Comment on Hankins et al, page 2269

Children with sickle cell anemia treated with hydroxyurea at 2 years of age maintain Hb F levels above 20% for 4 to 6 years with little hematologic toxicity and no increased risks of infection. Its ability to prevent subclinical organ damage, however, is yet to be proven.

More than 10 years ago the Multicenter Study of Hydroxyurea (MSH) showed reduction in painful crises, acute chest syndromes, and hospitalizations in adults with sickle cell anemia (SS) treated with hydroxyurea (HU).1  Hankins and colleagues now report an update of a phase 2 trial (Hydroxyurea Safety and Organ Toxicity [HUSOFT]) of hydroxyurea in children with SS started on HU before 2 years of age. The study demonstrates that oral HU maintains mean hemoglobin F (Hb F) levels higher than 20% for 4 to 6 years with little hematologic toxicity and without significant increased risks of infection. Using almost 20-year-old historic controls from the Comprehensive Study of Sickle Cell Disease (CSSCD),2  Hankins et al demonstrate a reduction in the rate of acute chest syndrome and improved growth rates. Reduction in rates of painful crises could not be assessed since no adequate historic or contemporary controls were available.

Clinically silent organ damage in the brain, spleen, lungs, and kidneys begins early in childhood in SS and often leads to significant disability and organ failure. Thus, it is important to determine whether HU can prevent occult and acute organ damage in children with SS. What is clear in this study is that HU treatment started before the age of 2 years and continued for 4 to 6 years does not uniformly prevent early signs of end organ disease in the spleen and brain. Among 14 children with measurements of baseline splenic function, only 3 had normal splenic function after 4 years of HU therapy. Perhaps HU treatment slows the progression of splenic deterioration; 6 (43%) of 14 were functionally asplenic after 4 years of therapy compared with a 94% incidence of asplenia in age-matched CSSCD historic controls. Three of 14 subjects had abnormal magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) central nervous system (CNS) studies after 4 years of therapy. It was not clear whether these lesions existed prior to HU treatment. One subject developed a silent CNS infarct between 4 and 6 years of therapy. Two children who were functionally asplenic before therapy regained normal splenic function, and 1 child resolved a mild CNS arterial stenosis on HU therapy.

Although children compared with adults seem to respond more uniformly to HU with higher Hb F levels, both children and adult subjects with SS demonstrate marked heterogeneity of clinical response to therapy so far. There is early evidence in adults that HU therapy is not uniformly accessible or beneficial.3,4  Reasons for lack of effectiveness of HU in adults with SS are not known but may include genetic variation in pretherapy Hb F and white blood count (WBC) levels, failure to push HU doses to optimal therapeutic levels, noncompliance, a perceived lack of response after short-term trials, and patient or physician concern for as-yet-undetermined long-term side effects of HU. Ten years from now do we want to say HU is efficacious in children but not effective? Further trials of HU in adults or children should incorporate means to determine what is responsible for this heterogeneous response in clinical outcomes and whether the drug will be both efficacious and effective. ▪

Charache S, Terrin ML, Moore RD, et al. Multicenter study of hydroxyurea in sickle cell anemia: effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.
N Engl J Med
Brown AK, Sleeper LA, Miller ST, et al. Reference values and hematologic changes from birth to 5 years in patients with sickle cell disease: Cooperative Study of Sickle Cell Disease.
Arch Pediatr Adolesc Med
Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.
J Am Med Assoc
Lanzkron S, Dover GJ. Hospitalization rates in patients with sickle cell disease (SCD) in the state of Maryland (MD): no change since approval of hydroxyurea (HU) [abstract].