Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with ␤-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n ‫؍‬ 296) or deferoxamine (n ‫؍‬ 290), with dosing of each according to baseline liver iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body iron balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body iron balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional iron overload. (Blood. 2006;107:3455-3462)

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

BACKGROUND Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was −348 μg per liter (95% confidence interval, −517 to −179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.)

Patients with ␤-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged > 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received > 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with > 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ؎ 11.2 mg Fe/g dry weight (dw; n ‫؍‬ 103; P < .001) and 3.1 ؎ 7.9 mg Fe/g dw (n ‫؍‬ 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n ‫؍‬ 196; P < .001) and 371 ng/mL (n ‫؍‬ 147; P < .001), respectively, after > 4 years' exposure. Investigator-assessed, drugrelated adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with ␤-thalassemia suggests treatment for < 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials-.gov as #NCT00171210. (Blood. 2011; 118(4):884-893)

Cardiac iron overload causes most deaths in ␤-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with ␤-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n ‫؍‬ 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n ‫؍‬ 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean ؎ coefficient of variation) improved from a baseline of 11.2 ms (؎ 40.5%) to 12.9 ms (؎ 49.5%) (؉16%; P < .001). LVEF (mean ؎ SD) was unchanged: 67.4 (؎ 5.7%) to 67.0 (؎ 6.0%) (؊0.3%; P ‫؍‬ .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (؎ 25.6%) to 32.5 ms (؎ 25.1%) (؉2%; P ‫؍‬ .57) and LVEF increased from baseline 67.7 (؎ 4.7%) to 69.6 (؎ 4.5%) (؉1.8%; P < .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials. gov as NCT00171821. (Blood. 2010;115: 2364-2371)

BackgroundProspective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important. Design and MethodsSeventy-one patients in the EPIC cardiac substudy elected to continue into the 3 rd year, allowing cardiac iron removal to be analyzed over three years. ResultsMean deferasirox dose during year 3 was 33.6±9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ±39.1% at baseline to 17.1 ms ±62.0% at end of study (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43±1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ±1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drugrelated adverse event in year 3 was increased serum creatinine (n=9, 12.7%). ConclusionsThree years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.

Key Points In β-thalassemia major patients with severe iron burden, deferasirox was noninferior to deferoxamine for myocardial iron removal. The ejection fraction was stable during treatment for both deferasirox and deferoxamine.

β-thalassemias are a heterogeneous group of hereditary hemoglobinopathies characterized by defects in the β-globin chain of hemoglobin and autosomal recessive inheritance. Homozygous or compound heterozygous forms have an imbalance in the production of α-and non-α-globin chains, resulting in ineffective erythropoiesis and decreased production of normal hemoglobin A. 1 Patients with β-thalassemia major have severe chronic hemolytic anemia and require regular blood transfusions from early childhood. 1-3 Chronic blood transfusion therapy is typically combined with iron chelation therapy (ICT) to prevent complications due to iron overload, such as cardiac morbidity, liver disease, and endocrine dysfunction. 1-3 Patients with β-thalassemia intermedia have symptoms in between carriers and those with β-thalassemia major: Anemia is often moderate, but patients may still have morbidity due to ineffective erythropoiesis and hemolysis, including ulcers, pulmonary hypertension, and pain. Some patients require occasional blood transfusions, although less frequently than patients with β-thalassemia major. 1,2 Historically, the prevalence of β-thalassemia has been highest in the Mediterranean region, the Middle East, and Southeast Asia and lowest in Northern Europe and North America. 4 Due to migration patterns, β-thalassemia is increasingly more common in non-endemic regions,