Study Provides More Support for Hydroxyurea Use in Patients With Sickle Cell Disease

Adults with sickle cell disease (SCD) should be treated with the maximum tolerated dose of hydroxyurea to reduce the risk of organ damage over the course of the disease, according to a report from the National Heart, Lung, and Blood Institute. These findings, published in PLoS One, lend further credence to the recommendations the agency set forth in its 2014 guidelines on the management of SCD.

Hydroxyurea is the only disease-modifying treatment approved by the U.S. Food and Drug Administration for the treatment of SCD. Yet, it is used inconsistently among this patient population. Previous studies that examined the patterns of hydroxyurea treatment reported conflicting results about the outcomes and dose-dependent effects of adhering – or not adhering – to therapy.

“Adults with sickle cell anemia who take hydroxyurea within the recommended dose range have better survival than those who take smaller doses. Simply taking hydroxyurea at any dose is not enough to realize this survival benefit,” James G. Taylor, VI, MD, corresponding author of the study told ASH Clinical News. “Our study results clarify the importance of prescribing according to recommended dosing guidelines. In essence, physicians underuse hydroxyurea in sickle cell anemia, and even when we do prescribe it, up to 20 percent of patients are not taking the minimum recommended dose.”

Dr. Taylor, lead author Courtney D. Fitzhugh, MD, from the National Heart, Lung, and Blood Institute and the National Institutes of Health in Bethesda, Maryland, and colleagues conducted a single-institution, retrospective analysis to determine how hydroxyurea dose affects fetal hemoglobin (HbF) response, organ damage (an important risk factor for death in SCD patients), and survival among adults with SCD.

A total of 383 adults with homozygous SCD were enrolled in the study between 2000 and 2010, with data collection taking place through 2012. The median age was 31 years (range = 18-74 years), and 66 percent (n=253) had previously been treated with hydroxyurea. The median follow-up was 2.6 years (range = 0.1-11.7 years).

Fifty-nine patients (15%) died during the study period at a median age of 46 years. Twenty of those deaths occurred outside a hospital, and autopsy reports were available for 19 patients (32%). The most common causes of death were pulmonary (n=11), sickle cell crisis (n=7), infection (n=6), and cardiac (n=5). The cause of death was unknown for nine patients and was listed as “SCD” on the death certificates of eight patients. Baseline factors that were later associated with mortality included higher alkaline phosphatase (p<0.0001), white blood cells (p=0.048), creatinine (p=0.043), and tricuspid regurgitation velocity (p=0.0082).

The patients who died were significantly older at the time of study enrollment (41.8 vs. 32.5 years, respectively; p=0.0067) and had lower HbF (p=0.0044). A lower proportion of these patients were prescribed hydroxyurea in the recommended dose range (15-35 mg/kg/day) compared with patients who survived (29% vs. 46%; p=0.0039).

Deceased patients also had more hepatic dysfunction, kidney dysfunction, and cardiopulmonary dysfunction.

Among the 66 percent of patients who were taking hydroxyurea, just 66 percent were on the recommended dose, with 18 percent treated below the recommended dose range. Among hydroxyurea-treated patients, the maximum HbF and mean corpuscular volume were greater among those who survived and those who died following treatment: 14.3±9.5 vs. 11.3±11.4 (p=0.0044) and 102.7±15.2 vs. 104.2±16.5 (p=0.57), respectively.

Patients treated with hydroxyurea also had improved survival (HR=0.58; 95% CI = 0.34-0.97; p=0.040). This benefit was even more pronounced in those taking 15 mg/kg to 35 mg/kg per day (HR=0.36; 95% CI 0.17-0.73; p=0.0050) or >35 mg/kg per day (HR=0.72; 95% CI 0.20-2.55; p=0.61) compared to those taking <15 mg/kg per day. “To our knowledge, this is the first study to demonstrate that doses below the recommended starting dose may not confer a survival benefit,” Dr. Fitzhugh and colleagues wrote.

Among patients who experienced hydroxyurea-induced HbF, the only marker of organ damage that was consistently lower during both a patient’s first and last visit was alkaline phosphatase levels: 95.4 versus 123.6, respectively (p=0.0065) and 96.1 versus 113.5 U/L, respectively (p=0.041). Other markers of organ damage, however, were not consistently improved in patients with the greatest hydroxyurea-induced HbF responses, and optimal hydroxyurea dosing alone was not shown to reduce organ injury.

Limitations of the study include study participants not being followed from birth – meaning the conclusions are applicable only to adults – and that treatment duration was unknown. Also, compliance and individual response to hydroxyurea were not monitored, and causality is not definitive due to the study’s retrospective design.

“A proper hydroxyurea dose is associated with higher HbF, less organ dysfunction, and improved survival,” Dr. Fitzhugh and colleagues concluded. “Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs.” These findings need to be validated in prospective trials, they added.


Fitzhugh CD, Hsieh MM, Allen D, et al. Hydroxyurea-increased fetal hemoglobin is associated with less organ damage and longer survival in adults with sickle cell anemia. PLOS One. 2015 November 17. [Epub ahead of print]