Treating babies who have sickle cell disease (SCD) with oral liquid hydroxyurea appears to prevent the onset of long-term complications triggered by this disease, according to results of a preliminary study by investigators at St. Jude Children's Research Hospital.
The study's findings are important because the onset of damage caused by SCD complications can occur as early as three months after birth. Starting treatment before those complications begin could dramatically reduce the chance of organ damage and premature death. A report on the study appears in the June 14 online edition of Blood.
In SCD, a genetic mutation causes oxygen-carrying protein hemoglobin (Hb) to form rigid cords in red blood cells, causing the cells to take on a bent, sickled shape. The sickled cells clog small blood vessels, causing pain and serious damage to the brain, kidneys, spleen and other organs; and the subsequent premature death of the abnormal red cells causes anemia. In the United States, SCD is found mostly among African Americans.
Hydroxyurea increases the production of fetal hemoglobin (HbF), the main oxygen transport protein in fetal red blood cells. Because HbF prevents red blood cells from "sickling," clinicians have used hydroxyurea for about a decade to reactivate HbF production in adults and older children with SCD. In addition, hydroxyurea reduces the severity of symptoms suffered by adolescents and adults with SCD, such as lung infections, organ damage, stunted growth, impaired brain development and acute chest syndrome (ACS). ACS refers to an infection in the lungs that causes difficulty breathing, pain and other symptoms and can be fatal.
The current St. Jude study was an extension of a previous clinical trial, Hydroxyurea Safety and Organ Toxicity (HUSOFT), which was the first in which young babies were treated with hydroxyurea. The original HUSOFT study, published in 2001, demonstrated that short-term oral liquid hydroxyurea therapy can be safe and effective in babies with SCA. In the extension study, these infants were followed for up to six years of therapy.
"Our results are promising and justify a larger multicenter clinical trial to confirm that treating babies with hydroxyurea is safe and effective," said Jane S. Hankins, M.D., a physician at the St. Jude Comprehensive Sickle Cell Center and the study's lead author. "If a larger trial supports our observations in the HUSOFT Extension, the treatment of sickle cell disease will undergo a significant change."
"This study is particularly encouraging because it suggests that we can treat babies with hydroxyurea for several years without side effects serious enough to limit the use of this drug," said Winfred Wang, M.D., St. Jude Comprehensive Sickle Cell Center director. "Our aim is to make sickle cell anemia a survivable disease that doesn't significantly reduce a person's quality of life." Wang is the senior author of the paper in Blood.
A two-year pilot study of 21 babies with SCD, the original HUSOFT was designed to examine the feasibility of treating infants with liquid hydroxyurea; to determine the toxicity of this drug in babies; to assess hydroxyurea's effects on fetal Hb levels; and to observe if this treatment could preserve spleen function. Patients received 20 milligrams/kilgrams of body weight/day (mg/kg/day) of hydroxyurea. All 21 patients who completed the initial study were enrolled by their parents into the HUSOFT Extension study. In that study, the dose of hydroxyurea was elevated from 20 to 30 mg/kg/day for an average of 4.0 years (range 2.1 - 6.0 years).
The aim of the HUSOFT Extension was to determine if this higher dose, given for an extended period of time, provided significant long-term benefits without causing unacceptable side effects in children ranging in age from 2.6 to 4.4 years (median age 3.4 years).
After four years of hydroxyurea therapy, the concentrations of Hb, HbF and the volume of red blood cells were significantly increased in the children receiving hydroxyurea. Moreover, the HbF level often exceeded 20 percent of the total amount of Hb, Hankins said. "In children who weren't treated with hydroxyurea, the level of HbF declined significantly," she added. "The fact that HbF levels rose in babies treated with hydroxyurea suggests that the drug is effective in babies, as well as in adolescents and adults."
Babies receiving hydroxyurea also weighed more and were taller than those untreated children 2 to 5 years old who had been observed in a previous, long- term national study called the Cooperative Study for Sickle Cell Disease. The average weight gain for babies in the St. Jude study was more than 4.5 pounds per year; and the gain in height was more than 3 inches, the researchers report.
"Hydroxyurea could also prove to be an effective way to improve the care of sickle cell disease patients who live in underprivileged areas of the world," said Russell E. Ware, M.D., Ph.D., director of the Hematology division of the Department of Hematology-Oncology at St. Jude. "Treatment with hydroxyurea requires periodic checkups, but the medication is relatively inexpensive and should be adaptable to countries with limited resources," he said. Ware is a co-author of the paper.
Other authors of the article include Zora Rogers (University of Texas, Dallas); Lynn W. Wynn, MSN, PNP, CCRP (St. Jude); Peter A. Lane (Emory University, Atlanta, GA); and J. Paul Scott (Medical College of Wisconsin, Milwaukee).
This work was supported in part by a General Clinical Research Center grant and ALSAC.