Compared with babies assigned to placebo in the randomized, two-year trial, those taking hydroxyurea showed no increase in genotoxic damage, said Patrick T. McGann, MD, of Baylor College of Medicine in Houston.
Moreover, children who continued on open-label hydroxyurea for up to three years following the randomized study's completion had fewer acute problems related to sickle cell disease such as hospital admissions for pain crises or acute chest syndrome, according to Zora Rogers, MD, of the University of Texas Southwestern Medical Center in Dallas.
Both researchers discussed findings from the two analyses at a press briefing held prior to their formal presentations at the American Society of Hematology's annual meeting.
Hydroxyurea is already widely accepted as a reasonably safe and effective treatment for adults and older children with sickle cell disease. It has also been used in young children, but with some worry that it might be more toxic in this population.
The drug inhibits DNA repair processes, which is why the drug is also used as a chemotherapy agent in various cancers. Infants may be more vulnerable than older people to such effects, McGann explained. He pointed out that leukemias, in particular, are far more common in two- and three-year-olds than in teenagers.
BABY HUG was designed to evaluate the drug in a placebo-controlled, randomized trial in infants nine to 18 months old. The primary results were published in The Lancet in May.
As part of the BABY HUG protocol, several genotoxicity assays were performed on the 193 study participants.
Both the hydroxyurea and placebo groups showed increases in the number of chromosome breaks during the course of the study. In the children taking the active drug, the mean number rose from 0.1 (SD 0.4) at baseline to 0.5 (SD 1.5) at study end.
McGann said this finding might have been a concern, but a similar increase was seen in the placebo group (mean 0.1 at baseline, 0.4 at study end).
Neither the number of chromatid breaks nor the percentage of micronucleated CD71-positive reticulocytes (another measure of chromosome damage) differed significantly between groups or within groups over time.
So-called VDJ (variable, diverse, and joining gene segments) recombination events also did not appear more frequent with hydroxyurea treatment, either over time or compared with the placebo group.
Rogers presented results from an extension to the randomized trial in which parents were offered open-label hydroxyurea for their children. A total of 133 accepted the offer. About 30 others declined but were available for at least 18 months of follow-up from the end of the randomized phase.
Children taking the drug in the extension showed significantly lower frequency of all major sickle-cell events, expressed as event rates per 100 patient-years:
- Emergency room visit for pain crisis: 28.8 with hydroxyurea versus 53.5 for no drug
- Episodic transfusion: 18.3 versus 35.9
- Any hospital admission: 72.9 versus 131.7
- Admission for acute chest syndrome: 10.8 versus 20.0
- Admission for febrile illness: 28.5 versus 61.5
- Admission for pain crisis: 19.1 versus 28.7
P values for all were less than 0.01 by log rank life test except for pain crisis admissions, for which the value was 0.015.
Rogers also said that no children became intolerant to the drug or stopped it permanently because of toxicity.
Susan Shurin, MD, acting director of the National Heart, Lung, and Blood Institute, which co-sponsored the trial, said the safety and efficacy questions about hydroxyurea in infants with sickle cell disease are "incredibly important."
"This is a very potent drug and, if it works, they would be on it for very long periods of time," she noted. At the same time, she said, an effective drug could prevent at least some of the organ damage and other irreversible complications of sickle cell disease.
"The key issues are to protect organ function and minimize the burden of disease," she said.
The BABY HUG trial was funded by the National Heart, Lung, and Blood Institute and the National Institute of Child Health and Human Development.
One co-author of McGann's study was an employee of Litron Laboratories. Other authors and Shurin said they had no relevant financial interests.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
American Society of HematologySource Reference: McGann P, et al "Genotoxicity associated with hydroxyurea exposure in infants with sickle cell anemia: Results from the BABY-HUG Phase III clinical trial" ASH 2011; Abstract 8.
American Society of HematologySource Reference: Rogers Z, et al "Hydroxyurea treatment of young children with sickle cell anemia: Safety and efficacy of continued treatment -- the BABY HUG Follow-up Study" ASH 2011; Abstract 7.