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 Time PeriodChelation Regimen 1984-2001DFO 35-45 mg/kg/d 5x/wk 2001-2004DFP 100 mg/kg/d (clinical trial) 2004 to mid-2005DFO 35 mg/kg/d 5x/wk (clinical trial ended)

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 deferasirox 1 Oral ChelatorDosing ScheduleToxicity Profile DeferiproneThrice daily Neutropenia Agranulocytosis DeferasiroxOnce dailyNausea, diarrhea Prior Therapy (baseline) Deferasirox (end of study) Satisfied or very satisfied with therapy23%91% Therapy convenient or very convenient22%93% Time lost to therapy for daily activities (mean ± SD, hrs/month) 30.1 ± 44.23.2 ± 8.6 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 Baseline Measurement Serum ferritin3560 µg/L LIC by MRI12.4 mg Fe/g dry wt Cardiac T2* by MRI10.6 ms Serum Cr and ALTWithin normal range

6. 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 Increased risk of complications Increased risk of cardiac disease 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. ParameterNormal Iron-Overloaded State MildModerateSevere LIC, mg Fe/g dry wt< 1.23–7> 7> 15 Serum ferritin μg/L< 300> 1000 to < 2500> 2500 Transferrin saturation, %20–50> 50 T2*, ms> 2014–208–14< 8 Alanine aminotransferase, U/L< 250> 250 Labile iron pool, μM0–0.4> 0.4

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

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

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

12. DFX 20DFX 30DFX 35 After 2 years: Cardiac T2* improved by 60% LIC improved by 85% Cardiac T2* (ms)/LIC (mg Fe/g dry wt) Improvement in Cardiac T2* and LIC Over 2 Years of Therapy April 2005April 2006April 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 VariableResult After 2 Years Deferasirox Treatment Serum ferritinDecreased to 389 µg/L LICNormalized to 1.3 mg Fe/g dry wt Cardiac T2*Improved to 17 ms

14. Adverse event Frequency, n (%) Before dose escalationAfter dose escalation Median exposure (weeks)115.436.1 ALT increase12 (5.4)7 (3.1) Vomiting17 (7.6)6 (2.7) Abdominal pain15 (6.7)3 (1.3) Abdominal pain (upper) 3 (1.3) Nausea 24 (10.7)3 (1.3) Serum creatinine increase13 (5.8)3 (1.3) Rash19 (8.5)2 (0.9) Diarrhea12 (5.4)2 (0.9) Most common drug-related adverse events, as assessed by investigators (observed in > 1 patient after dose escalation to > 30 mg/kg/d) Deferasirox > 30 mg/kg/d: Safety 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 Porter J, et al. Poster presented at ASH 2007 [poster 986]. ULN = upper limit of normal Drug-related adverse eventNumber of pts (%) Nausea25 (15.3%) Diarrhea17 (10.4%) Vomiting11 (6.7%) Abdominal pain10 (6.1%) Skin rash9 (5.5%)

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 and should 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