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In 212 thalassemia major patients, repeated assessments for cardiac and hepatic iron (LIC) assessed by Magnetic Resonance Imaging (MRI – T2*) have been performed. The chelation regimes were either desferrioxamine (DFO), deferiprone (DFP), combination of DFO and DFP (Comb) or deferasirox (DFX). In general over the last few years, tailoring of chelation therapy has been principally guided by the cardiac iron loading. As many patients had been found to have excess cardiac iron, the majority (48%) had been placed on Comb. Patients were grouped according to the degree of siderosis. A T2* of 9.1 acceptable. Taking into account that the change in T2* is not necessarily linear with respect to time and as the overall time of exposure to DFO, DFP and Comb regimes was significantly greater than that with DFX it was unjustified to perform comparative analysis using the total time period of the patients who were on any of the non DFX regimes. Therefore, to compare the efficacy of the four regimes on LIC, we performed an analysis using student T test to assess the rate of change only between the first and second MRI in patients with comparable LIC according to each chelation regime with adjustment for overall time of exposure (Table 1). Using the same data and applying linear regression analysis (Table 2) we compared the effect of DFO to the other three regimes in the annual rate of increasing hepatic T2*. Only Comb is effective at all levels of hepatic iron loading in reducing the iron content. DFX is effective in the mildly iron loaded patients and for the moderately iron loaded patients, its efficacy approaches statistical significance. DFP does not seem to significantly decrease LIC at any level of hepatic iron load however the numbers of patients in that group are very small. Interestingly DFO seems the least effective at all levels of hepatic iron loading and particularly in the heavy loaded patients. This factor may be related to poor compliance to its use as the patients who have reached such levels of iron load are more often those who are not compliant. In the comparison analysis to DFO, only Comb is significantly better and DFP and DFX are equivalent to it. In addition Comb is more effective than DFX and DFP in that over 12 months it would increase the T2* by 3.8ms (p 9ms, 4 of 11 on DFO, 5 of 6 on DFX, 7 of 11 on DFP and 3 of 22 on Comb fell below 9. It is of note that DFO only maintains LIC and that a number of patients in the normal range increased LIC. Taking this data into account the DFX and DFP results are compatible with those seen both in the clinic and in trials. It is apparent however that combination therapy is the most effective regime for reducing hepatic iron significantly. As with cardiac iron loading, by knowing the degree of hepatic iron loading by the non-invasive T2* measurement and being able to manipulate patients chelation regimes, it seems possible to be able to have patients free of excess hepatic iron and potentially reduce other iron related morbidities as well. Table 1 | | Annual estimated mean change in T2* according to severity of hepatic siderosis | |:----------------------------------------------:| ------------------------------------------------------------------------------ | -------- | | Regime | Heavy | Moderate | Mild | | | ΔT2* | p | ΔT2** | p | ΔT2* | p | | *tm= mean time (in months) between MRI studies | | DFO n= 42 tm*= 24.6 | 0.05 | 0.5 | 0.57 | 0.37 | 0.1 | 0.7 | | DFP n= 11 tm= 23.8 | 0.56 | 0.25 | 0.88 | 0.31 | 3.5 | 0.19 | | Comb n= 101 tm=21.7 | 1.17 | 0.0064 | 3.6

241 thalassemia major patients have had repeated evaluation of cardiac iron assessed by Magnetic Resonance Imaging (MRI) over a median interval of 15 months (range 2.6–72.6). We compared changes in T2* between MRI studies with desferrioxamine (DFO) – (number of patients (n)=31, total MRIs (nMRI)=116), deferiprone (DFP) − (n=41 nMRI=94) and combination of DFO and DFP (Comb) − (n=143 nMRI=347) using repeated measurement analysis with correlated error terms and time varying covariates. Patients were divided into four groups according to their baseline cardiac T2* (Heavy load £ 8 ms, moderate load 8–14, mild 314–20 and normal 320). Table 1 shows the overall assessment excluding patients on DFX. These were not included in that assessment as the total period of exposure was statistically significantly less than that of the other regimes. Analysis was therefore performed using student T test to assess the rate of change between the first and second MRI in the T2* values in patients with comparable cardiac siderosis according to each chelation regime adjusted for overall time of exposure (Table 2). With linear regression analysis (Table3) we compared the effect of DFO to the other three regimes in the annual rate of increasing cardiac T2*. The results have been adjusted for baseline T2* and time of exposure to therapy. Both DFP and Comb regimes are superior to DFO in reducing cardiac siderosis. This indicates that over one year DFP and Comb regimes will have a greater increase in T2* than that achieved by DFO. In addition, Comb seems to be superior to DFX as it would increase the T2* by 2ms/year above that which can be achieved by DFX (p=0.007). DFP achieves 1.7ms/year above the annual improvement with DFX but the difference is not statistically significant. The estimated difference in annual improvement of T2* between Comb and DFP is 0.33ms/year (p=0.07) These data confirm that which is seen in clinical practice according to the chelation regimes used. It is clear that the combination of DFO and DFP is the most rapid regime for reducing cardiac iron and seems to be effective at all levels of cardiac siderosis. The ability to assess tissue iron in the heart is extremely clinically valuable and allows preemptive intervention in order to reduce cardiac morbidity and mortality by the selection of the most appropriate chelation therapy according to the MRI findings. Table1 Annual estimated mean change in T2* according to severity of cardiac siderosis Regime Heavy Moderate Mild ΔT2* p ΔT2* p ΔT2* p DFO 0.61 n.s 1.06 n.s. −1.5 n.s. DFP 0.55 Table 2 Annual estimated mean change in T2* according to severity of cardiac siderosis Regime Heavy Moderate Mild ΔT2* P ΔT2* p ΔT2* p *tm= mean time (in months) between MRI studies DFO n= 73 tm*= 23 0.73 0.05 1.07 0.09 0.9 0.4 DFP n= 53 tm=18.5 1.95 0.14 3.2 0.0045 3.9 0.06 Comb n= 152 tm=21.2 1.98 Table 3 Mean estimated difference in T2* Standard Error p DFP v. DFO 2.1 0.99 0.033 Comb v DFO 2.4 0.69