S123: SAFETY AND EFFICACY OF EARLY-START DEFERIPRONE IN INFANTS AND YOUNG CHILDREN WITH BETA-THALASSEMIA (START STUDY)

Abstract

Background: Patients with beta-thalassemia may need regular red blood cell transfusions in infancy.1 In the absence of iron chelation therapy, frequent transfusions cause iron to accumulate, which can lead to morbidity, organ damage, and death. However, in very young children, current practice is to delay chelation therapy until receipt of 10–20 transfusions, or until serum ferritin (SF) has reached 1000 μg/L, due to concerns over excessive iron depletion with deferoxamine.1,2 Unfortunately, this delay may increase the risk of iron accumulation in endocrine glands where toxicities could later manifest.3 Aims: START (NCT03591575) evaluated the safety and efficacy of the oral iron chelator deferiprone (DFP) in children with transfusion-dependent beta-thalassemia who did not yet meet the criteria for starting chelation therapy per standard practice. Methods: Infants and children receiving regular blood transfusions (2 minimum) and whose SF level was between 200–600 μg/L were randomly assigned 1:1 to DFP oral solution or placebo until SF exceeded 1000 μg/L at 2 consecutive visits or 12 months of therapy. DFP was initiated at 25 mg/kg/d and increased to 50 mg/kg/d after 2 weeks; based on iron load, DFP was increased to 75 mg/kg/d. Efficacy was assessed by monthly SF measurements to monitor iron load. The primary endpoint was the percentage of patients in each group with SF <1000 μg/L. All patients provided informed consent or assent. Results: The study enrolled 64 patients; 32 per group. The mean (SD) age was 3.03 (2.42) years in the DFP group and 2.63 (1.70) years in the placebo group; participants were 62.5% and 65.6% male in the DFP and placebo groups, respectively. There were no group statistical differences in the baseline demographics. The primary reason for withdrawal was SF levels that exceeded 1000 μg/L at 2 consecutive visits, which occurred in 25% of patients receiving DFP vs 63% of patients receiving placebo (P=0.0051). After completing 12 months of treatment, 65.6% of patients receiving DFP had a SF level <1000 mg/L vs 37.5% receiving placebo (P=0.0446). The percentage of patients who reached the 1000 mg/L SF threshold increased more rapidly in the placebo group vs the DFP group, and the difference in rates between the 2 groups was significant (P=0.0407). A summary of adverse events (AEs) is shown in Table 1. There were no significant group differences in the number of overall AEs (P=1.0000), serious AEs (P=0.4258), or the number of AEs that were considered to be at least possibly related to the study treatment (P=1.0000). Two patients receiving DFP withdrew from the study due to AEs: 1 patient experienced agranulocytosis and 1 patient experienced neutropenia of moderate severity and both patients recovered. Conclusions: Initiation of DFP chelation therapy at a lower threshold of SF values than currently recommended was safe and efficacious in preventing iron overload in most transfusion-dependent children. After 12 months of treatment, the number of patients with a SF level <1000 μg/L was significantly higher in the DFP group vs the placebo group. Moreover, there were significantly more patients who withdrew due to elevated SF levels in the placebo group (62.5%) vs the DFP group (25%). The safety and tolerability profile of DFP administered for up to 12 months in infants and young children was comparable to the profile established in older age groups and there were no instances of iron depletion.