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
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
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
Mild
• Completely asymptomatic until adult life
• Non–transfusion-dependent
Taher A, et al. Br J Haematol. 2011;152:512-523.
Severe
• Presentation at younger ages
• Transfusion dependency
β-Thalassaemia Intermedia
• “Highly diverse” group of β-thalassaemia syndromes
characterized by red blood cells that are sufficiently shortlived 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 βthalassaemia is common, particularly in the Mediterranean
and Middle East2
1. Taher A, et al. Br J Haematol. 2011;152:512-523. 2. Weatherall DJ, Clegg JB. The Thalassaemia
Syndromes. 4th ed. Wiley-Blackwell; 2001.
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;152:512-523. 2. Taher A, et al. Blood Cell Mol Dis. 2006;37:12-20.
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;141:388-397.
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; 2001. 2.Vichinsky EP. Ann NY Acad Sci. 2005;1054:18-24. 3.Vichinsky E. ASH
Education Book. 2007:1:79-83.
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;101:791-800. 2. Higgs DR, Weatherall DJ. Cell Mol Life Sci. 2009;66:1154-1162.
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;147:634-640.
Mechanism of Iron Overload in
Nontransfused Patients
Ineffective erythropoiesis
Chronic anaemia
Hypoxia
↑ HIFs
↑ GDF15
↑ Release of
recycled iron
from RES
macrophages
↓ Hepcidin
↑ Erythropoietin
↑ Ferroportin
↑ Duodenal iron
↑ LIC
absorption
Abbreviations: GDF15, growth differentiation factor 15; HIF, hypoxiainducible transcription factor; LIC, liver iron concentration; RES,
reticuloendothelial system.
With permission from Taher A, et al. Br J Haematol. 2011;152:512-523.
↓
Serum
ferritin
GDF-15 Levels in 55 Untreated Patients
with β-Thalassaemia Intermedia
1,000,000
Abbreviation: β-TI, beta thalassaemia intermedia.
With permission from Musallam KM, et al. Blood Cells Mol Dis. 2011;47:232-234.
-
β-TI
(This
report)
PKD
RARS
-CDA I
α-Thal
10
Thal-trait
100
SS
1,000
HV
GDF-15
(pg/mL
10,000
-
β-Thal
100,000
GDF-15 Levels Correlated with Clinical
Severity Score in β-TI
Mild
60,000
Moderate
Severe
GDF-15 (pg/mL)
50,000
40,000
30,000
20,000
10,000
r = .830
P <.001
0
0
1
2
3
4
5
6 7 8 9 10 11 12 13 14 15 16 17 18
Clinical Severity Score
With permission from Musallam KM, et al. Blood Cells Mol Dis. 2011;47:232-234.
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. 2009. 2. Taher A, et al. Br J Haematol. 2009;147:634-640.
Iron Overload in β-TI
3000
2500
2000
Serum Ferritin (µg/L)
Ferritin increases with age, indicating accumulation of iron
with time despite transfusion naïvety
1500
1000
500
0
0
10
20
30
Age (years)
40
50
Serum Ferritin Level Increases with Age (r = 0.653, P <.001)
With permission from Taher A, et al. Br J Haematol. 2010;150:486-489.
60
Complications vs Age
Complications in 120 treatment-naïve patients with β-TI
<≤10
10 years
years
11–20years
years
11-20
21–32 years
years
21-32
*
45
40.0
40
Frequency (%)
*
30
*
26.7
10
5
0
30.0
26.7
*
25
15
*
33.3
35
20
>32 years
years
>32
20.0
16.7
20.0
16.7
13.3
6.7
3.3
3.3
13.3
10.0
6.7
3.3
10.0
6.7
3.3
0
10.0
13.3
10.0
6.7
3.3
20.0
16.7
16.7
13.3
10.0
6.7
3.3
0 0
3.3
0
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;150:486-489.
23.3
*
20.0
16.7
13.3
6.7
23.3
0
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;22:593-597.
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;101:791-800.
2. Lal A, et al. N Engl J Med. 2011;364:710-718.
Iron Overload in HbH
Ferritin also positively correlated with age in HbH
85% of patients are iron overloaded
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;343:544-550.
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
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.
Measuring and Interpreting Serum Ferritin
Advantages
Disadvantages
• Easy to assess
• Indirect measurement of iron burden
• Inexpensive
• Fluctuates in response to inflammation,
abnormal liver function, ascorbate
deficiencies
• Repeat serial measures are useful
for monitoring chelation therapy
• Positive correlation with morbidity
and mortality
• Allows longitudinal follow-up of
patients
• Individual measures may not provide
reliable indication of iron levels and
response to chelation therapy
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; 2008. 3. Brittenham GM, et al. Blood. 2003;101:15-19.
Measuring LIC by Liver Biopsy
Advantages
Disadvantages
• Direct measurement of LIC
• Quantitative, specific, and sensitive
• Invasive; painful; potentially
serious complications,
eg, bleeding
• Allows for measurement of non-haeme
storage iron
• Risk of sampling error, especially in
patients with cirrhosis
• Provides information on liver
histology/pathology
• Inadequate standardization
between laboratories
• Positive correlation with morbidity and
mortality
• Difficult to follow up
• Validated reference standard
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; 2008. 3. Brittenham GM, et al. Blood. 2003;101:15-19.
Measuring LIC with MRI
Advantages
Disadvantages
• Assesses iron content throughout
the liver
• Indirect measurement of LIC
• Increasingly available worldwide
• Requires MRI imager with dedicated
imaging method
• Status of liver and heart can be
assessed in parallel
• Children younger than age 7 years
require a general anaesthetic
• Validated relationship with LIC
• Allows longitudinal patient follow-up
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; 2008. 3. Brittenham GM, et al. Blood. 2003;101:15-19.
Correlation Between R2 MRI and
Liver Biopsy
R2 MRI has been studied, standardized, and
validated in several iron loading states, including
hereditary haemochromatosis, betathalassaemia, 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.
Serum Ferritin and LIC by SQUID
Parameter
Thalassaemia:
Transfusion-Independent
Thalassaemia:
Transfused
Sickle Cell Disease
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)
766* (50–2681)
1733 (391–5591)
2412‡ (508–6778)
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)
0
30.5 (9.2–61.3)
13.5* (1.0–36.1)
RBC transfusions,
mL/kg/year (range)
0
171 (87–304)
104* (9–309)
Patients, N (F/M)
Serum ferritin, μg/L (range)
LIC, μg/g liver (range)
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;49:329-332.
Serum Ferritin and LIC by Liver Biopsy
TM
TI
P-value
11/11
14/8
.5
23 ± 10
20 ± 5
.08
HCV-positive (%)
73
16
<.0001
Spleen present (%)
100
14
<.0001
11.3 ± 0.3
8.8 ± 1.1
<.0001
11.8 ± 7
2748 ± 2510
11.3 ± 6
627 ± 309
.39
.0001
Gender (M/F)
Age (years)
Mean Hb (g/dL)
LIC (mg/g dry wt)*
Serum ferritin (μg/L)
• 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;92:583-588.
Serum Ferritin Underestimates
Iron Burden by MRI in β-TI
TI
Linear (TI)
Serum Ferritin Level (μg/L)
10000
TM
Linear (TM)
9000
A significant positive correlation with serum ferritin levels was observed
(R = 0.64; P <.001)
7000
LIC values measure by MRI were similar to those in patients with TM,
6000
but serum ferritin levels were significantly lower
8000
5000
4000
3000
2000
1000
0
0
5
10
15
20
25
30
35
40
45
LIC (mg Fe/g dry wt)
LIC correlated with serum ferritin levels in patients with TI (R = 0.64; P <.001)
With permission from Taher A, et al. Haematologica. 2008;93:1584-1586.
Musallam KM, Taher AT. N Engl J Med. 2011;364:1476.
50
LIC vs Morbidity in 168 Patients from
Lebanon and Italy
Parameter
Age (years), mean (SD)
Male, n (%)
Splenectomized, n (%)
Transfusion history, n (%)
None
Occasional
Regular
Total Hb (g/dL), mean (SD)
Fetal Hb (%), mean (SD)
Platelet count (x109/L), mean (SD)
NRBC count (x106/L), median (IQR)
Serum ferritin (ng/mL), median (IQR)
LIC (mg Fe/g dw), mean (SD)
Morbidity, n (%)
Osteoporosis
Pulmonary hypertension
Abnormal liver function
Thrombosis
Extramedullary hematopoiesis
Leg ulcers
Hypothyroidism
Hypogonadism
Heart failure
Diabetes mellitus
With permission from Musallam KM, et al. Haematologica. 2011;96:1605-1612.
Value
35.2 (12.6)
73 (42.9)
121 (72.0)
44 (26.2)
80 (47.6)
44 (26.2)
8.8 (1.6)
44.5 (31.1)
609.4 (346.0)
422.5 (11653)
773.3 (938.5)
8.4 (6.7)
77 (45.8)
56 (33.3)
54 (32.1)
44 (26.2)
43 (25.6)
41 (24.4)
30 (17.9)
28 (16.7)
9 (5.4)
6 (3.6)
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;96:1605-1612.
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;96:1605-1612.
Iron Chelation
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;115:1886-1892.
Slide courtesy of Dr. Taher.
In the OPTIMAL CARE Study
Chelated Patients: 336/584
Complication
Parameter
RR
95% CI
P-value
EMH
Splenectomy
Transfusion
Hydroxyurea
Age >35 y
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Transfusion
Age >35 y
Hb ≥9 g/dL
Ferritin ≥1000 ng/mL
Splenectomy
Transfusion
Age >35 y
Female
Splenectomy
Transfusion
Iron chelation
Ferritin ≥1000 ng/mL
0.44
0.06
0.52
2.59
4.11
0.33
0.42
0.53
0.06
2.60
0.41
1.86
6.59
0.28
2.76
1.96
5.19
0.36
0.30
1.74
0.26–0.73
0.03–0.09
0.30–0.91
1.08–6.19
1.99–8.47
0.18–0.58
0.20–0.90
0.29–0.95
0.02–0.17
1.39–4.87
0.23–0.71
1.09–3.16
3.09–14.05
0.16–0.48
1.56–4.87
1.18–3.25
2.72–9.90
0.21–0.62
0.18–0.51
1.00–3.02
.001
<.001
.022
.032
<.001
<.001
.025
.032
<.001
.003
.001
.023
<.001
<.001
<.001
.010
<.001
<.001
<.001
.049
Pulmonary hypertension
Heart failure
Thrombosis
Cholelithiasis
Abnormal liver function
With permission from Taher AT, et al. Blood. 2010;115:1886-1892.
In the OPTIMAL CARE Study
Chelated patients: 336/584
Complication
Parameter
Leg ulcers
Hypothyroidism
Osteoporosis
Hypogonadism
Iron
RR
95% CI
Age >35 yrs
2.09
1.05–4.16
Splenectomy
3.98
1.68–9.39
Transfusion
0.39
0.20–0.76
Hydroxyurea
0.10
0.02–0.43
Splenectomy
6.04
2.03–17.92
Hydroxyurea
0.05
0.01–0.45
Age >35 yrs
3.51
2.06–5.99
chelathion
therapy was protective
for hypogonadism,
Female
1.97
1.19–3.27
hypertension,
cholelithiasis,
and
osteoporosis.
Splenectomy
4.73
2.72-8.24
Transfusion
3.10
1.64–5.85
Hydroxyurea
0.02
0.01–0.09
Iron chelation
0.40
0.24–0.68
Female
2.98
1.79–4.96
Ferritin ≥1000 ng/mL
2.63
1.59–4.36
Transfusion
16.13
4.85–52.63
Hydroxyurea
4.32
2.49–7.49
Iron chelation
2.51
1.48–4.26
With permission from Taher AT, et al. Blood. 2010;115:1886-1892.
P-value
.036
.002
.006
.002
.001
.003
<.001
pulmonary
.009
<.001
<.001
<.001
.001
<.001
<.001
<.001
<.001
.001
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;137:267-271.
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;122:305-310.
Reduction in Iron Burden with Deferasirox at Year 1
in Patients with β-TI
Mean Values
Baseline
12 Months
P-value
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
.02
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
.02
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
Serum ferritin, µg/L
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;148:332-334.
Slide courtesy of Dr. Taher.
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):1-694. Abstr 1279. 2. Ladis V, et al. Br J Haematol. 2010; 151:504-508.
Effect of Deferasirox on Serum Ferritin and LIC in
Patients with β-TI and Nontransfusional Iron Overload
40
Serum ferritin at baseline
Serum ferritin at 1 year
Serum ferritin at 2 years
LIC (mg Fe/g dw
Serum Ferritin Levels (ng/mL)
3000
2000
LIC at baseline
LIC at 1 year
LIC at 2 years
30
20
1000
10
0
Patients
0
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):1-694. Abstr 1279.
With permission from Ladis V, et al. Br J Haematol. 2010;151:504-508.
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):1-694. Abstr 1279. 2. Ladis V, et al. Br J Haematol. 2010;151:504-508.
Deferasirox Significantly Reduces Liver
Iron Concentration In Non–TransfusionDependent Thalassaemia Patients with
Iron Overload
Results from the 1-Year Randomized,
Double-Blind, Placebo-Controlled
Phase II THALASSA Study
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.
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.
LIC Change from Baseline to Week 52
Least Squares Mean (mg Fe/g dw)
Deferasirox Significantly Reduces LIC
Compared with Placebo
1
0
Starting Deferasirox Dose
5 mg/kg/day
0.38
10 mg/kg/day
Placebo
–1
Study met its primary endpoint
–1.95
–2
–3
P = .001
–3.80
–4
P = .009
P <.001
Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.
Slide courtesy of Dr. Taher.
Deferasirox Significantly Reduces SF
Compared with Placebo
SF Change from Baseline to Week 52
Least Squares Mean (ng/mL)
150
100
Starting deferasirox dose
50
0
5 mg/kg/day
115
10 mg/kg/day
Placebo
–50
–100
–150
–121
P <.001
–200
–222
–250
P = .088
P <.001
Taher AT, et al. Presented at: 53rd ASH Annual Meeting; Dec 13, 2011: Abstr 902.
Slide courtesy of Dr. Taher.
Most Common (≥3 Patients Overall)
Drug-Related AEs
Adverse events,
Deferasirox
5 mg/kg/d
n = 55
Deferasirox
10 mg/kg/d
n = 55
Placebo
5 mg/kg/d
n = 28
Placebo
10 mg/kg/d
n = 28
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)
0
1 (3.6)
8 (4.8)
Diarrhea
0
5 (9.1)
0
1 (3.6)
6 (3.6)
Headache
2 (3.6)
1 (1.8)
0
2 (7.2)
5 (3.0)
Upper abdominal pain
2 (3.6)
1 (1.8)
0
0
3 (1.8)
Abdominal pain
1 (1.8)
1 (1.8)
1 (3.6)
0
3 (1.8)
n (%)
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.
Total
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.
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