in the higher exposure group.

“We identified that higher hydroxyurea exposure is associated with having a median HbF that is ≥5% higher and a MCV that is ≥7 fl higher than having lower exposure,” investigators wrote. “These favorable outcomes resulted from both higher adherence, as represented by the higher number of days of confirmed hydroxyurea exposure, and a higher prescribed hydroxyurea dose.”

Creary and colleagues the findings indicate the need for technology-based interventions that promote and resolve barriers to hydroxyurea exposure, but other disease-modifying therapies available for pediatric sickle cell anemia.

“However, the findings also support the need to optimize hydroxyurea prescribing in the real-world clinical setting, such as evaluating the safety and effectiveness of prescribing higher doses of hydroxyurea to less adherent patients, especially for patients whose medication adherence behavior is challenging to change,” they wrote.

The study, “Impact of hydroxyurea dose and adherence on hematologic outcomes for children with sickle cell anemia,” was published online in Pediatric Blood & Cancer.

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