1. Clinical Case:
Managing Iron Overload in a Patient with Transfusion-Independent Thalassaemia Intermedia
Ali T. Taher, MD
Professor Department of Internal Medicine American University of Beirut Medical Center Beirut, Lebanon 1

2. Patient Presentation 26-year-old fisherman of Mediterranean origin
Diagnosed with thalassaemia intermedia at age 3 years
Chief symptoms were pallor, mild anaemia, and mild splenomegaly
Transfused once during childhood, before splenectomy
Referred for evaluation of iron overload
Physical exam nonrevealing
Haemoglobin level 9.6 g/dL
Steady-state serum ferritin level 520 ng/mL 2 2

3. Decision Point 1 What Is the Best Next Step?
a. Perform liver iron concentration measurement using MRI
b. Send patient home, since transfusion history is insignificant
c. Reassure patient, since ferritin level is relatively low
d. Perform liver iron concentration measurement using biopsy

4. Decision Point 1 What Is the Best Next Step?
a. Perform liver iron concentration measurement using MRI
CORRECT: Noninvasive; validated in thalassaemia intermedia patients; allows longitudinal follow-up
b. Send patient home, since transfusion history is insignificant
INCORRECT: Transfusion-independent thalassaemia intermedia patients are at risk of iron overload secondary to increased intestinal absorption and ineffective erythropoiesis
c. Reassure patient, since ferritin level is relatively low
INCORRECT: Serum ferritin is unreliable and underestimates iron burden in thalassaemia intermedia
d. Perform liver iron concentration measurement using biopsy
INCORRECT: Invasive; risk of sampling error; inadequate standardization between labs; follow-up difficult

5. Serum Ferritin vs LIC Measurement by R2 MRI in Patients with TI
10,000
Linear TI
9000 TM
8000
Linear TM
7000
6000
Serum Ferritin Level (ng/mL)
5000
4000
3000
2000
1000
Moreover, in cross sectional studies, it has been found that patients with thalassemia intermedia have ferritin levels lower than those of thalassemia major patients with the same LIC. This may be attributed to the different mechanisim of iron overload in both populations. Where thalassemia major patients develop iron overload due to repeated blood transfusions, non transfused patients with thalassemia intermedia develop iron overload secondary to chronic anemia and hypoxia which result increased intestinal iron absorption and release from the RES (thus depleting macrophage ferritin). 5 10 15 20 25 30 35 40 45 50
LIC (mg Fe/g dry weight)
LIC correlated with serum ferritin levels in patients with TI (R = 0.64; P <.001)
Abbreviations: LIC, liver iron concentration; TI, thalassaemia intermedia; TM, thalassaemia major. With permission from Taher A, et al. Haematologica. 2008;93: 5 5

6. LIC Measurement by R2 MRI in TI vs TM
LIC Calculated from the Equations of the Plots of LIC vs Serum Ferritin
Serum Ferritin (μg/L)
LIC (mg Fe/g dry wt)
In TM
In TI
500
2.7
5.8
1000
5.4
11.6
1500
8.2
17.4
2000
10.9
23.2
Extrapolating from the above table: when LIC = 7 mg Fe/g dry wt → serum ferritin is 604 μg/L in patients with TI
LICs in patients with TM were not significantly different from values in patients with TI, whereas serum ferritin levels were statistically different between TI and TM
Taher A, et al. Haematologica. 2008;93:

7. Case Continues
Patient’s liver iron concentration on R2 MRI was 11 mg Fe/g dry weight
Patient also underwent MRI T2* of the heart to evaluate for cardiac iron overload
Cardiac T2* = 36 ms (normal >20 ms) 7 7

8. Decision Point 2 What Is the Best Next Step?
a. Repeat cardiac MRI T2* because it must be wrong
b. Repeat liver MRI periodically and start iron chelation therapy when LIC >15 mg Fe/g dry weight
c. Start iron chelation therapy with desferrioxamine
d. Initiate phlebotomy

9. Decision Point 2 What Is the Best Next Step?
a. Repeat cardiac MRI T2* because it must be wrong
INCORRECT: Cardiac iron overload may be absent despite significant hepatic iron overload in patients with thalassaemia intermedia
b. Repeat liver MRI periodically and start iron chelation therapy when LIC >15 mg Fe/g dry weight
INCORRECT: Current recommendation in thalassaemia intermedia is to start chelation at LIC >7 mg Fe/g dry weight
c. Start iron chelation therapy with desferrioxamine
CORRECT: Proven effective and safe in thalassaemia intermedia
d. Initiate phlebotomy
INCORRECT: Patient has advantage of being transfusion-independent; phlebotomy will induce anaemia and mandate later transfusion

10. Iron Overload and Desferrioxamine Chelation Therapy in Thalassaemia Intermedia
6-month trial of 12-hour infusion of desferrioxamine in 10 transfusion-independent thalassaemia intermedia patients
To determine optimal dosage for iron elimination, 5 regimens were administered each day for 3 consecutive days
20, 40, 60, 80, and 100 mg/kg/day
Maximum dose not exceeding 2 g/day
Significant lowering of serum ferritin after 6 months, with tolerable safety profile
Cossu P, et al. Eur J Pediatr. 1981;137:

11. Urinary Iron Excretion by Dose of Desferrioxamine and Age of Patients with Thalassaemia Intermedia
20 mg/kg (r = .81)
60 mg/kg
40 mg/kg (r = .79)
60 mg/kg (r = .82) 10
40 mg/kg
Urinary Iron (mg/24h) 5
20 mg/kg 5 10 15
Age (Years)
Significant urinary iron excretion (UIE) after 12 hours of continuous desferrioxamine (except in patients aged <1 year)
In some patients, substantial UIE despite modest serum ferritin levels
Serum ferritin levels of no value in predicting UIE
With permission from Cossu P, et al. Eur J Pediatr. 1981;137:

12. Case Continues
After 6 months of desferrioxamine therapy the patient was re-evaluated using liver R2 MRI
LIC = 10.5 mg Fe/g dry weight
Patient’s wife admitted he was skipping most of his doses because the idea of carrying a pump around at his age created major discomfort 12 12

13. Decision Point 3 What Is the Best Next Step?
a. Increase desferrioxamine dose
b. Shift the patient to deferasirox
c. Decrease desferrioxamine dose
d. Send patient to counseling

14. Decision Point 3 What Is the Best Next Step?
a. Increase desferrioxamine dose
INCORRECT: The patient is noncompliant, and safety issues will ensue
b. Shift the patient to deferasirox
CORRECT: Given patient’s dissatisfaction with infusion treatment, an oral chelator seems a more promising alternative than continuing on desferrioxamine
c. Decrease desferrioxamine dose
INCORRECT: The patient’s noncompliance is not related to nontolerance (ie, side effects) but rather psychosocial burden
d. Send patient to counseling
INCORRECT: No current evidence on efficacy

15. Reduction in Iron Burden with Deferasirox at Year 1 in Patients with TI
Mean values
Baseline
12 months
P-value
Serum ferritin, µg/L
2030 ± 1340
1165 ± 684
.02
Liver T2, ms
20.1 ± 4.1
23.7 ± 6.2
.01
Liver T2*, ms
3.4 ± 3.0
4.4 ± 3.0
Cardiac T2*, ms
38.9 ± 5.9
39.8 ± 4.5
.64
LVEF, %
66.3 ± 8.1
66.9 ± 7.9
.76
Aspartate aminotransferase, U/L
64.8 ± 29.6
42.5 ± 18.1
.04
Alanine aminotransferase, U/L
63.5 ± 29.5
36.5 ± 17.6
Serum creatinine, mg/dL
0.67 ± 0.15
0.75 ± 0.19
.07
Cystatin C, mg/L
0.98 ± 0.23
1.13 ± 0.27
.094
Mean cardiac T2* and LVEF (both normal at baseline), serum creatinine, and cystatin C did not significantly change after 12 months of treatment with deferasirox
Deferasirox can effectively reduce iron burden in patients with TI
Abbreviations: LVEF, left ventricular ejection fraction; TI, thalassaemia intermedia.
With permission from Voskaridou E, et al. Haematologica. 2009;94(suppl 2):79(abstr 0204).

16. Deferasirox for Nontransfusional Iron Overload in Patients with Thalassaemia Intermedia
6 male, 5 female
Mean age 31.7 years
10 splenectomized
Deferasirox regimen
1 year (n = 11), 2 years (n = 4)
10 mg/kg/day (n = 7), 20 mg/kg/day (n = 4)
Dose adjustment after first year
Ladis V, et al. Haematologica. 2009;94(suppl 2):509(abstr 1279).

17. LIC (mg Fe/g dry weight)
Effect of Deferasirox on Serum Ferritin and LIC in Patients with TI and Nontransfusional Iron Overload
Serum ferritin at baseline
Serum ferritin at 1 year
Serum ferritin at 2 years
LIC at baseline
LIC at 1 year
LIC at 2 years
1000
2000
3000
Serum Ferritin Levels (ng/mL)
Patients 40 30
LIC (mg Fe/g dry weight) 20 10
Patients
1 patient, who was noncompliant, did not show decrease of iron overload and was excluded from graph
Changes in LIC and ferritin levels were related to deferasirox dose, but even patients with severe iron load, treated with 10 mg/kg/day, responded well
With permission from Ladis V, et al. Haematologica. 2009;94(suppl 2):509(abstr 1279).

18. Safety of Deferasirox During Treatment of up to 2 Years
Treatment was well tolerated
No serious adverse events were noted
Creatinine and cystatin C levels did not change during treatment
Transaminase levels significantly decreased in year 1 (P = .0002) and year 2 (P = .024) of treatment
This improvement probably due to decreased hepatic siderosis
Ladis V, et al. Haematologica. 2009;94(suppl 2):509(abstr 1279).

19. Ongoing Clinical Evaluation of Deferasirox
Prospective, randomized, double-blind, placebo-controlled triala
Patients (age ≥10 years) with non–transfusion-dependent β-thalassaemia (no transfusion required within 6 months prior to the study)
2 doses: 5 mg/kg/day and 10 mg/kg/day
Screening 4 weeks; treatment period 52 weeks
Primary objective
To assess the efficacy of deferasirox in patients with non–transfusion-dependent β-thalassaemia, based on the change in LIC from baseline after 1 year of treatment compared with placebo-treated patients
aAli T. Taher, MD, principal investigator; Study ID ICL670A2209.

20. Case Continues Patient was shifted to deferasirox 20 mg/kg/day
Over the next 2 years his liver R2 MRI measurements improved
Year 1 LIC = 5.3 mg Fe/g dry weight
Year 2 LIC = 2.9 mg Fe/g dry weight 20 20

21. Conclusions
Iron overload occurs in patients with thalassaemia intermedia in the absence of blood transfusions
Serum ferritin underestimates the severity of iron overload in patients with thalassaemia intermedia
Hence, the use of R2 MRI to measure LIC is favored
Initial results of the oral iron chelator deferasirox indicate that it can effectively and safely reduce iron burden in this patient population 21 21