Continued improvement in myocardial T2* over two years of deferasirox therapy in  -thalassemia major patients with cardiac iron overload

Abstract

BackgroundThe efficacy of cardiac iron chelation in transfusion-dependent patients has been demonstrated in one-year prospective trials. Since normalization of cardiac T2* takes several years, the efficacy and safety of deferasirox was assessed for two years in patients with β-thalassemia major in the cardiac sub-study of the EPIC trial. Design and MethodsEligible patients with myocardial T2* greater than 5 to less than 20 ms received deferasirox, with the primary endpoint being the change in T2* from baseline to two years. ResultsBaseline myocardial T2* was severe (>5 to <10 ms) in 39 patients, and moderate-to-mild (10 to <20 ms) in 62 patients. Mean deferasirox dose was 33.1±3.7 mg/kg/d in the one-year core study increasing to 36.1±7.7 mg/kg/d during the second year of treatment. Geometric mean myocardial T2* increased from a baseline of 11.2 to 14.8 ms at two years (P<0.001). In patients with moderate-to-mild baseline T2*, an increase was seen from 14.7 to 20.1 ms, with normalization (≥20 ms) in 56.7% of patients. In those with severe cardiac iron overload at baseline, 42.9% improved to the moderate-to-mild group. The incidence of drug-related adverse events did not increase during the extension relative to the core study and included (≥5%) increased serum creatinine, rash and increased alanine aminotransferase. ConclusionsContinuous treatment with deferasirox for two years with a target dose of 40 mg/kg/d continued to remove iron from the heart in patients with β-thalassemia major and mild, moderate and severe cardiac siderosis. (Clinicaltrials.gov identifier: NCT 00171821) Key words: β-thalassemia major, cardiac iron overload, deferasirox, iron chelation, myocardial T2*. Haematologica 2011;96(1):48-54. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Pennell DJ, Porter JB, Cappellini MD, Chan LL, El-Beshlawy A, Aydinok Y, Ibrahim H, Li C-K, Viprakasit V, Elalfy MS, Kattamis A, Smith G, Habr D, Domokos G, Roubert B, and Taher A. Continued improvement in myocardial T2* over two years of deferasirox therapy in β-thalassemia major patients with cardiac iron overload.Continued improvement in myocardial T2* over two years of deferasirox therapy in β-thalassemia major patients with cardiac iron overload

Sustained improvements in myocardial T2* over 2 years in severely iron‐overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine

“…The extension period of the study was not designed to detect differences between the chelation regimens since patients were no longer randomized. The relative improvement in myocardial T2* from baseline in deferasirox patients was consistent with previous 2-year data from the single-armed EPIC cardiac substudy [18] and also indicated a greater improvement in myocardial T2* in the second year compared with the first. Variation in the rate of improvement between CORDELIA and trials based on other chelation strategies, including DFO and/or deferiprone, should be interpreted with caution as a result of differences in study design and patient populations [9,10,12,19].…”

“…There was a steady reduction in mT2* in patients with baseline LIC !15 mg Fe/g dw, consistent with other deferasirox studies over 2 years [15,18]. Patient numbers in the LIC <15 mg Fe/g dw DFO arm were too low for meaningful interpretation of differences, but in patients with G mean myocardial T2* <10 ms at baseline, G mean levels improved to above the clinically relevant threshold of 10 ms at month 24 for both treatment groups.…”

“…Consistent with the 1-year data from CORDELIA [8] and other prospective clinical trials with deferasirox [7,13,18,26], mean LVEF remained stable in both cohorts of patients treated for up to 2 years. It is notable that no patients treated with either deferasirox or DFO experienced clinical heart failure in the extension; patients were, however, closely monitored by CMR every 6 months, a resource that may not be readily available in countries with limited access to equipment.…”

Impact of Iron Assessment by MRI

“…22,23 Therefore, MRI has become the de facto standard for all recent clinical trials on iron chelation and the clinical standard of care in major thalassemia centers. 10,24 In clinical practice, validation is more important than calibration. For inaccessible organs such as the pituitary and pancreas glands, absolute iron concentrations may never be derived; however, the R2 and R2* values associated with glandular dysfunction and destruction are under investigation.…”

Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with -thalassemia major

“…1,2 Although all available iron chelators have demonstrated efficacy in removing cardiac iron, prospective data beyond one year of treatment are rather limited. [3][4][5][6][7][8][9][10] As removal of cardiac iron may take several years, it is imperative to assess the effects of longer-term iron chelation therapy in the context of efficacy, safety and cardiac function. Results from the EPIC (Evaluation of Patients' Iron Chelation with Exjade ® ) cardiac substudy have shown continued, significant reduction of cardiac iron, as assessed by T2* cardiovascular magnetic resonance (CMR) over two years of deferasirox treatment in patients with mild-to-moderate (T2* 10 to <20 ms) and severe (T2* >5 to <10 ms) myocardial siderosis.…”