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We present results from a prospective, multicenter, open-label, single-arm study evaluating response of cardiac and liver iron to deferasirox therapy for 18 months. Twenty-eight patients with abnormal T2* and normal left ventricular ejection fraction were enrolled from 4 US centers. All patients initially received deferasirox doses of 30 to 40 mg/kg per day. Patients were severely iron overloaded: mean liver iron concentration (LIC) 20.3 mg Fe/g dry weight, serum ferritin 4417 ng/mL, and cardiac T2* 8.6 ms. In the intent-to-treat population, 48% reached the primary endpoint (cardiac T2* improvement at 18 months, P = not significant). There were 2 deaths: 1 from congestive heart failure and 1 from sepsis. In the 22 patients completing the trial, LIC and cardiac T2* improvements were 16% (P = .06) and 14% (P = .07), respectively. Cardiac T2* improvement (13 patients) was predicted by initial LIC, final LIC, and percentage LIC change, but not initial cardiac T2*. Cardiac iron improved 24% in patients having LIC in the lower 2 quartiles and worsened 8.7% in patients having LIC in the upper 2 quartiles. Left ventricular ejection fraction was unchanged at all time points. Monotherapy with deferasirox was effective in patients with mild to moderate iron stores but failed to remove cardiac iron in patients with severe hepatic iron burdens. This study was registered at www.clinicaltrials.gov as #NCT00447694.

The US04 trial was a multicenter, open-label, single arm trial of deferasirox monotherapy (30–40 mg/kg/day) for 18 months. Cardiac iron response was bimodal with improvements observed in patients with mild to moderate initial somatic iron stores; relationship of cardiac response to labile plasma iron is now presented. Labile plasma iron was measured at baseline, six months, and 12 months. In patients having a favorable cardiac response at 18 months, initial labile plasma iron was elevated in only 31% of patients at baseline and no patient at six or 12 months. Cardiac non-responders had elevated labile plasma iron in 50% of patients at baseline, 50% patients at six months, and 38% of patients at 12 months. Risk of abnormal labile plasma iron and cardiac response increased with initial liver iron concentration. Persistently increased labile plasma iron predicts cardiac non-response to deferasirox but labile plasma iron suppression does not guarantee favorable cardiac outcome. Study registered at www.clinicaltrials.gov (NCT00447694).

The trial CICL670AUS04 was a single-arm, open-label study of the cardiac efficacy of 18 months of deferasirox monotherapy [1]. Cardiac response in this study was related to the degree of liver siderosis. Patients with mild to moderate liver siderosis improved their cardiac T2* while more severely siderotic patients did not, regardless of initial cardiac iron burden. In this letter, we report 2-year data in those patients who completed a 6-month extension phase (N 5 10). Cardiac and liver iron improved steadily during the 24-month period, with final cardiac T2* and LIC improving 37% and 27%, respectively, in this cohort. Serum ferritin and LVEF were not statistically different at anytime-point. When the extension phase (18-24 months) was considered in isolation, serum ferritin, liver iron concentration, and left ventricular ejection fraction were nearly identical to 18 month results. Despite this, cardiac T2* continued to trend higher, increasing 12.7% from 9.5 ms to 10.7 ms (P 5 0.06). Thus defersirox continued to demonstrate cardiac efficacy in patients with mild to moderate hepatic siderosis throughout 2 years of therapy.

Abstract 4069 Poster Board III-1004 Introduction Transfused patients with β-thal major are known to experience clinical consequences of cardiac iron overload despite the widespread use of iron chelation therapy. Approximately 71% of patients will suffer cardiomyopathy, congestive heart failure (CHF) and death. Previous trials have confirmed the efficacy of deferasirox (Exjade®) in removing cardiac iron in patients with β-thal major. This ongoing study evaluates the effects of deferasirox on cardiac iron and left ventricular ejection fraction (LVEF) in patients with β-thal major in a prospective, single-arm, multi-center trial using cardiac MRI T2*. All patients have completed 18 months of therapy and we also report preliminary results from 24 months. Methods 28 patients were enrolled at four US centers. Entry criteria included MRI evidence of cardiac iron (T2* Baseline: All 26 evaluable patients (7 M/19 F; aged 10–44 years) received ≥150 lifetime transfusions. SF was 4307 ± 613 ng/mL (312–12,655), cardiac T2* was 9.5 ± 0.8 ms (1.8–16.1), LIC was 20.6 ± 3.15 mg Fe/g dry weight (dw; 3.6–62.3) and LVEF was 61.8 ± 0.8%. Results At the time of analysis, 22 and 9 patients had 18- and 24-month evaluations, respectively. Six patients discontinued the core trial due to patient decision (n=2), adverse events (AEs; n=2) or abnormal lab tests (n=2). Two of these patients died after discontinuing; the first enrolled with markedly elevated baseline cardiac iron (T2* = 1.8 ms) and died secondary to CHF. The second patient withdrew due to an AE and died 2 months later due to sepsis and multi-organ failure. 18-month results: At 18 months, 10/22 patients were on 40 mg/kg/day. The mean improvement in cardiac T2* from baseline in all patients was 2.2 ms (22%; P=0.016), with 13 patients improving, four remaining stable (T2* change 18.5 mg Fe/g dw, mean T2* worsened 1.4% per month (P 24-month results: At 24 months, 7/9 patients were on 40 mg/kg/day. Relative to the 18-month time-point, 8/9 patients (89%) increased their cardiac T2*, with a mean improvement of 2.7% per month. Mean LIC, SF and LVEF were unchanged over the extension. Safety parameters from patients treated with 30–40 mg/kg/day deferasirox (n=25) were in line with previous studies at 20–30 mg/kg/day. Conclusions Deferasirox monotherapy resulted in statistically significant improvements in cardiac and hepatic iron after 18 months. Baseline LIC Disclosures: Wood: Novartis: Research Funding. Thompson:Novartis: Research Funding. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Glynos:Novartis Pharmaceuticals: Employment. Kang:Novartis Pharmaceuticals: Employment, Equity Ownership. Giardina:Novartis: Research Funding, Speakers Bureau. Harmatz:Ferrokin: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Coates:Hope Pharma: Consultancy, Research Funding; Sangart Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Background: Chronic red cell transfusions in patients with MDS result in iron overload, potentially causing hepatic, cardiac and endocrine dysfunction if untreated. DFX, a once-daily, oral iron chelator, has demonstrated dose-dependent reductions in SF and LIC in a variety of iron-overloaded patients. This study, CICL670AUS02, is the first prospective study evaluating the effects of DFX on LIC, SF and LPI in lower-risk patients with MDS. Methods: The study evaluated efficacy and safety of DFX in patients with IPSS Low- and Int-1-risk MDS at three US centers. Initial DFX dose was 20 mg/kg/day with adjustments to 10 or 30 mg/kg/day based on safety and efficacy. LIC was assessed by R2 MRI at baseline (BL), 6 and 12 months (mos). SF, safety analyses and trough LPI levels were also assessed. Baseline characteristics (n=24): Male/female ratio: 16/8; all Caucasian; mean age: 68 years (range 55–81); IPSS Low: 10; Int-1: 14. Time from initial diagnosis: 0.5 μmol/L). 6-month values: 15/24 patients completed 6 mos. Mean SF (±SEM): 3650±384 μg/L at BL, 3638±870 μg/L at 6 mos (n=13); mean decrease of 12.2 μg/L (P=0.685). Mean LIC (±SEM): 23.10±2.40 mg Fe/g dw at BL, 16.87±1.88 mg Fe/g dw at 6 mos (n=14); mean decrease of 6.2 mg Fe/g dw (P=0.013). Mean LPI (±SEM): 0.82±0.16 μmol/L at BL, 0.12 ± 0.05 μmol/L at 6 mos (n=15); mean decrease of 0.70 μmol/L (P=0.170). 12-month values (n=9): Nine patients completed 12 mos of treatment. Mean dose in the nine completers was 20.1 mg/kg/day; three patients increased to 30 mg/kg/day and two decreased to 10 mg/kg/day. Mean SF (±SEM): 4416±1269 μg/L at BL, 2685±316 μg/L at 12 mos; mean decrease of 1730 μg/L (P=0.301; Figure). Mean LIC (±SEM): 23.72±3.82 mg Fe/g dw at BL, 16.79±3.80 mg Fe/g dw at 12 mos; mean decrease of 6.93 mg Fe/g dw (P=0.203). 78% of the nine completers achieved decreases in SF of ≥500 μg/L and >20% from BL. Mean LPI (±SEM; n=8): 0.82±0.19 μmol/L at BL, 0.13±0.10 μmol/L at 12 mos; mean decrease of 0.76 μmol/L (P=0.023) Safety Analysis (n=24): Increases in serum creatinine (SCr) to >33% above BL on ≥2 occasions (highest value 1.7 mg/dL) were seen in seven patients (29%) while on study. New cases of thrombocytopenia (worst value 39×109/L) and neutropenia (worst value 0.50×109/L) developed in one patient each during the study; these were assessed as unrelated to study drug. There were 15 discontinuations (63%): three due to unrelated deaths (two congestive cardiac failure, one subdural hemorrhage); four patients withdrew consent for unknown reasons; two from MDS progression; five because of adverse events (AEs), four of which were related to study drug (one diarrhea, two increased SCr, one increased liver enzymes) and one unrelated (splenic infarct); and one from unsatisfactory therapeutic effect. There were 14 serious AEs reported in 11 patients; 13/14 were considered unrelated to study drug; 1/14 (severe diarrhea/lower abdominal cramping) was related to study drug and the patient completely recovered within 1 day. Conclusions: Sequential LIC measurements in this MDS cohort demonstrated a significant decrease by month 6 and further decreases by month 12 in patients who completed 1 year of treatment. LPI normalized in 80% of the patients. Two thirds of this heavily transfused population discontinued the trial mainly due to disease-related complications; four patients discontinued due to drug-related AEs. Larger studies are continuing to evaluate the clinical benefit of DFX in patients with MDS. Figure Figure