Managing Iron Overload in Beta Thalassemia Major: Focus on Cardiac Iron

1. Managing Iron Overload in Beta Thalassemia Major: Focus on Cardiac Iron Ali Taher, MD American University of Beirut Lebanon

2. Baseline Patient Characteristics • At presentation • 22-year-old male patient diagnosed with beta thalassemia major at age 6 months • Normal ECG • Echocardiography showed LVEF of 70% • No history of hepatitis B • Hepatitis C-positive by PCR • Received peg-interferon and ribavirin from March 2003 until March 2004, after which PCR was negative ECG = electrocardiogram; LVEF = left ventricular ejection fraction; PCR = polymerase chain reaction

3. Treatment History: Iron Chelation Therapy • Patient transfused for 21 years (since 1983): total of 14 blood transfusions/year • Serum ferritin range: 1823-4350 µg/L • Received calcium and folic acid supplements • Patient expressed dissatisfaction with burdensome subcutaneous regimen • Was often noncompliant with treatment DFO = deferoxamine; DFP = deferiprone

4. Oral Chelators: Potential to Improve Compliance • ESCALATOR Study (N=237): Compared pt ratings for satisfaction and convenience with prior tx (DFO or DFP) vs deferasirox1 1. Taher A, et al. Acta Haematologica. 2010;123:220-225.

5. Deferasirox Therapy • Patient was willing to switch to deferasirox • In year prior to starting deferasirox, patient received 14 transfusions, each 2 units PRBC (9530 mL total)  2.3 units PRBC/mo ALT = alanine aminotransferase; Cr = creatinine; LIC = liver iron concentration; MRI = magnetic resonance imaging; PRBC = packed red blood cells

6. Increased risk of complications Increased risk of cardiac disease Iron Overload Assessment Patient has moderate-to-severe iron overload serum ferritin is 3560 µg/L; LIC = 12.4 mg Fe/g dry wt; cardiac T2*= 10.6 ms Jensen PD, et al. Blood. 2003;101:4632-4639. Data from Jensen PD, et al. Blood. 2003;101:91-96. Olivieri NF, Brittenham GM. Blood. 1997;89:739-761.

7. Deferasirox Dosing by Transfusion Requirements and Therapeutic Goals Recommended initial deferasirox dosage 20 mg/kg/d Starting dosages may also be modified as follows: Deferasirox dosage Transfusion requirement Therapeutic goal 30 mg/kg/d Reduction of body iron PRBCs > 14 mL/kg/mo(~4 adult units) Maintenance of body iron 10 mg/kg/d PRBCs < 7 mL/kg/mo(~2 adult units) For patients well managed on DFO, suggested starting dosage may be numerically half DFO dosage, eg: Deferasirox 20 mg/kg/d DFO 40 mg/kg/d 5 d/wk EXJADE® (deferasirox) Basic Prescribing Information. Novartis Pharma AG. National Prescribing Information should be followed.

8. Serum Ferritin After 7 Mo Deferasirox 20 mg/kg/d Serum Ferritin (μg/L) Deferasirox 20 mg/kg/d Months

9. Case Study Details: Response to Dosage Increase • Patient’s dosage increased to 30 mg/kg/d • Dosage further increased to 35 mg/kg/d after 4 months because serum ferritin level was relatively unchanged • Patient continued to receive 2.3 units PRBC/month

10. Treatment and Assessments: Serum Ferritin Over 2 Years Serum ferritin levels decreased to 389 μg/L Serum Ferritin (μg/L) DFX 20 DFX 30 DFX 35 Months DFX 20 = deferasirox 20 mg/kg/dayDFX 30 = deferasirox 30 mg/kg/dayDFX 35 = deferasirox 35 mg/kg/day

11. Treatment and Assessments:Serum Creatinine and ALT Over 2 Years Serum Cr ULN Serum Cr > 33% above baseline Creatinine (µmol/L)/ALT (U/L) ALT ULN DFX 20 DFX 30 DFX 35 Months

12. DFX 20 DFX 30 DFX 35 Improvement in Cardiac T2* and LIC Over 2 Years of Therapy Cardiac T2* (ms)/LIC (mg Fe/g dry wt) After 2 years: Cardiac T2* improved by 60% LIC improved by 85% April 2005 April 2006 April 2007

13. Successful Chelation Achieved Via Titration • Although patient received deferasirox 20 mg/kg/d for almost 7 months, serum ferritin levels remained stable • Dosage was increased to 30 mg/kg/d for 4 months and then to 35 mg/kg/d • Patient did not experience any progressive increases in serum creatinine or liver enzyme levels

14. Deferasirox > 30 mg/kg/d: Safety Most common drug-related adverse events, as assessed by investigators (observed in > 1 patient after dose escalation to > 30 mg/kg/d) Taher A, et al. Br J Haematol. 2009;147:752-759.

15. Follow-Up • At this time, deferasirox treatment was stopped, because serum ferritin levels were < 500 µg/L at 2 consecutive study visits • Deferasirox dosage lowered to 0 mg/kg/d as of 18 May 2007 and later reinitiated when serum ferritin rose to > 1000 µg/L

16. Follow-Up: Serum Ferritin < 500 µg/L at 2 Consecutive Visits • Prescribing information suggests temporary discontinuation of deferasirox when serum ferritin levels drop to < 500 µg/L • However, patient still had • Continuous transfusion requirement and cardiac iron overload (cardiac T2* = 17 ms) • No evidence of iron chelator-related toxicity • Consider decreasing dose when serum ferritin levels drop to < 1000 µg/L; titrate to 500 µg/L instead of discontinuing treatment

17. In total, 163 patients (25.0%) achieved serum ferritin levels ≤ 1000 μg/L after a median of 1.2 years on deferasirox Most common drug-related adverse events were transient and mild to moderate in severity 10 pts (6.1%) had 2 consecutive serum creatinine increases of > 33% above baseline and ULN; most were only marginally > ULN and none were > 2x ULN All increases were nonprogressive and responded promptly to dose reduction Safety Profile in Patients Who Achieved Serum Ferritin Levels ≤ 1000 μg/L ULN = upper limit of normal Porter J, et al. Poster presented at ASH 2007 [poster 986].

18. Successful Chelation Achieved:Key Lessons Deferasirox effectively removes iron from the blood and organs Deferasirox at 30-40 mg/kg/d is effective in patients with liver and cardiac iron overload Adjustments should be made in steps of 5 or 10 mg/kg/d andshould be tailored to individual patient response and therapeutic goals (maintenance or reduction of iron burden) Careful dose titration is necessary to avoid overchelation; however, treatment should not be interrupted based on serum ferritin values alone