Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study

Abstract

The long-term efficacy and toxicity of hydroxyurea for infants are undefined, and its role in preventing organ dysfunction is unknown. Short-term feasibility of hydroxyurea administration, toxicities, hematologic effects, and effect on spleen function in infants with sickle cell anemia (SCA) were reported (Hydroxyurea Safety and Organ Toxicity [HUSOFT] trial). These infants completing 2 years of hydroxyurea therapy (20 mg/kg/d) were offered study extension with dose escalation to 30 mg/kg/d. Patients were monitored with laboratory tests and biannual imaging studies. Hematologic indices were compared with predicted age-specific values and event rates compared with historic rates. All 21 subjects completing the original trial enrolled in the extension study: median age, 3.4 years old (range, 2.6 to 4.4 years); 12 females; 20 with Hb SS, 1 with Hb S/beta0-thalassemia. Seventeen patients completed 4 years of hydroxyurea, and 11 completed 6 years. After 4 years, hydroxyurea was associated with increased hemoglobin concentration, percentage of fetal hemoglobin (Hb F), and mean corpuscular volume (MCV) and decreased reticulocytes, white blood cells (WBCs), and platelets (P < .01). Patients experienced 7.5 acute chest syndrome (ACS) events per 100 person-years, compared with 24.5 events per 100 person-years among historic controls (P = .001). Treated patients had better spleen function than expected and improved growth rates. Infants with SCA tolerate prolonged hydroxyurea therapy with sustained hematologic benefits, fewer ACS events, improved growth, and possibly preserved organ function.

Figure 1.

Fetal hemoglobin (Hb F) levels during extended hydroxyurea therapy in infants with SCA. The upper curve (♦) represents the study patients receiving extended hydroxyurea therapy (mean ± SD values for Hb F), while the bottom 2 curves represent the expected values for untreated American (▪) and Jamaican children (▴) with SCA. Average fetal hemoglobin levels remain close to 20% during extended hydroxyurea therapy.

Figure 2.

Radionuclide liver-spleen scan showing normalization of splenic uptake after extended hydroxyurea therapy. A 7-month-old child with markedly decreased splenic uptake at baseline (arrow in top panel) regained splenic uptake after 4 years of hydroxyurea therapy (bottom panel). The arrow in the lower panel denotes the location of splenic uptake and indicates a slightly enlarged spleen measuring 9.3 cm in length.

Figure 3.

Growth curves for children with sickle cell anemia receiving extended hydroxyurea therapy. The 3rd (▪), 50th (▴), and 97th (•) percentiles for healthy children are illustrated as dotted lines, while the patients (♦) are illustrated as a solid line. Boys increased their average growth rate during hydroxyurea therapy from the 25th percentile for weight and 40th percentile for height to about the 50th percentile for both weight and height after 4 years of hydroxyurea therapy. Girls maintained average growth rates during the treatment period.