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
Time Period
Chelation Regimen
1984-2001
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)
• 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
Oral Chelators: Potential to Improve Compliance
Oral Chelator
Dosing Schedule
Toxicity Profile
Deferiprone
Thrice daily
Neutropenia
Agranulocytosis
Deferasirox
Once daily
Nausea, diarrhea
● ESCALATOR Study (N=237): Compared pt ratings for satisfaction and
convenience with prior tx (DFO or DFP) vs deferasirox1
Prior Therapy
Deferasirox
(baseline)
(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
Baseline Measurement
Serum ferritin
LIC by MRI
Cardiac T2* by MRI
Serum Cr and ALT
3560 µg/L
12.4 mg Fe/g dry wt
10.6 ms
Within normal range
ALT = alanine aminotransferase; Cr = creatinine; LIC = liver iron concentration; MRI = magnetic resonance imaging;
PRBC = packed red blood cells
Iron Overload Assessment
Increased risk of complications
Increased risk of cardiac disease
Iron-Overloaded State
Parameter
Normal
Mild
Moderate
Severe
LIC, mg Fe/g dry wt
< 1.2
3–7
>7
> 15
Serum ferritin μg/L
< 300
Transferrin saturation, %
20–50
> 1000 to < 2500
> 2500
> 50
T2*, ms
> 20
14–20
8–14
<8
Alanine aminotransferase, U/L
< 250
> 250
Labile iron pool, μM
0–0.4
> 0.4
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.
Deferasirox Dosing by Transfusion Requirements
and Therapeutic Goals
Recommended initial
deferasirox dosage
20 mg/kg/d
Starting dosages may also be modified as follows:
Transfusion requirement
Therapeutic goal
Deferasirox dosage
PRBCs > 14 mL/kg/mo
(~4 adult units)
Reduction of body iron
30 mg/kg/d
PRBCs < 7 mL/kg/mo
(~2 adult units)
Maintenance of body iron
10 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
EXJADE® (deferasirox) Basic Prescribing Information. Novartis Pharma AG.
National Prescribing Information should be followed.
Deferasirox 20 mg/kg/d
Serum Ferritin (μg/L)
Serum Ferritin After 7 Mo Deferasirox
20 mg/kg/d
Deferasirox 20 mg/kg/d
Months
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
Treatment and Assessments: Serum Ferritin
Over 2 Years
Serum Ferritin (μg/L)
6,000
Serum ferritin levels
decreased to 389 μg/L
5,000
4,000
3,000
2,000
1,000
0
DFX 20
Apr- Jun- Aug05
05
05
DFX 20 = deferasirox 20 mg/kg/day
DFX 30 = deferasirox 30 mg/kg/day
DFX 35 = deferasirox 35 mg/kg/day
DFX 30
Oct05
Dec05
DFX 35
Feb06
Apr06
Months
Jun06
Aug06
Oct06
Dec06
Feb07
Apr07
Treatment and Assessments:
Serum Creatinine and ALT Over 2 Years
Creatinine (µmol/L)/ALT (U/L)
Serum Cr ULN
Serum Cr > 33% above baseline
ALT ULN
DFX 20
DFX 30
DFX 35
Months
Cardiac T2* (ms)/LIC (mg Fe/g dry wt)
Improvement in Cardiac T2* and LIC Over
2 Years of Therapy
After 2 years:
Cardiac T2*
improved
by 60%
LIC improved
by 85%
DFX 20
April 2005
DFX 30
DFX 35
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
Serum ferritin
LIC
Cardiac T2*
Result After 2 Years Deferasirox Treatment
Decreased to 389 µg/L
Normalized to 1.3 mg Fe/g dry wt
Improved to 17 ms
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)
Frequency, n (%)
Adverse event
Median exposure (weeks)
Before dose escalation After dose escalation
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)
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)
Abdominal pain (upper)
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
Safety Profile in Patients Who Achieved Serum
Ferritin Levels ≤ 1000 μg/L
● 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
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%)
● 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
ULN = upper limit of normal
Porter J, et al. Poster presented at ASH 2007 [poster 986].
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