Dr. Ali Taher - Thalassemia intermedia

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EHA & WFH
HIGHLIGHTS
July 30-31, 2010
Rest House Tyr
Lebanon
THALASSEMIA INTERMEDIA
TREATMENT STRATEGIES
Ali Taher, M.D.
American University of Beirut Medical Center
Beirut - Lebanon
Tyr | July 2010
THALASSEMIA INTERMEDIA
REVISITED
Part I
β-Thalassemia intermedia (TI)
● “Highly diverse” group of β-thalassemia syndromes where red blood
cells are sufficiently short-lived to cause anemia but not necessarily
the need for regular blood transfusions.
● Clinical phenotypes lie in severity between those of β-thalassemia
minor and β-thalassemia major (TM).
● Arises from defective gene(s) leading to partial suppression of
β-globin protein production.
Mild
Completely asymptomatic
until adult life
Severe
Presentation at age 2–6 years
Retarded growth and development
Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.
Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.
Determinants of disease severity
● Molecular factors
– 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 HbF
– co-inheritance of -thalassaemia
– increased production of -globin chains by triplicated or
quaduplicated -genotype associated to β-heterozygosity; also
from interaction of β- and δβ-thalassaemia
● Environmental factors may influence severity of
symptoms, e.g.
– social conditions
– nutrition
– availability of medical care
HbF = fetal hemoglobin.
Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.
Pathophysiology summarized
Excess free
α-globin chains
Denaturation
Degradation
Formation of heme
and hemichromes
• Ineffective erythropoiesis
Iron-mediated toxicity
Membrane
• Chronic anemia
and hemolysis
Ineffective
binding of
Hemolysis
• erythropoiesis
Iron overload IgG
Removal of
and C3
damaged red cells
Increased
erythropoietin
synthesis
Skeletal
deformities,
osteopenia
Reduced tissue
oxygenation
Anemia
Erythroid
marrow
expansion
Splenomegaly
Increased
Iron absorption
Iron overload
Olivieri NF, et al. N Engl J Med. 1999;341:99-109.
Prevalence of common
complications in TI vs TM
Complication
(% of patients affected)
Splenectomy
Cholecystectomy
Gallstones
Extramedullary hemopoiesis
Leg ulcers
Thrombotic events
Cardiopathy*
Pulmonary hypertension†
Abnormal liver enzymes
HCV infection
Hypogonadism
Diabetes mellitus
Hypothyroidism
TI
Lebanon
(n = 37)
90
85
55
20
20
28
3
50
20
7
5
3
3
TM
Italy
(n = 63)
67
68
63
24
33
22
5
17
22
33
3
2
2
Lebanon
(n = 40)
95
15
10
0
0
0
10
10
55
7
80
12.5
15
Italy
(n = 60)
83
7
23
0
0
0
25
11
68
98
93
10
11
*Fractional shortening < 35%. †Defined as pulmonary artery systolic pressure > 30 mmHg; a well-enveloped tricuspid
regurgitant jet velocity could be detected in only 20 patients, so frequency was assessed in these patients only.
HCV = hepatitis C virus.
Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.
Overview on Practices in Thalassemia Intermedia
Management Aiming for Lowering Complication-rates
Across a Region of Endemicity: the OPTIMAL CARE study
● Retrospective review of 584 TI patients from six
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 ;115:1886-92.
Overall study population
Parameter
Frequency
n (%)
Complications
Frequency
n (%)
Age (yrs)
<18
18-35
>35
172 (29.5 )
288 (49.3)
124 (21.2)
Male : Female
291 (49.8) : 293 (50.2)
Splenectomized
325 (55.7)
Serum ferritin (ng/ml)
<1000
1000-2500
>2500
376 (64.4)
179 (30.6)
29 (5)
Osteoporosis
EMH
Hypogonadism
Cholelithiasis
Thrombosis
Pulmonary hypertension
Abnormal liver function
Leg ulcers
Hypothyroidisim
Heart failure
Diabetes mellitus
134 (22.9)
124 (21.2)
101 (17.3)
100 (17.1)
82 (14)
64 (11)
57 (9.8)
46 (7.9)
33 (5.7)
25 (4.3)
10 (1.7)
EMH = extramedullary hematopoiesis
Taher AT, et al. Blood. 2010 ;115:1886-92.
120 Treatment-naïve patients
Hemoglobin (g/dl)
12.0
10.0
8.0
6.0
Age vs. hemoglobin level (rs=-0.679, P<0.001)
4.0
2.0
0.0
0
20
40
Age (years)
60
Serum ferritin (ng/ml)
3000
2500
2000
Age vs. serum ferritin level (rs=0.653, P<0.001)
1500
1000
500
0
0
20
40
Age (years)
60
Taher A, et al. Br J Haematol 2010. Epub ahead of print.
Complications vs. Age
● Complications in 120 treatment-naïve patients with TI
< 10 years
11-20 years
40.0
40
Frequency (%)
*26.7
30
*26.7
25
10
5
0
* = statistically significant trend
*30.0
33.3
35
15
>32 years
*
45
20
21-32 years
20.0
16.7
13.3
6.7
*
20.0
23.3
*
20.0
16.7
16.7 16.7
13.3
6.7
3.3
3.3
13.3
10.0
10.0 10.0
6.7
6.7
3.3
3.3
0.0
13.3
10.0
6.7
3.3
23.3
20.0
16.7
13.3
10.0
6.7
3.3
0.0
0.0
3.3
0.0
0.0
Taher A, et al. Br J Haematol 2010. Epub ahead of print.
TREATMENT OPTIONS
Part I
Splenectomy
● Less common than in the past
– before age 5 years it carries a high risk of infection
and is therefore not generally recommended
● Main indications include
–
–
–
–
–
growth retardation or poor health
leukopenia
thrombocytopenia
increased transfusion demand
symptomatic splenomegaly
● Primarily done in regularly transfused TM patients
Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.
Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.
Splenectomy: adverse events
● Thromboembolic events
● Pulmonary hypertension
● Infection
– 10-year follow-up of 221 splenectomized patients,
6 of whom died of sepsis
– no need to “wait & see” in such patients with fever
Cappellini MD, et al. Br J Haematol. 2000;111:467-73.
Atichartakarn V, et al. Int J Hematol. 2003; 78:139-45.
Pinna AD, et al. Surg Gynecol Obstet. 1988;167:109-13.
In the OPTIMAL CARE study
splenectomized patients: 325/584
Complication
Parameter
RR
95% CI
p-value
EMH
Splenectomy
Transfusion
Hydroxyurea
Age > 35 yrs
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Transfusion
Age > 35 yrs
Hb ≥ 9 g/dl
Ferritin ≥ 1000 ng/ml
Splenectomy
Transfusion
Age > 35 yrs
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
0.001
<0.001
0.022
0.032
<0.001
<0.001
0.025
0.032
<0.001
0.003
0.001
0.023
<0.001
<0.001
<0.001
0.010
<0.001
<0.001
<0.001
0.049
Pulmonary
hypertension
Heart failure
Thrombosis
Cholelithiasis
Abnormal liver
function
EMH = extramedullary hematopoiesis.
Taher AT, et al. Blood. 2010 ;115:1886-92.
In the OPTIMAL CARE study
splenectomized patients: 325/584
Complication
Parameter
RR
95% CI
p-value
Leg Ulcers
•
Age > 35 yrs
2.09
1.05-4.16
0.036
Splenectomy
3.98
1.68-9.39
0.002
Transfusion
0.39
0.20-0.76
0.006
Hydroxyurea
0.10
0.02-0.43
0.002
Hypothyroidism
Splenectomy
6.04
2.03-17.92
0.001
Hydroxyurea
0.05 associated
0.01-0.45 with
0.003
Splenectomy was
independently
an increased
Osteoporosis
> 35disease-related
yrs
3.51
2.06-5.99
<0.001
risk of Age
most
complications.
Female
1.97
1.19-3.27
0.009
Splenectomy
4.73
2.72-8.24
<0.001
Transfusion
3.10
1.64-5.85
<0.001
Hydroxyurea
0.02
0.01-0.09
<0.001
Iron chelation
0.40
0.24-0.68
0.001
Hypogonadism
Female
2.98
1.79-4.96
<0.001
Ferritin ≥ 1000 ng/ml 2.63
1.59-4.36
<0.001
Transfusion
16.13
4.85-52.63
<0.001
Hydroxyurea
4.32
2.49-7.49
<0.001
Iron chelation
2.51
1.48-4.26
0.001
Taher AT, et al. Blood. 2010 ;115:1886-92.
Thrombin generation (nM)
Splenectomy vs. hypercoagulability
150
Splenectomized TI
patients
120
Non-splenectomized
TI patients
90
Higher rates of prcoagulant RBCs and activatedNormal
platelets
in
controls
splenectomized patients.
60
Splenectomized
controls
Taher A, et al. Blood
Rev. 2008;22:283-92.
30
0
0
10
30
60
90
120
150
Time (seconds)
Representative examples of time course of thrombin generation in the presence of erythroid
thalassemic cells as source of phospholipids
Cappellini MD, et al. Br J Hematol. 2000;111:467–73. Reprinted with permission.
Thromboembolic events in a large
cohort of TI patients
● Patients (N = 8,860)
– 6,670 with TM
– 2,190 with TI
– 61 (0.9%) with TM
– 85 (3.9%) with TI
● Risk factors for developing
thrombosis in TI were
–
–
–
–
Type of event
● 146 (1.65%) thrombotic events
TM (n = 61)
TI (n = 85)
age (> 20 years)
previous thromboembolic event
family history
splenectomy
Thromboembolic events (%)
DVT = deep vein thrombosis; PE = pulmonary embolism;
PVT = portal vein thrombosis; STP = superficial thrombophlebitis.
Taher A, et al. Thromb Haemost. 2006;96:488-91.
Asymptomatic brain damage in
splenectomized adults with TI
• 30 patients underwent brain MRI and PET scanning
– 18 (60%) had abnormal MRI findings
– 19 (63.3%) had abnormal PET findings
– 26 (86.7%) had abnormal MRI, abnormal PET, or both
MRI = magnetic resonance imaging;
PET = positron emission tomography.
Taher AT, et al. J Thromb Haemot. 2010;8:54-9.
Taher AT, et al. Blood (ASH Annual Meeting Abstracts), 2009; 114 (22): 4077.
Splenectomy vs. thrombosis in the
OPTIMAL CARE study
● Three Groups of patients were identified: Group I, splenectomized
patients with a documented TEE (n = 73); Group II, age- and sexmatched splenectomized patients without TEE (n = 73); and Group
III, age- and sex-matched non-splenectomized patients without TEE
(n = 73)
Type of thromboembolic event
n (%)
DVT, n (%)
46 (63.0)
PE*, n (%)
13 (17.8)
STP, n (%)
12 (16.4)
PVT, n (%)
11 (15.1)
Stroke, n (%)
4 (5.5)
*All patients who had PE had confirmed DVT
DVT = deep vein thrombosis; PE = pulmonary embolism; STP = superficial thrombophlebitis;
PVT = portal vein thrombosis
Taher A, et al. J Thromb Haemost. 2010. Epub ahead of print.
Comparative analysis
Mean age ± SD, years
Male: Female
Mean Hb ± SD, g/dl
Mean HbF ± SD, %
Mean NRBC count ± SD, x106/l
Mean platelet count ± SD, x109/l
Group I
Splenectomized
with TEE
n = 73
33.1 ± 11.7
33:40
9.0 ± 1.3
45.9 ± 28.0
436.5 ± 205.5
712.6 ± 192.5
Group II
Splenectomized
without TEE
n = 73
33.3 ± 11.9
35:38
8.8 ± 1.2
54.4 ± 32.8
279.0 ± 105.2
506.3 ± 142.1
Group III
Nonsplenectomized
n = 73
33.4 ± 13.1
34:39
8.7 ± 1.3
44.2 ± 27.2
239.5 ± 128.7
319.2 ± 122.0
PHT, n (%)
HF, n (%)
DM, n (%)
Abnormal liver function, n (%)
Family history of TEE
Thrombophilia, n (%)
Malignancy, n (%)
Transfused, n (%)
Antiplatelet or anticoagulant use, n (%)
Hydroxyurea use, n (%)
25 (34.2)
7 (9.6)
4 (5.5)
2 (2.7)
3 (4.7)
3 (4.7)
1 (1.4)
32 (43.8)
1 (1.4)
13 (17.8)
17 (23.3)
5 (6.8)
5 (6.8)
2 (2.7)
1 (1.4)
2 (2.7)
2 (2.7)
48 (65.8)
3 (4.1)
17 (23.3)
3 (4.1)
1 (1.4)
1 (1.4)
3 (4.1)
3 (4.7)
2 (2.7)
0 (0)
54 (74.0)
2 (2.7)
29 (27.4)
Parameter
P-value
0.991
0.946
0.174
0.429
<0.001
<0.001
<0.001
0.101
0.256
0.863
0.554
0.863
0.363
0.001
0.598
0.383
TEE = thromboembolic events; Hb = total hemoglobin; NRBC = nucleated red blood cell; HbF = fetal hemoglobin; PHT = pulmonary hypertension; HF
= heart failure; DM = diabetes mellitus.
Taher A, et al. J Thromb Haemost. 2010. Epub ahead of print.
Multivariate analysis
Parameter
NRBC count ≥ 300 x 106/l
Group
Group III
Group II
OR
1.00
5.35
95% CI
Referent
2.31-12.35
P-value
<0.001
Platelet count ≥ 500 x 109/l
PHT
Group I
11.11
3.85-32.26
Group III
Group II
1.00
8.70
Referent
3.14-23.81
Group I had significantly higher NRBC, <0.001
Group I
76.92
22.22-250.00
platelets, PHT occurrence, and were mostly
Group IIInon-transfused.
1.00
Referent
Group II
4.00
0.99-16.13
0.020
Transfusion naivety
Group I
7.30
1.60-33.33
Group III
Group II
Group I
1.00
1.67
3.64
Referent
0.82-3.38
1.82-7.30
0.001
NRBC = nucleated red blood cell; PHT = pulmonary hypertension; OR = adjusted odds ratio; CI = confidence interval.
Taher A, et al. J Thromb Haemost. 2010. Epub ahead of print.
Time-to-thrombosis (TTT) since
splenectomy
• The median TTT following splenectomy was 8 years (range, 1-33 years)
• The median TTT was significantly shorter in patients with a NRBC
count ≥ 300 x 106/l, a platelet count ≥ 500 x 109/l , and who were
transfusion naïve .
Taher A, et al. J Thromb Haemost. 2010. Epub ahead of print.
Anticoagulants in TI
The available data on the use of
anticoagulants, antiplatelet, or other
agents in β-thalassemia are either
lacking or involve small, poorly
controlled and/or relatively low-quality
studies.
Taher AT, et al. Thromb Hemost 2006;96:488-91.
Current evidence for the benefit of
transfusions in TI
● Failure to thrive in childhood in the presence of
significant anemia
● Increasing anemia not attributable to rectifiable factors
● Delayed or poor pubertal growth spurt
● Progressive splenic enlargement
● Evidence of
–
–
–
–
–
bone deformities
clinically relevant tendency to thrombosis
leg ulcers
EMH
pulmonary hypertension
● Prior to surgical procedures
Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.
In the OPTIMAL CARE study
Occasionally-regularly transfused patients: 445/584
Complication
Parameter
RR
95% CI
p-value
EMH
Splenectomy
Transfusion
Hydroxyurea
Age > 35 yrs
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Transfusion
Age > 35 yrs
Hb ≥ 9 g/dl
Ferritin ≥ 1000 ng/ml
Splenectomy
Transfusion
Age > 35 yrs
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
0.001
<0.001
0.022
0.032
<0.001
<0.001
0.025
0.032
<0.001
0.003
0.001
0.023
<0.001
<0.001
<0.001
0.010
<0.001
<0.001
<0.001
0.049
Pulmonary
hypertension
Heart failure
Thrombosis
Cholelithiasis
Abnormal liver
function
Taher AT, et al. Blood. 2010 ;115:1886-92.
In the OPTIMAL CARE study
Occasionally-regularly transfused patients: 445/584
Complication
Parameter
RR
95% CI
p-value
Leg Ulcers
Age > 35 yrs
2.09
1.05-4.16
0.036
Splenectomy
3.98
1.68-9.39
0.002
Transfusion
0.39
0.20-0.76
0.006
Hydroxyurea
0.10
0.02-0.43
0.002
Hypothyroidism
Splenectomy
6.04
2.03-17.92
0.001
• Transfusion therapy
was
protective
for
thrombosis,
Hydroxyurea
0.05
0.01-0.45
0.003 EMH, PHT,
cholelithiasis,
and leg
ulcers. <0.001
Osteoporosis HF,
Age
> 35 yrs
3.51
2.06-5.99
Female
1.97
1.19-3.27
0.009
Splenectomy
4.73
2.72-8.24
<0.001
• Transfusion therapy
was
associated
with
an
increased
risk of
Transfusion
3.10
1.64-5.85
<0.001
endcorinopathy.
Hydroxyurea
0.02
0.01-0.09
<0.001
Iron chelation
0.40
0.24-0.68
0.001
Hypogonadism
Female
2.98
1.79-4.96
<0.001
Ferritin ≥ 1000 ng/ml 2.63
1.59-4.36
<0.001
Transfusion
16.13
4.85-52.63
<0.001
Hydroxyurea
4.32
2.49-7.49
<0.001
Iron chelation
2.51
1.48-4.26
0.001
Only significant associations presented
Taher AT, et al. Blood. 2010 ;115:1886-92.
Asymptomatic brain damage
Probability of abnormality vs age
Age and transfusion history
vs no. of abnormalities
No. of abnormalities
1.0
0
Occasionally transfused
0.9
1
>1
6
Transfusion-naive patients 5had higher incidence
4
and multiplicity 3of lesions
0.8
0.7
2
0.6
Patients (n)
Probability of abnormality
1.1
0.5
0.4
0.3
0.2
0.1
1
0
Non-transfused
6
5
4
10
15
20
25
30
35
40
45
50
55
60
3
2
Age (years)
1
0
≤ 30
30–40
40–50
> 50
Age (years)
Taher AT, et al. J Thromb Haemot. 2010;8:54-9.
Iron overload
• Iron overload occurs even in TI patients who have not
been transfused
- iron loading: 2–5 g Fe/year; iron toxicity develops from age 5
years
• Is much lower than in age-matched patients with
transfusion-dependent TM
• Although the rate of iron loading differs between TM and
TI, the consequences are apparent in both groups of
patients and include
- Liver
- Heart (?long-term)
- endocrine organs
Cossu P, et al. Eur J Pediatr. 1981;137:267-71.
Origa R, et al. Br J Hematol. 2007;136:326-32.
Pippard MJ, et al. Lancet. 1979;2:819-21.
Mechanism of iron
overload in non-transfused
patients
Ineffective
erythropoiesis
Chronic anemia
Hypoxia
↑ HIFs
↑ GDF15
↑ Release of
recycled iron
from RES
macrophages
↓ Hepcidin
↑ Erythropoietin
↑ Ferroportin
↑ Duodenal
iron absorption
↑ LIC
GDF15 = growth differentiation factor 15;
HIF = hypoxia-inducible transcription factor.
Taher A, et al. Br J Haematol .2009;147:634-40.
↓ Serum
ferritin
Serum ferritin underestimates
iron burden in TI
Serum ferritin level (μg/L)
10,000
9,000
8,000
7,000
6,000
5,000
4,000
3,000
2,000
1,000
0
TI
Linear (TI)
TM
Linear (TM)
A significant positive correlation with serum ferritin
levels was observed (R = 0.64; p < 0.001).
LIC values were similar to those in patients with TM,
but serum ferritin levels were significantly lower.
0
5
10
15
20
25
30
35
40
45
50
LIC (mg Fe/g dry wt)
LIC correlated with serum ferritin levels in patients with TI (R = 0.64; p < 0.001)
Taher A, et al. Haematologica. 2008;93:1584-86.
Recommendations for iron chelation
therapy in TI
Age ≥ 4 years
Age < 4 years
Observation
Hemoglobin ≥ 9 g/dl
Hemoglobin < 9 g/dl
Initiate
transfusions
Monitor LIC and
serum ferritin
Transfusions > 10 Units
LIC > 7 mg Fe/g dw, or
serum ferritin > 500 ng/ml
LIC > 7 mg Fe/g dw, or
serum ferritin > 500 ng/ml
Start iron chelation
therapy
Start iron chelation
therapy
Start iron chelation
therapy
Continue
observation
Monitor LIC and
serum ferritin
Taher A, et al. Br J Haematol .2009;147:634-40.
In the OPTIMAL CARE study
Chelated patients: 336/584
Complication
Parameter
RR
95% CI
p-value
EMH
Splenectomy
Transfusion
Hydroxyurea
Age > 35 yrs
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Transfusion
Age > 35 yrs
Hb ≥ 9 g/dl
Ferritin ≥ 1000 ng/ml
Splenectomy
Transfusion
Age > 35 yrs
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
0.001
<0.001
0.022
0.032
<0.001
<0.001
0.025
0.032
<0.001
0.003
0.001
0.023
<0.001
<0.001
<0.001
0.010
<0.001
<0.001
<0.001
0.049
Pulmonary
hypertension
Heart failure
Thrombosis
Cholelithiasis
Abnormal liver
function
Taher AT, et al. Blood. 2010 ;115:1886-92.
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
0.036
Splenectomy
3.98
1.68-9.39
0.002
Transfusion
0.39
0.20-0.76
0.006
Hydroxyurea
0.10
0.02-0.43
0.002
Hypothyroidism
Splenectomy
6.04
2.03-17.92
0.001
Hydroxyurea
0.05
0.01-0.45
0.003
Osteoporosis
Age > 35 yrs
3.51
2.06-5.99
<0.001
Iron chelathionFemale
therapy was protective
for hypogonadism,
1.97
1.19-3.27
0.009
2.72-8.24
<0.001
PHT, Splenectomy
cholelithiasis,4.73
and osteoporosis.
Transfusion
3.10
1.64-5.85
<0.001
Hydroxyurea
0.02
0.01-0.09
<0.001
Iron chelation
0.40
0.24-0.68
0.001
Hypogonadism
Female
2.98
1.79-4.96
<0.001
Ferritin ≥ 1000 ng/ml 2.63
1.59-4.36
<0.001
Transfusion
16.13
4.85-52.63
<0.001
Hydroxyurea
4.32
2.49-7.49
<0.001
Iron chelation
2.51
1.48-4.26
0.001
Taher AT, et al. Blood. 2010 ;115:1886-92.
Iron chelation therapy
●
●
Deferoxamine1
– significant decline in serum ferritin after 6 months of deferoxamine treatment
– significant UIE after 12 hours of continuous deferoxamine
(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
• no significant differences in excretion across doses
Deferiprone2
– significant reductions seen in mean serum ferritin, hepatic iron,
red-cell membrane iron, and serum NTBI levels
– serum ferritin ± SD: initial 2,168 ± 1,142 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
1Cossu
UIE = urinary iron excretion.
2Pootrakul
P, et al. Eur J Pediatr. 1981;137:267-71.
P, et al. Br J Hematol. 2003;122:305-10.
Reduction in iron burden with
deferasirox at year 1 in patients with 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;148:332-4.
Deferasirox for nontransfusional iron overload in
patients with TI
●
11 patients with thalassemia 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).
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
2000
1000
0
●
●
Patients
40
LIC (mg Fe/g dry weight)
Serum Ferritin Levels (ng/mL)
3000
LIC at baseline
LIC at 1 year
LIC at 2 years
30
20
10
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
With permission from Ladis V, et al. Haematologica. 2009;94(suppl 2):509(abstr 1279).
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).
Ongoing clinical evaluation of
deferasirox in TI
● Prospective, randomized, double-blind, placebo-controlled
trial
● Patients (age ≥10 years) with non–transfusion-dependent
β-thalassemia (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-thalassemia, based on the
change in LIC from baseline after 1 year of treatment compared
with placebo-treated patients
Ali T. Taher, MD, principal investigator; Study ID ICL670A2209.
Taher AT, et al. Blood (ASH Annual Meeting Abstracts), 2009; 114 (22):5111.
Modulation of fetal hemoglobin
production
● The clinical picture of TI could be greatly improved by an even
partial reduction in the degree of the non-α to α globin chain
imbalance.
● Several drugs have been tried in an attempt to reactivate γ-chain
synthesis and HbF production:
 5-azacytidine,
 Hydroxycarbamide
 Erythropoietin
 Butyric acid derivatives
 Hemin
● Results are encouraging especially with combined therapy
Borgna-Pignatti C. Br J Haematol. 2007;138:291–304.
Hydroxycarbamide
● Experience from Iran and India
– most patients were reported to have become transfusionindependent
– in patients who were not transfused, the Hb concentration
increased
– the combination of hydroxycarbamide with L-carnitine or
magnesium could be more effective in improving hematologic
parameters and cardiac status in patients with TI than
hydroxyurea alone
● Experience from Europe
– constant increase of the erythrocyte volume and in HbF, but
only a modest effect on total Hb concentration
Karimi M, et al. J Pediatr Hematol Oncol. 2005;27:380-5.
Dixit A, et al. Ann Hematol. 2005;84:441-6.
Karimi M, et al. Eur J Haematol. 2010;84:52-8.
Hydroxycarbamide (Cont’d)
● Co-inheritance of α-thalassemia, the Xmn-1
HBG2 polymorphism, and the underlying βglobin genotype may be predictive of a good
response to hydroxycarbamide; Hb E/βthalassemia patients generally have a good
response
● Treatment with hydroxycarbamide has also
shown promising results in decreasing plasma
markers of thrombin generation
Singer ST, et al. Br J Haematol. 2005;131:378-88.
Panigrahi I, et al. Hematology. 2005;10:61-3.
Ataga KI, et al. Br J Haematol. 2007;139:3-13.
In the OPTIMAL CARE study
Patients on hydroxyurea: 202/584
Complication
Parameter
RR
95% CI
p-value
EMH
Splenectomy
Transfusion
Hydroxyurea
Age > 35 yrs
Splenectomy
Transfusion
Hydroxyurea
Iron chelation
Transfusion
Age > 35 yrs
Hb ≥ 9 g/dl
Ferritin ≥ 1000 ng/ml
Splenectomy
Transfusion
Age > 35 yrs
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
0.001
<0.001
0.022
0.032
<0.001
<0.001
0.025
0.032
<0.001
0.003
0.001
0.023
<0.001
<0.001
<0.001
0.010
<0.001
<0.001
<0.001
0.049
Pulmonary
hypertension
Heart failure
Thrombosis
Cholelithiasis
Abnormal liver
function
EMH = extramedullary hematopoiesis.
Taher AT, et al. Blood. 2010 ;115:1886-92.
In the OPTIMAL CARE study
Patients on hydroxyurea: 202/584
Complication
Parameter
RR
95% CI
p-value
Leg Ulcers
Age > 35 yrs
2.09
1.05-4.16
0.036
Splenectomy
3.98
1.68-9.39
0.002
Transfusion
0.39
0.20-0.76
0.006
Hydroxyurea
0.10
0.02-0.43
0.002
Hypothyroidism
Splenectomy
6.04
2.03-17.92
0.001
0.05
0.01-0.45
0.003
•Osteoporosis
HydroxyureaHydroxyurea
treatment
was
protective
for
EMH,
PHT,
Age > 35 yrs
3.51
2.06-5.99
<0.001
ulcers,Female
hypothyroidism,
osteoporosis.
1.97 and1.19-3.27
0.009
Splenectomy
4.73
2.72-8.24
<0.001
Transfusion
3.10
1.64-5.85
<0.001
Hydroxyurea
0.02
0.01-0.09
<0.001
Iron chelation
0.40
0.24-0.68
0.001
Hypogonadism
Female
2.98
1.79-4.96
<0.001
Ferritin ≥ 1000 ng/ml 2.63
1.59-4.36
<0.001
Transfusion
16.13
4.85-52.63
<0.001
Hydroxyurea
4.32
2.49-7.49
<0.001
Iron chelation
2.51
1.48-4.26
0.001
leg
Taher AT, et al. Blood. 2010 ;115:1886-92.
OPTIMAL CARE
Multimodality therapy
Y
Hydroxyurea
Y
Transfusion
Iron chelation
Mean number
of complications
N
N
Y
N
Y
N
Y
N
Y
N
Y
N
0.83
1.31
1.30
2.00
0.85
2.02
1.54
2.43
Taher AT, et al. Blood. 2010 ;115:1886-92.
Take-home message
● Our understanding of the molecular basis and pathophysiology of TI
significantly increased
● Iron overload and hypercoagulability
increasing attention in TI
are
recently
receiving
● Despite various treatment options are available, no clear guidelines
exist
● Several studies are challenging the role of splenectomy yet
highlighting the benefit of transfusion, iron chelation therapy, and
fetal hemoglobin induction in the management of TI; thus these
approaches merit large prospective evaluation
● The role of antiplatelets/anticoagulants in TI merits investigation
A
N
N
O
U
N
C
E
M
E
N
T
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