1. Iron Overload and Its Management in Non–Transfusion-Dependent Thalassaemia (NTDT)
Ali Taher, MD, FRCP
Professor
Department of Internal Medicine
American University of Beirut Medical Center
Beirut, Lebanon

2. Definition
Non–transfusion-dependent thalassaemia (NTDT) is a group of thalassaemias for which patients do not require regular red cell transfusions for survival
They may require occasional transfusions for growth failure, pregnancy, infections…
There are 5 NTDTs
β-Thalassaemia intermedia
Haemoglobin E β-thalassaemia
Haemoglobin H disease
Haemoglobin S β-thalassaemia
Haemoglobin C thalassaemia

3. Varying Severity
These diseases form a spectrum, with 1 end being non–transfusion-dependent
Early recognition is vital to prevent placing children on lifelong transfusion therapy
Presentation at younger ages
Transfusion dependency
Completely asymptomatic until adult life
Non–transfusion-dependent
Severe
Mild
Taher A, et al. Br J Haematol. 2011;152:

4. β-Thalassaemia Intermedia
“Highly diverse” group of β-thalassaemia syndromes characterized by red blood cells that are sufficiently short- lived to cause anaemia, without patients necessarily requiring regular blood transfusions1
The severity of the clinical phenotypes varies between those of β-thalassaemia minor and β-thalassaemia major1
Thalassaemia intermedia arises from defective gene(s) leading to partial suppression of β-globin protein production1
Occurs at low frequencies in all populations where β- thalassaemia is common, particularly in the Mediterranean and Middle East2
1. Taher A, et al. Br J Haematol. 2011;152: Weatherall DJ, Clegg JB. The Thalassaemia
Syndromes. 4th ed. Wiley-Blackwell; 2001. 4

5. Determinants of Disease Severity in β-Thalassaemia Intermedia
Molecular factors1,2
Inheritance of a mild or silent β-chain mutation
Presence of a polymorphism for the enzyme Xmn-1 in the G-promoter region, associated with increased fetal haemoglobin
Coinheritance of -thalassaemia
Increased production of -globin chains by triplicated or quadruplicated -genotype associated with β-heterozygosity; also from interaction of β- and δβ-thalassaemia
Environmental factors may influence severity of symptoms2
Social conditions
Nutrition
Availability of medical care
1. Taher A, et al. Br J Haematol. 2011;152: Taher A, et al. Blood Cell Mol Dis. 2006;37:12-20.

6. Haemoglobin E β-Thalassaemia
Result of coinheritance of the structural variant haemoglobin E and 1 of the numerous β-thalassaemia alleles
Clinical severity varies with
The severity of the inherited β-allele
Genetic and environmental modifiers
Common in Southeast Asia, Bangladesh, and East India
Olivieri NF, et al. Br J Haematol. 2008;141:

7. Haemoglobin E β-Thalassaemia
β0- and β+-thal = 2%–5%1
HbE = 5%–50%2
At least 20 million people have HbE traits worldwide1
Nearly 1 million are at risk of HbE β-thalassaemia3
1. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. 4th ed. WileyBlackwell; Vichinsky EP. Ann NY Acad Sci. 2005;1054: Vichinsky E. ASH Education Book. 2007:1:79-83.

8. Haemoglobin H Disease
Result of inactivation of 3 out of 4 α-globin genes1
Variable severity depending on molecular pathology2
Deletional forms (-α/--) are mild and non–transfusion-dependent2
1 deletional and 1 nondeletional allele (αND/--) manifest a severe phenotype, sometimes requiring regular transfusion2
Common in Southeast Asia2
1. Chui D, et al. Blood. 2003;101: Higgs DR, Weatherall DJ. Cell Mol Life Sci. 2009;66:
Higgs DR, Weatherall DL. Cell Mol Life Sci. 2009;66:
Chui D, et al. Blood. 2003; 101:

9. Iron Overload in NTDT
Despite no regular transfusion therapy, NTDT patients accumulate iron with age
The mechanism is mainly increased iron absorption from the gastrointestinal tract
Occasional transfusion therapy can also increase iron loading
Due to variability, iron overload in NTDT requires regular monitoring and a tailored approach to management
Taher A, et al. Br J Haematol. 2009;147:

10. Mechanism of Iron Overload in Nontransfused Patients
↑ Erythropoietin
↑ Duodenal iron absorption
↑ Ferroportin
↑ Release of recycled iron from RES macrophages
↑ GDF15
↑ HIFs
↓ Hepcidin
↑ LIC
↓ Serum ferritin
Ineffective erythropoiesis
Chronic anaemia
Hypoxia
Combination of ineffective erythropoiesis, anemia, and hypoxia leads to a compensatory increase in serum levels of erythropoietin (EPO) as well as a decrease in serum levels of hepcidin, which controls the concentration of ferroportin on the intestinal epithelium. Two proposed regulators of hepcidin production are growth differentiation factor 15 (GDF15), secreted by erythroid precursors, and hypoxia inducible transcription factors (HIFs). Regardless of the signaling mechanism, the end result is suppression of hepcidin levels, increased intestinal iron absorption, and increased release of recycled iron from the reticuloendothelial system, which leads to depletion of macrophage iron, relatively low levels of serum ferritin, and preferential portal and hepatocyte iron loading. The pathophysiology of iron loading in TI appears similar to that observed in patients with hereditary forms of hemochromatosis, which are characterized by impaired hepcidin production.
Abbreviations: GDF15, growth differentiation factor 15; HIF, hypoxia-inducible transcription factor; LIC, liver iron concentration; RES, reticuloendothelial system.
With permission from Taher A, et al. Br J Haematol. 2011;152:

11. GDF-15 Levels in 55 Untreated Patients with β-Thalassaemia IntermediaHV SS
Thal-trait
α-Thal
β-Thal
CDA I
RARS
PKD
β-TI
(This report)
GDF-15 (pg/mL
Abbreviation: β-TI, beta thalassaemia intermedia.
With permission from Musallam KM, et al. Blood Cells Mol Dis. 2011;47:

12. GDF-15 Levels Correlated with Clinical Severity Score in β-TI
Mild
Moderate
Severe
r = .830
P <.001
With permission from Musallam KM, et al. Blood Cells Mol Dis. 2011;47:

13. Iron Overload in β-Thalassaemia Intermedia
Iron overload occurs even in thalassaemia intermedia (TI) patients who have not been transfused1,2
Iron loading: 2–5 g Fe/year1; iron develops from age 5 years2
It is much lower than in age-matched patients with transfusion-dependent thalassaemia major (TM)2
Although the rate of iron loading differs between TM and TI, the consequences are apparent in both groups of patients and include liver, heart, and endocrine organs1,2
1. Cappellini MD, et al. “Thalassaemia Intermedia.” In: ESH Handbook on Disorders of Erythropoiesis, Erythrocytes
and Iron Metabolism. Beaumont C, et al, eds. ESH Taher A, et al. Br J Haematol. 2009;147:

14. Serum Ferritin Level Increases with Age (r = 0.653, P <.001)
Iron Overload in β-TI
Ferritin increases with age, indicating accumulation of iron with time despite transfusion naïvety
Ferritin increases with age indicating accumulation of iron with time despite transfusion naïvety
Serum Ferritin Level Increases with Age (r = 0.653, P <.001)
With permission from Taher A, et al. Br J Haematol. 2010;150:

15. Complications in 120 treatment-naïve patients with β-TI
Complications vs Age
Complications in 120 treatment-naïve patients with β-TI
≤10 years
11–20 years
21–32 years
>32 years * * * * * *
* Statistically significant trend.
Abbreviations: ALF, abnormal liver function; DM, diabetes mellitus; EMH, extramedullary haematopoiesis; HF, heart failure; PHT, pulmonary hypertension.
With permission from Taher A, et al. Br J Haematol. 2010;150:

16. Iron Overload in HbE β-Thalassaemia
Variable non–transfusional iron accumulation
Early studies found substantial iron overload and evidence of end-organ damage
Results of follow-up studies show highly variable rates of iron accumulation from periods ranging from 3 to 11 years
Olivieri NF, et al. J Pediatr Hematol Oncol. 2000;22:

17. Iron Overload in HbH
High serum ferritin levels observed in older haemoglobin H α-thalassaemia patients1
Serum ferritin levels increase with age and correlate with liver iron concentration2
1. Chui DH, et al. Blood. 2003;101:
2. Lal A, et al. N Engl J Med. 2011;364:

18. Iron Overload in HbH
Ferritin also positively correlated with age in HbH
85% of patients are iron overloaded
Liver MRI showing a signal intensity of
<1 (indicating iron overload) in 85% (51/60) of patients. This was significantly (P <.001) inversely correlated with serum ferritin levels
Significant (P <.001) correlation between serum ferritin and age in
114 patients with HbH disease
With permission from Chen FE, et al. N Eng J Med. 2000;343:

19. Assessment of Iron Overload
There are several methods to assess total body iron; each carrying their own advantages and disadvantages
Serum ferritin
SQUID
Liver iron concentration by biopsy or MRI
Abbreviations: MRI, magnetic resonance imaging; SQUID, superconducting quantum interference device.

20. Measuring and Interpreting Serum Ferritin
Advantages
Disadvantages
Easy to assess
Inexpensive
Repeat serial measures are useful for monitoring chelation therapy
Positive correlation with morbidity and mortality
Allows longitudinal follow-up of patients
Indirect measurement of iron burden
Fluctuates in response to inflammation, abnormal liver function, ascorbate deficiencies
Individual measures may not provide reliable indication of iron levels and response to chelation therapy
The measurement of serum ferritin levels is an indirect measure of body iron. Long-term serial assessment is useful for monitoring chelation therapy
The predictive value of serum ferritin for major complications of iron overload varies according to the type and severity of underlying anemia and the mechanism of iron loading
Serial measurement of serum ferritin is a simple, reliable, indirect measure of total body iron
Taher A, et al. Semin Hematol. 2007;44(2 suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia,
Cyprus; Brittenham GM, et al. Blood. 2003;101:15-19.

21. Measuring LIC by Liver Biopsy
Advantages
Disadvantages
Direct measurement of LIC
Validated reference standard
Quantitative, specific, and sensitive
Allows for measurement of non-haeme storage iron
Provides information on liver histology/pathology
Positive correlation with morbidity and mortality
Invasive; painful; potentially serious complications, eg, bleeding
Risk of sampling error, especially in patients with cirrhosis
Inadequate standardization between laboratories
Difficult to follow up
Liver biopsy is the validated standard method for assessing LIC. It provides a direct measurement of LIC, being quantitative, specific and sensitive, and has been shown to be positively correlated with morbidity and mortality
However, the technique is invasive and can be painful, carrying a risk of potentially serious complications such as bleeding. In addition, there is a significant risk of sampling error and there is currently poor standardization between laboratories
Taher A, et al. Semin Hematol. 2007;44(2 Suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia,
Cyprus; Brittenham GM, et al. Blood. 2003;101:15-19.

22. Measuring LIC with MRI Advantages Disadvantages
Assesses iron content throughout the liver
Increasingly available worldwide
Status of liver and heart can be assessed in parallel
Validated relationship with LIC
Allows longitudinal patient follow-up
Indirect measurement of LIC
Requires MRI imager with dedicated imaging method
Children younger than age 7 years require a general anaesthetic
Different magnetic resonance imaging (MRI) techniques are useful for measuring iron levels in both the heart and liver
MRI can produce images in two different ways. Both methods can be used to estimate iron
Gradient echo imaging produces images for calculating T2* and R2*
Spin echo imaging produces images for calculating T2 and R2
Taher A, et al. Semin Hematol. 2007;44(2 Suppl 3):S2-S6. 2. TIF. Guidelines for the clinical management of thalassaemia. 2nd ed. Nicosia,
Cyprus; Brittenham GM, et al. Blood. 2003;101:15-19.

23. Correlation Between R2 MRI and Liver Biopsy
R2 MRI has been studied, standardized, and validated in several iron loading states, including hereditary haemochromatosis, beta-thalassaemia, and HbE/beta-thalassaemia. It has been found to significantly correlate with liver biopsy value across all these diseases. Therefore, it has been approved for usage by the FDA, TGA, and EMEA.

24. Serum Ferritin and LIC by SQUID
Parameter
Thalassaemia: Transfusion-Independent
Thalassaemia: Transfused
Sickle Cell Disease
Patients, N (F/M)
26 (17/9)
89 (43/46)
45 (26/19)
Age, years (range)
25.3* (7–55)
13.4 (3–42)
14.1 (5–50)
Weight, kg (range)
54† (21–89)
39 (13–70)
48* (20–96)
Serum ferritin, μg/L (range)
766* (50–2681)
1733 (391–5591)
2412‡ (508–6778)
LIC, μg/g liver (range)
2241 (451–5524)
2195 (712–5994)
1902 (646–4826)
ALT, U/L (range)
34 (9–81)
28 (12–136)
39 (11–104)
Hb, g/dL (range)
8.5* (6.2–10.7)
9.9 (7.6–12.5)
9.7 (7.3–12.0)
Desferrioxamine, mg/kg/day (range)
30.5 (9.2–61.3)
13.5* (1.0–36.1)
RBC transfusions, mL/kg/year (range)
171 (87–304)
104* (9–309)
β-thalassemia intermedia and HbE/β-thalassemia
Differences relative to the transfused group were tested using the U test.
*P <.001; †P <.01; ‡P <.05.
With permission from Pakbaz Z, et al. Pediatr Blood Cancer. 2007;49: 24

25. Serum Ferritin and LIC by Liver BiopsyTM TI
P-value
Gender (M/F)
11/11
14/8 .5
Age (years)
23 ± 10
20 ± 5
.08
HCV-positive (%) 73 16
<.0001
Spleen present (%)
100 14
Mean Hb (g/dL)
11.3 ± 0.3
8.8 ± 1.1
LIC (mg/g dry wt)*
11.8 ± 7
11.3 ± 6
.39
Serum ferritin (μg/L)
2748 ± 2510
627 ± 309
.0001
Only beta-thal
Serum ferritin was significantly lower in patients with TI than in those with TM, despite similar LIC by SQUID and liver biopsy
*LIC normal range is .03–1.04 mg/g dry wt.
With permission from Origa R, et al. Haematologica. 2007;92: 25 25

26. Serum Ferritin Underestimates Iron Burden by MRI in β-TITM
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000 5 10 15 20 25 30 35 40 45 50
LIC (mg Fe/g dry wt)
Serum Ferritin Level (μg/L)
Linear (TI)
Linear (TM)
A significant positive correlation with serum ferritin levels was observed (R = 0.64; P <.001)
LIC values measure by MRI were similar to those in patients with TM, but serum ferritin levels were significantly lower
LIC correlated with serum ferritin levels in patients with TI (R = 0.64; P <.001)
With permission from Taher A, et al. Haematologica. 2008;93:
Musallam KM, Taher AT. N Engl J Med. 2011;364:1476. 26 26

27. LIC vs Morbidity in 168 Patients from Lebanon and Italy
Parameter
Value
Age (years), mean (SD)
35.2 (12.6)
Male, n (%)
73 (42.9)
Splenectomized, n (%)
121 (72.0)
Transfusion history, n (%)
None
44 (26.2)
Occasional
80 (47.6)
Regular
Total Hb (g/dL), mean (SD)
8.8 (1.6)
Fetal Hb (%), mean (SD)
44.5 (31.1)
Platelet count (x109/L), mean (SD)
609.4 (346.0)
NRBC count (x106/L), median (IQR)
422.5 (11653)
Serum ferritin (ng/mL), median (IQR)
773.3 (938.5)
LIC (mg Fe/g dw), mean (SD)
8.4 (6.7)
Morbidity, n (%)
Osteoporosis
77 (45.8)
Pulmonary hypertension
56 (33.3)
Abnormal liver function
54 (32.1)
Thrombosis
Extramedullary hematopoiesis
43 (25.6)
Leg ulcers
41 (24.4)
Hypothyroidism
30 (17.9)
Hypogonadism
28 (16.7)
Heart failure
9 (5.4)
Diabetes mellitus
6 (3.6)
With permission from Musallam KM, et al. Haematologica. 2011;96:

28. LIC and Vascular Morbidity
Patients with an LIC ≥7 mg Fe/g dw had a significantly higher rate of vascular morbidity compared with patients with an LIC <7 mg Fe/g dw, in all groups of phenotype severity
With permission from Musallam KM, et al. Haematologica. 2011;96:

29. LIC and Endocrine and Bone Morbidity
Patients with an LIC ≥6 mg Fe/g dw had a significantly higher rate of endocrine morbidity compared with patients with an LIC <6 mg Fe/g dw,
in all groups of phenotype severity
A 1-mg increase in LIC was significantly associated with a significantly increased risk of developing thrombosis, pulmonary hypertension, hypothryroidism, hypogonadism, and osteoporosis
With permission from Musallam KM, et al. Haematologica. 2011;96:

30. Iron chelation

31. Overview on Practices in Thalassaemia Intermedia Management Aiming for Lowering Complication Rates Across a Region of Endemicity—The OPTIMAL CARE Study
Retrospective review of 584 TI patients from 6 comprehensive care centers in the Middle East and Italy
N = 127
N = 153
N = 200
N = 51
N = 12
N = 41
Taher AT, et al. Blood. 2010;115:
Slide courtesy of Dr. Taher.

32. In the OPTIMAL CARE Study Chelated Patients: 336/584
Complication
Parameter RR
95% CI
P-value
EMH
Splenectomy
0.44
0.26–0.73
.001
Transfusion
0.06
0.03–0.09
<.001
Hydroxyurea
0.52
0.30–0.91
.022
Pulmonary hypertension
Age >35 y
2.59
1.08–6.19
.032
4.11
1.99–8.47
0.33
0.18–0.58
0.42
0.20–0.90
.025
Iron chelation
0.53
0.29–0.95
Heart failure
0.02–0.17
Thrombosis
2.60
1.39–4.87
.003
Hb ≥9 g/dL
0.41
0.23–0.71
Ferritin ≥1000 ng/mL
1.86
1.09–3.16
.023
6.59
3.09–14.05
0.28
0.16–0.48
Cholelithiasis
2.76
1.56–4.87
Female
1.96
1.18–3.25
.010
5.19
2.72–9.90
0.36
0.21–0.62
0.30
0.18–0.51
Abnormal liver function
1.74
1.00–3.02
.049
With permission from Taher AT, et al. Blood. 2010;115:

33. In the OPTIMAL CARE Study Chelated patients: 336/584
Complication
Parameter RR
95% CI
P-value
Leg ulcers
Age >35 yrs
2.09
1.05–4.16
.036
Splenectomy
3.98
1.68–9.39
.002
Transfusion
0.39
0.20–0.76
.006
Hydroxyurea
0.10
0.02–0.43
Hypothyroidism
6.04
2.03–17.92
.001
0.05
0.01–0.45
.003
Osteoporosis
3.51
2.06–5.99
<.001
Female
1.97
1.19–3.27
.009
4.73
3.10
1.64–5.85
0.02
0.01–0.09
Iron chelation
0.40
0.24–0.68
Hypogonadism
2.98
1.79–4.96
Ferritin ≥1000 ng/mL
2.63
1.59–4.36
16.13
4.85–52.63
4.32
2.49–7.49
2.51
1.48–4.26
Iron chelathion therapy was protective for hypogonadism, pulmonary hypertension, cholelithiasis, and osteoporosis.
With permission from Taher AT, et al. Blood. 2010;115:

34. Iron Chelation Therapy in Thalassaemia Intermedia Desferrioxamine
Significant decline in serum ferritin after 6 months of desferrioxamine treatment
Significant urinary iron excretion (UIE) after 12 hours of continuous desferrioxamine (except in patients age <1 year)
In some patients, substantial UIE despite modest serum ferritin levels
Serum ferritin levels of no value in predicting UIE
No significant differences in excretion across doses
Cossu P, et al. Eur J Pediatr. 1981;137:

35. Iron Chelation Therapy in Thalassaemia Intermedia Deferiprone
Significant reductions seen in mean serum ferritin, hepatic iron, red-cell membrane iron, and serum NTBI levels
Serum ferritin ± SD
Initial 2168 ± 1142 μg/L
Final 418 ± 247 μg/L
Significant mean increase in serum erythropoietin also observed
Increase in Hb values in 3 patients; reduction in transfusion requirements in 4 patients
Abbreviation: NTBI, non–transferrin-bound iron.
Pootrakul P, et al. Br J Hematol. 2003;122:

36. Reduction in Iron Burden with Deferasirox at Year 1 in Patients with β-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
Voskaridou E, et al. Br J Haematol. 2010;148:
Slide courtesy of Dr. Taher.

37. Deferasirox for Nontransfusional Iron Overload in Patients with β-TI
11 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
1. Ladis V, et al. Haematologica. 2009;94(suppl 2): Abstr Ladis V, et al. Br J Haematol. 2010; 151:

38. Effect of Deferasirox on Serum Ferritin and LIC in Patients with β-TI and Nontransfusional Iron Overload
1000
2000
3000
Serum Ferritin Levels (ng/mL)
Patients 40
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 30
LIC (mg Fe/g dw 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
Ladis V, et al. Haematologica. 2009;94(suppl 2): Abstr 1279.
With permission from Ladis V, et al. Br J Haematol. 2010;151:

39. 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
1. Ladis V, et al. Haematologica. 2009;94(suppl 2): Abstr Ladis V, et al. Br J Haematol. 2010;151:

40. Deferasirox Significantly Reduces Liver Iron Concentration In Non–Transfusion-Dependent Thalassaemia Patients with Iron Overload
Results from the 1-Year Randomized, Double-Blind, Placebo-Controlled Phase II THALASSA Study

41. Aim of the THALASSA Study
Primary objective: To assess the efficacy of 2 deferasirox regimens (starting doses 5 and 10 mg/kg/day) in patients with NTDT, based on the change in LIC from baseline after 1 year of treatment compared with placebo-treated patients
Other objectives
To compare change from baseline in serum ferritin (SF) over 1 year of treatment between deferasirox and placebo treatment groups
To evaluate the safety of both regimens of deferasirox vs placebo
To evaluate the relationship between SF and LIC
To evaluate the iron accumulation rate based on LIC assessment in patients treated with placebo
Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.

42. Key Inclusion/Exclusion Criteria
Inclusion criteria
Male or female age ≥10 years with NTDT
No transfusions within the previous 6 months prior to study entry
LIC ≥5 mg Fe/g dw by R2 MRI
SF >300 ng/mL
Exclusion criteria
HbS variants of thalassaemia syndromes
Anticipated regular transfusions during the study
Chelation within 1 month prior to study treatment
History of deferasirox exposure
Lab values–creatinine clearance ≤60 mL/min, serum creatinine >ULN and ALT >5 x ULN at screening
Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal.
Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.

43. Deferasirox Significantly Reduces LIC Compared with Placebo
–1.95
–3.80
0.38
Placebo
5 mg/kg/day
10 mg/kg/day
Starting Deferasirox Dose 1 –1 –2 –3 –4
LIC Change from Baseline to Week 52 Least Squares Mean (mg Fe/g dw)
P = .001
P <.001
P = .009
Study met its primary endpoint
Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.
Slide courtesy of Dr. Taher.

44. Deferasirox Significantly Reduces SF Compared with Placebo
–121
–222
115
Placebo
5 mg/kg/day
10 mg/kg/day
Starting deferasirox dose
SF Change from Baseline to Week 52 Least Squares Mean (ng/mL)
P <.001
P = .088
150
100 50
–50
–100
–150
–200
–250
Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.
Slide courtesy of Dr. Taher.

45. Most Common (≥3 Patients Overall) Drug-Related AEs
Adverse events, n (%)
Deferasirox 5 mg/kg/d n = 55
Deferasirox mg/kg/d n = 55
Placebo 5 mg/kg/d n = 28
Placebo mg/kg/d n = 28
Total n = 166
Nausea
3 (5.5)
4 (7.3)
1 (3.6)
3 (10.7)
11 (6.6)
Skin rash
2 (3.6)
5 (9.1)
8 (4.8)
Diarrhea
6 (3.6)
Headache
1 (1.8)
2 (7.2)
5 (3.0)
Upper abdominal pain
3 (1.8)
Abdominal pain
Overall AE incidence comparable between deferasirox and placebo
Most drug-related AEs were of mild-to-moderate severity and resolved without discontinuation of treatment
Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.
Slide courtesy of Dr. Taher.

46. THALASSA in Brief
THALASSA is the first multinational, randomized, double-blind, placebo-controlled study evaluating iron chelation therapy in NTDT patients
High baseline iron burden and increasing LIC and SF in placebo highlight the need for iron chelation therapy
Compared with placebo, deferasirox at starting doses 5 and 10 mg/kg/d with dose escalations up to 20 mg/kg/d in patients with high levels of iron overload significantly reduced LIC and SF
Deferasirox 10 mg/kg/d was superior to 5 mg/kg/d in reducing LIC
Lower dose range than required in transfusion-dependent thalassaemia patients (20–40 mg/kg/d)
Overall frequency of AEs with deferasirox in both dose groups was comparable with placebo
Based on benefit/risk profile of deferasirox in NTDT patients, chelation therapy should be considered when LIC >5 mg Fe/g dw
Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.

47. Conclusions
Despite being non–transfusion-dependent, NTDT patients are still at an increased risk of complications, including iron overload
Total body iron should be periodically assessed and chelation therapy tailored accordingly
In the THALASSA study, deferasirox was shown to be safe and efficacious in reducing iron in NTDT and is awaiting approval