Background: Children with transfusion-dependent beta thalassemia will develop iron overload unless treated with an iron chelator such as deferiprone (DFP), deferasirox (DFX), or deferoxamine (DFO). Current practice delays chelation therapy until patients reach the iron overload criteria of serum ferritin (SF) levels ≥1000 µg/L or >10 transfusions. This “late-start” strategy was thought to minimize toxicity risks of iron depletion from biological stores or iron-bound proteins, such as transferrin, observed during “early-start” studies with DFO. This delay may increase the risk of iron overload toxicities later in life due to labile iron accumulation in organs difficult to reach with chelation. DFP is a membrane-permeable iron chelator with a lower iron affinity (pFe3+=19.3) than DFO (pFe3+=26.6), DFX (pFe3+=23.5), or transferrin (pFe3+=22.3). These pharmacological properties suggest “early-start” DFP could reduce the risks/toxicities associated with early iron overload and iron depletion by shuttling labile iron to transferrin. Previously, we reported that “early-start” DFP can be safely initiated in infants and young children with beta-thalassemia (START study NCT03591575) and maintain subthreshold SF levels in significantly more patients than placebo for up to 12 months. Aims: To evaluate the ability of “early-start” DFP to shuttle iron to transferrin in infants and young children with transfusion-dependent beta thalassemia using transferrin-saturation (TSAT) measurements from the START study. Methods: Infants or children with beta thalassemia who received ≥2 blood transfusions and had SF levels between 200–600 μg/L were randomly assigned 1:1 to DFP or placebo. Double-blinding continued until study end. Treatment continued until SF levels were ≥1000 μg/L at 2 consecutive visits (SF threshold) or 12 months. Patients started at 25 mg/kg/d DFP, escalated to 50 mg/kg/d DFP, with some to 75 mg/kg/d DFP, depending on iron load. The efficacy endpoint included imputation of % patients not reaching the SF threshold each month. DFP’s ability to shuttle iron to transferrin was evaluated at each month by comparing: 1) proportion of patients with ≥60% TSAT and 2) mean TSAT levels for DFP vs placebo groups. All iron measured in serum is total bound iron, which is the basis for calculating TSAT. The patient’s parent or legal guardian provided written informed consent before any study intervention. Results: Mean (SD) age was 3.0 (2.4) and 2.6 (1.7) years in the DFP (n=32; 63% male) and placebo (n=32; 66% male) groups, respectively. At month 12, 66% of patients receiving DFP remained below the SF threshold versus 39% of patients receiving placebo (p=0.045). Significantly more patients had TSAT ≥60% early with DFP than placebo at months 3–6 (each p<0.05); range: DFP 56%–66%, placebo 16%–34%. Similarly, mean TSAT levels with DFP were significantly higher than with placebo at months 3, 4, 6, 9, and 11 (each p<0.05); range: DFP 60%–69%, placebo 41%–55%. At 12 months, no DFP-treated patients were iron-depleted or reported iron depletion-associated adverse events (AEs). There were no significant differences between DFP and placebo in number of AEs (p=1.00), serious AEs (p=0.43), or AEs possibly related to DFP (p=1.00). Summary/Conclusion: Early-start DFP chelation therapy initiated before reaching current iron-load criteria was safe and efficacious in preventing iron overload in most transfusion-dependent children with beta thalassemia. START provides the first clinical evidence supporting preclinical studies that DFP can shuttle iron from labile pools to transferrin.