1. Cardiac Effects of Iron Overload
Dudley Pennell, MD, FRCP, FACC, FES
Director, CMR Unit Royal Brompton Hospital
Professor of Cardiology
National Heart and Lung Institute
Imperial College
London, United Kingdom

2. Why Is the Heart Important in Thalassemia Major?
Death by heart failure in 71% of patients Median age at death: 35 years
% of UK Thalassemia Major Deaths
IO = iron overload
Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42-50.

3. Excitation/contraction
Cardiac Iron Toxicity
Fibroblast
Stimulate fibrotic response
DMT1 = divalent metal transporter 1; LVDC = L-type voltage-dependent channels; NTBI = non-transferrin-bound iron; Tf = transferrin
LVDC
Tf-Fe
Tf-mediated
(minimal)
Fe2+
Fe3+
DMT1
???
NTBI
Ryanodine-sensitive
Sarcoplasmic
Lysosomes
calcium reuptake
reticulum
More free iron
Excitation/contraction
coupling
Liposomal
membrane 2+
Mitochondria
damage Fe K+
Depolarization and
Respiratory chain
repolarization
enzymes Fe 3+
Na+
Nucleus
Na+ - Ca2+
Intracellular ion
concentrations
Na+ - K+ ATPase
Gene expression
Iron interactions
Iron storage
Iron uptake
When the antioxidant capacity of the cell is exceeded, ROS are formed, damaging organelles, interfering with electrical and mechanical processes, and triggering apoptosis.
ROS = reactive oxygen species.
Wood JC, et al. Ann NY Acad Sci. 2005;1054:

4. Measuring Myocardial T2*
5 ms ms ms ms ms ms ms ms ms
Signal = Ke-TE/T2*
Normal
Moderate
Severe
TE = echo time
Anderson LJ. Eur Heart J. 2001;22:

5. Proportion of Patients With Heart Failure
Kaplan-Meier Curves: T2* and Heart Failure
< 6 ms
6-8 ms
Proportion of Patients With Heart Failure
8-10 ms
> 10 ms
Follow-up Time (days)
Kirk P. Circulation. 2009;120:

6. T2* - Cardiac Risk Ranging90 80 70 60 50 40 30 20 10
100
Left Ventricular Ejection Fraction (%)
Heart T2* (ms)
High
Intermediate
Low
Anderson LJ. Eur Heart J. 2001;22:

7. Deferiprone vs DFO in Beta Thalassemia Major With Asymptomatic Myocardial Siderosis
RCT in 61 pts previously maintained on sc DFO
Compared continued DFO maintenance 43 mg/kg/d vs switch to oral deferiprone 90 mg/kg/d
At 12 months:
Improvement in myocardial T2* 27% with deferiprone vs 13% with DFO; P = .023
Increase in LVEF 3.1% with deferiprone vs 0.3% with DFO; P = .003
DFO = deferoxamine; LVEF = left ventricular ejection fraction
Pennell D, et al. Blood. 2006;107:

8. Effect of Combined DFO + Deferiprone vs Placebo on Cardiac Iron in Thalassemia Major
Randomized, placebo-controlled trial in 65 pts previously maintained on subcutaneous DFO
Compared continued DFO maintenance + placebo vs continued DFO maintenance + deferiprone
At 12 months:
Increase in geometric mean for myocardial T2* 50% with combination vs 24% with placebo; P = .02
Increase in absolute LVEF 2.6% with combination vs 0.6% with placebo; P = .05
Tanner MA. Circulation. 2007;115:

9. EPIC Cardiac Substudy: Cardiac T2* in Treatment Arm
10 to < 20 ms
> 5 to < 10 ms
all patients
65.2
68.2
66.1
65.8
68.7
68.4
67.1
67.7
67.4 55 60 65 70 75
Baseline 6 12
Time (months)
Mean LVEF (%) 80
P = .53
No change
7.4
8.2‡
14.6
17.4**
11.2
12.9† 2 4 6 8 10 12 14 16 18 20
Baseline
Time (months)
Mean Cardiac T2* (ms)
**n = 64, P < .0001; †n = 105, P < .0001; ‡n = 41, P = Pennell D, et al. Blood. 2010;115:2364.

10. EHA 2010: EPIC Cardiac Substudy Extension
Myocardial T2* Over 2 Years in Patients With Beta Thalassemia and Myocardial Siderosis
Mean deferasirox dose:
33.1 mg/kg/d in core study
36.1 mg/kg/d during extension * * * *
Geometric Mean Myocardial T2* (ms) * *
* P < .001 versus baseline
N = 101
N = 101
N = 85
Time (months)
Pennell D, et al. Presented at EHA Abstract 498.

11. EHA 2010: EPIC Cardiac Substudy Extension (cont)
After 2 years of deferasirox treatment:
57% of patients with mild-to-moderate baseline cardiac siderosis (10 to < 20 ms) were normalized ( ≥ 20 ms)
43% of patients with severe baseline cardiac siderosis (> 5 to < 10 ms) improved to mild-to-moderate category
Pennell D, et al. Presented at EHA Abstract 498.

12. Prior DFO Monotherapy (n = 63)
EHA 2010: EPIC Cardiac Substudy Extension: Stratified by Previous Chelation Regimen
Evaluated effect of 2 years of deferasirox treatment in patients with beta thalassemia and myocardial siderosis
Stratified by prior chelation (DFO or combined DFO-DPO)
Prior DFO Monotherapy (n = 63)
Prior DFO-DPO (n = 32)
↑ in geometric mean for myocardial T2*
28%1
35%1
% of pts with increase > 4% in T2*
79%
69%
Mean change in LVEF
1.2% ± 4.5%2
−1.7 % ± 5.8% [NS]
↓ in mean LIC
9.6 ± 12.7 mg Fe/g dw3
12.4 ± 12.5 mg Fe/g dw3
↓ in median SF
2227 ng/mL3
2559 ng/mL3
1. P < P = P < .001.
DPO = deferiprone; dw = dry weight; LIC = liver iron concentration; SF = serum ferritin
Pennell D, et al. Published at EHA Abstract 1805.

13. CORDELIA: RCT Deferasirox vs DFO
Screening
23 days
1-year study Rx in Core study
96 patients deferasirox
96 patients DFO
1-year study Rx in Extension study
Randomize eligible patients (1:1 ratio)
Followed by 5-day washout
End Core / Start Extension
End
Extension
Continuing in the extension is optional and requires re-consent by participants. 13

14. Conclusions
Cardiac disease is the leading cause of death in beta thalassemia major
T2* MRI scan is useful for early detection of cardiac IO and cardiac risk ranging
Deferasirox, deferiprone, and deferiprone+DFO are shown to significantly improve myocardial T2*
Deferiprone is shown to improve LVEF
EHA 2010: First prospective 2-year data on cardiac iron removal with chelation
Continued therapy with deferasirox ≥ 30 mg/kg/d effectively removed cardiac iron, well tolerated