Managing Iron Overload in Beta Thalassemia Major:

Focus on Cardiac Iron

Ali Taher, MD American University of Beirut

Lebanon

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

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 Period Chelation Regimen1984-2001 DFO 35-45 mg/kg/d 5x/wk

2001-2004 DFP 100 mg/kg/d (clinical trial)

2004 to mid-2005 DFO 35 mg/kg/d 5x/wk (clinical trial ended)

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

Oral Chelator Dosing Schedule Toxicity Profile

Deferiprone Thrice daily NeutropeniaAgranulocytosis

Deferasirox Once daily Nausea, diarrhea

Prior Therapy (baseline)

Deferasirox (end of study)

Satisfied or very satisfied with therapy 23% 91%

Therapy convenient or very convenient 22% 93%

Time lost to therapy for daily activities (mean ± SD, hrs/month) 30.1 ± 44.2 3.2 ± 8.6

1. Taher A, et al. Acta Haematologica. 2010;123:220-225.

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 MeasurementSerum ferritin 3560 µg/L

LIC by MRI 12.4 mg Fe/g dry wt

Cardiac T2* by MRI 10.6 ms

Serum Cr and ALT Within normal range

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.

Parameter Normal

Iron-Overloaded StateMild Moderate Severe

LIC, mg Fe/g dry wt < 1.2 3–7 > 7 > 15

Serum ferritin μg/L < 300 > 1000 to < 2500 > 2500

Transferrin saturation, % 20–50 > 50

T2*, ms > 20 14–20 8–14 < 8

Alanine aminotransferase, U/L < 250 > 250

Labile iron pool, μM 0–0.4 > 0.4

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.

Serum Ferritin After 7 Mo Deferasirox 20 mg/kg/d

Months

Deferasirox 20 mg/kg/d

Seru

m F

erriti

n (μ

g/L)

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

Months

Seru

m F

erriti

n (μ

g/L)

0

1,000

2,000

3,000

4,000

5,000

6,000

Apr-05

Jun-05

Aug-05

Oct-05

Dec-05

Feb-06

Apr-06

Jun-06

Aug-06

Oct-06

Dec-06

Feb-07

Apr-07

Serum ferritin levels decreased to 389 μg/L

DFX 20 DFX 30 DFX 35

Treatment and Assessments: Serum Ferritin Over 2 Years

DFX 20 = deferasirox 20 mg/kg/dayDFX 30 = deferasirox 30 mg/kg/dayDFX 35 = deferasirox 35 mg/kg/day

Months

Crea

tinin

e (µ

mol

/L)/

ALT

(U/L

)Treatment and Assessments:Serum Creatinine and ALT Over 2 Years

DFX 20 DFX 30 DFX 35

Serum Cr ULN

ALT ULN

Serum Cr > 33% above baseline

After 2 years: Cardiac T2* improved by 60%

LIC improved by 85%

Card

iac

T2*

(ms)

/LIC

(mg

Fe/g

dry

w

t)Improvement in Cardiac T2* and LIC Over 2 Years of Therapy

April 2005 April 2006 April 2007

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

Variable Result After 2 Years Deferasirox TreatmentSerum ferritin Decreased to 389 µg/L

LIC Normalized to 1.3 mg Fe/g dry wt

Cardiac T2* Improved to 17 ms

Adverse eventFrequency, n (%)

Before dose escalation After dose escalation

Median exposure (weeks) 115.4 36.1

ALT increase 12 (5.4) 7 (3.1)

Vomiting 17 (7.6) 6 (2.7)

Abdominal pain 15 (6.7) 3 (1.3)

Abdominal pain (upper) 3 (1.3) 3 (1.3)

Nausea 24 (10.7) 3 (1.3)

Serum creatinine increase 13 (5.8) 3 (1.3)

Rash 19 (8.5) 2 (0.9)

Diarrhea 12 (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.

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

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

● 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 event Number of pts (%)Nausea 25 (15.3%)

Diarrhea 17 (10.4%)

Vomiting 11 (6.7%)

Abdominal pain 10 (6.1%)

Skin rash 9 (5.5%)

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