EHA & WFHHIGHLIGHTS
July 30-31, 2010Rest 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
● “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.
Presentation at age 2–6 yearsRetarded growth and development
Completely asymptomatic until adult life
Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.
β-Thalassemia intermedia (TI)
SevereMild
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
Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.HbF = fetal hemoglobin.
HemolysisIneffective
erythropoiesis
Membranebinding of
IgG and C3
AnemiaIncreased
erythropoietinsynthesis
Skeletaldeformities,osteopenia
Erythroidmarrow
expansionIron overload
Splenomegaly
Excess free α-globin chains Denaturation
Degradation
Formation of heme and hemichromes
Iron-mediated toxicity
Removal ofdamaged red cells
Increased Iron absorption
Reduced tissueoxygenation
Pathophysiology summarized
Olivieri NF, et al. N Engl J Med. 1999;341:99-109.
• Ineffective erythropoiesis• Chronic anemia and hemolysis
• Iron overload
• Ineffective erythropoiesis• Chronic anemia and hemolysis
• Iron overload
Prevalence of common complications in TI vs TM
Complication (% of patients affected)
TI TM
Lebanon Italy Lebanon Italy
(n = 37) (n = 63) (n = 40) (n = 60)
Splenectomy 90 67 95 83
Cholecystectomy 85 68 15 7
Gallstones 55 63 10 23
Extramedullary hemopoiesis 20 24 0 0
Leg ulcers 20 33 0 0
Thrombotic events 28 22 0 0
Cardiopathy* 3 5 10 25
Pulmonary hypertension† 50 17 10 11
Abnormal liver enzymes 20 22 55 68
HCV infection 7 33 7 98
Hypogonadism 5 3 80 93
Diabetes mellitus 3 2 12.5 10
Hypothyroidism 3 2 15 11
Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.HCV = hepatitis C virus.
*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.
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
Taher AT, et al. Blood. 2010 ;115:1886-92.
N = 12
N = 127
N = 51
N = 153
N = 200
N = 41
ParameterFrequencyn (%)
Age (yrs)
<18 172 (29.5 )18-35 288 (49.3) >35 124 (21.2)
Male : Female 291 (49.8) : 293 (50.2)
Splenectomized 325 (55.7)
Serum ferritin (ng/ml)
<1000 376 (64.4)1000-2500 179 (30.6)>2500 29 (5)
Overall study population
ComplicationsFrequencyn (%)
OsteoporosisEMHHypogonadism CholelithiasisThrombosis Pulmonary hypertensionAbnormal liver functionLeg ulcers HypothyroidisimHeart failureDiabetes 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
Age vs. hemoglobin level (rs=-0.679, P<0.001)
Age vs. serum ferritin level (rs=0.653, P<0.001)
Taher A, et al. Br J Haematol 2010. Epub ahead of print.
Complications vs. Age
● Complications in 120 treatment-naïve patients with TI
*
* **
*
** = statistically significant trend
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.
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.
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
In the OPTIMAL CARE studysplenectomized patients: 325/584
Complication Parameter RR 95% CI p-value
EMH Splenectomy 0.44 0.26-0.73 0.001Transfusion 0.06 0.03-0.09 <0.001Hydroxyurea 0.52 0.30-0.91 0.022
Pulmonary hypertension
Age > 35 yrs 2.59 1.08-6.19 0.032Splenectomy 4.11 1.99-8.47 <0.001Transfusion 0.33 0.18-0.58 <0.001Hydroxyurea 0.42 0.20-0.90 0.025Iron chelation 0.53 0.29-0.95 0.032
Heart failure Transfusion 0.06 0.02-0.17 <0.001Thrombosis Age > 35 yrs 2.60 1.39-4.87 0.003
Hb ≥ 9 g/dl 0.41 0.23-0.71 0.001Ferritin ≥ 1000 ng/ml 1.86 1.09-3.16 0.023Splenectomy 6.59 3.09-14.05 <0.001Transfusion 0.28 0.16-0.48 <0.001
Cholelithiasis Age > 35 yrs 2.76 1.56-4.87 <0.001Female 1.96 1.18-3.25 0.010Splenectomy 5.19 2.72-9.90 <0.001Transfusion 0.36 0.21-0.62 <0.001Iron chelation 0.30 0.18-0.51 <0.001
Abnormal liver function
Ferritin ≥ 1000 ng/ml 1.74 1.00-3.02 0.049
Taher AT, et al. Blood. 2010 ;115:1886-92. EMH = extramedullary hematopoiesis.
Complication Parameter RR 95% CI p-value
Leg Ulcers Age > 35 yrs 2.09 1.05-4.16 0.036Splenectomy 3.98 1.68-9.39 0.002Transfusion 0.39 0.20-0.76 0.006Hydroxyurea 0.10 0.02-0.43 0.002
Hypothyroidism Splenectomy 6.04 2.03-17.92 0.001Hydroxyurea 0.05 0.01-0.45 0.003
Osteoporosis Age > 35 yrs 3.51 2.06-5.99 <0.001Female 1.97 1.19-3.27 0.009Splenectomy 4.73 2.72-8.24 <0.001Transfusion 3.10 1.64-5.85 <0.001Hydroxyurea 0.02 0.01-0.09 <0.001Iron chelation 0.40 0.24-0.68 0.001
Hypogonadism Female 2.98 1.79-4.96 <0.001Ferritin ≥ 1000 ng/ml 2.63 1.59-4.36 <0.001Transfusion 16.13 4.85-52.63 <0.001Hydroxyurea 4.32 2.49-7.49 <0.001Iron chelation 2.51 1.48-4.26 0.001
In the OPTIMAL CARE studysplenectomized patients: 325/584
Taher AT, et al. Blood. 2010 ;115:1886-92.
• Splenectomy was independently associated with an increased risk of most disease-related complications.
• Splenectomy was independently associated with an increased risk of most disease-related complications.
Representative examples of time course of thrombin generation in the presence of erythroid thalassemic cells as source of phospholipids
150
120
90
60
30
0
0 10 30 60 90 120 150
Time (seconds)
Th
rom
bin
gen
erat
ion
(n
M)
Splenectomized TI patients
Non-splenectomized TI patients
Normal controls
Splenectomized controls
Cappellini MD, et al. Br J Hematol. 2000;111:467–73. Reprinted with permission.
Splenectomy vs. hypercoagulability
Higher rates of prcoagulant RBCs and activated platelets in splenectomized patients.
Taher A, et al. Blood Rev. 2008;22:283-92.
Higher rates of prcoagulant RBCs and activated platelets in splenectomized patients.
Taher A, et al. Blood Rev. 2008;22:283-92.
Thromboembolic events in a large cohort of TI patients
● Patients (N = 8,860)– 6,670 with TM
– 2,190 with TI
● 146 (1.65%) thrombotic events – 61 (0.9%) with TM
– 85 (3.9%) with TI
● Risk factors for developing thrombosis in TI were– age (> 20 years)
– previous thromboembolic event
– family history
– splenectomy
Taher A, et al. Thromb Haemost. 2006;96:488-91.DVT = deep vein thrombosis; PE = pulmonary embolism; PVT = portal vein thrombosis; STP = superficial thrombophlebitis.DVT = deep vein thrombosis; PE = pulmonary embolism; PVT = portal vein thrombosis; STP = superficial thrombophlebitis.
Thromboembolic events (%)
Typ
e o
f ev
ent
TM (n = 61)
TI (n = 85)
• 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.
Asymptomatic brain damage in splenectomized adults with TI
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 sex-matched splenectomized patients without TEE (n = 73); and Group III, age- and sex-matched non-splenectomized patients without TEE (n = 73)
Taher A, et al. J Thromb Haemost. 2010. Epub ahead of print.
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 DVTDVT = deep vein thrombosis; PE = pulmonary embolism; STP = superficial thrombophlebitis; PVT = portal vein thrombosis
Parameter
Group ISplenectomized with TEEn = 73
Group IISplenectomized without TEEn = 73
Group IIINon-splenectomizedn = 73
P-value
Mean age ± SD, years 33.1 ± 11.7 33.3 ± 11.9 33.4 ± 13.1 0.991Male: Female 33:40 35:38 34:39 0.946Mean Hb ± SD, g/dl 9.0 ± 1.3 8.8 ± 1.2 8.7 ± 1.3 0.174Mean HbF ± SD, % 45.9 ± 28.0 54.4 ± 32.8 44.2 ± 27.2 0.429Mean NRBC count ± SD, x106/l 436.5 ± 205.5 279.0 ± 105.2 239.5 ± 128.7 <0.001
Mean platelet count ± SD, x109/l 712.6 ± 192.5 506.3 ± 142.1 319.2 ± 122.0 <0.001
PHT, n (%) 25 (34.2) 17 (23.3) 3 (4.1) <0.001HF, n (%) 7 (9.6) 5 (6.8) 1 (1.4) 0.101DM, n (%) 4 (5.5) 5 (6.8) 1 (1.4) 0.256Abnormal liver function, n (%) 2 (2.7) 2 (2.7) 3 (4.1) 0.863Family history of TEE 3 (4.7) 1 (1.4) 3 (4.7) 0.554Thrombophilia, n (%) 3 (4.7) 2 (2.7) 2 (2.7) 0.863Malignancy, n (%) 1 (1.4) 2 (2.7) 0 (0) 0.363Transfused, n (%) 32 (43.8) 48 (65.8) 54 (74.0) 0.001Antiplatelet or anticoagulant use, n (%) 1 (1.4) 3 (4.1) 2 (2.7) 0.598
Hydroxyurea use, n (%) 13 (17.8) 17 (23.3) 29 (27.4) 0.383
Comparative analysis
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.
Parameter Group OR 95% CI P-value
NRBC count ≥ 300 x 106/l Group III 1.00 Referent
<0.001Group II 5.35 2.31-12.35
Group I 11.11 3.85-32.26
Platelet count ≥ 500 x 109/l Group III 1.00 Referent
<0.001Group II 8.70 3.14-23.81
Group I 76.92 22.22-250.00
PHT Group III 1.00 Referent
0.020Group II 4.00 0.99-16.13
Group I 7.30 1.60-33.33
Transfusion naivety Group III 1.00 Referent0.001Group II 1.67 0.82-3.38
Group I 3.64 1.82-7.30
Multivariate analysis
Group I had significantly higher NRBC, platelets, PHT occurrence, and were mostly
non-transfused.
Group I had significantly higher NRBC, platelets, PHT occurrence, and were mostly
non-transfused.
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.
• 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.
Complication Parameter RR 95% CI p-value
EMH Splenectomy 0.44 0.26-0.73 0.001Transfusion 0.06 0.03-0.09 <0.001Hydroxyurea 0.52 0.30-0.91 0.022
Pulmonary hypertension
Age > 35 yrs 2.59 1.08-6.19 0.032Splenectomy 4.11 1.99-8.47 <0.001Transfusion 0.33 0.18-0.58 <0.001Hydroxyurea 0.42 0.20-0.90 0.025Iron chelation 0.53 0.29-0.95 0.032
Heart failure Transfusion 0.06 0.02-0.17 <0.001Thrombosis Age > 35 yrs 2.60 1.39-4.87 0.003
Hb ≥ 9 g/dl 0.41 0.23-0.71 0.001Ferritin ≥ 1000 ng/ml 1.86 1.09-3.16 0.023Splenectomy 6.59 3.09-14.05 <0.001Transfusion 0.28 0.16-0.48 <0.001
Cholelithiasis Age > 35 yrs 2.76 1.56-4.87 <0.001Female 1.96 1.18-3.25 0.010Splenectomy 5.19 2.72-9.90 <0.001Transfusion 0.36 0.21-0.62 <0.001Iron chelation 0.30 0.18-0.51 <0.001
Abnormal liver function
Ferritin ≥ 1000 ng/ml 1.74 1.00-3.02 0.049
In the OPTIMAL CARE study Occasionally-regularly transfused patients: 445/584
Taher AT, et al. Blood. 2010 ;115:1886-92.
Complication Parameter RR 95% CI p-value
Leg Ulcers Age > 35 yrs 2.09 1.05-4.16 0.036Splenectomy 3.98 1.68-9.39 0.002Transfusion 0.39 0.20-0.76 0.006Hydroxyurea 0.10 0.02-0.43 0.002
Hypothyroidism Splenectomy 6.04 2.03-17.92 0.001Hydroxyurea 0.05 0.01-0.45 0.003
Osteoporosis Age > 35 yrs 3.51 2.06-5.99 <0.001Female 1.97 1.19-3.27 0.009Splenectomy 4.73 2.72-8.24 <0.001Transfusion 3.10 1.64-5.85 <0.001Hydroxyurea 0.02 0.01-0.09 <0.001Iron chelation 0.40 0.24-0.68 0.001
Hypogonadism Female 2.98 1.79-4.96 <0.001Ferritin ≥ 1000 ng/ml 2.63 1.59-4.36 <0.001Transfusion 16.13 4.85-52.63 <0.001Hydroxyurea 4.32 2.49-7.49 <0.001Iron chelation 2.51 1.48-4.26 0.001
In the OPTIMAL CARE studyOccasionally-regularly transfused patients: 445/584
Only significant associations presented Taher AT, et al. Blood. 2010 ;115:1886-92.
• Transfusion therapy was protective for thrombosis, EMH, PHT, HF, cholelithiasis, and leg ulcers.
• Transfusion therapy was associated with an increased risk of endcorinopathy.
• Transfusion therapy was protective for thrombosis, EMH, PHT, HF, cholelithiasis, and leg ulcers.
• Transfusion therapy was associated with an increased risk of endcorinopathy.
≤ 30 30–40 40–50 > 50
Age and transfusion history vs no. of abnormalities
Probability of abnormality vs age
Pro
bab
ilit
y o
f ab
no
rmal
ity
Age (years)
Non-transfused
Occasionally transfused
Pat
ien
ts (
n)
0
1
2
3
4
5
6
Age (years)
No. of abnormalities0 > 11
10 15 20 25 30 35 40 45 50 55 600.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
0
1
2
3
4
5
6
Transfusion-naive patients had higher incidence and multiplicity of lesions
Transfusion-naive patients had higher incidence and multiplicity of lesions
Taher AT, et al. J Thromb Haemot. 2010;8:54-9.
Asymptomatic brain damage
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.
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
↑ Duodenal iron absorption
↑ Ferroportin
↑ Release of recycled iron
from RES macrophages
↑ Erythropoietin
Ineffective erythropoiesis
Chronic anemia
Hypoxia
↑ GDF15↑ HIFs
↓ Hepcidin
↑ LIC
↓ Serum ferritin
Mechanism of iron overload in non-transfused
patients
Taher A, et al. Br J Haematol .2009;147:634-40.GDF15 = growth differentiation factor 15; HIF = hypoxia-inducible transcription factor.
1,0002,000
3,0004,0005,0006,0007,000
8,0009,000
10,000
0 5 10 15 20 25 30 35 40 45 50
LIC (mg Fe/g dry wt)
Ser
um fe
rriti
n le
vel (
μg/
L)
TI TMLinear (TI) Linear (TM)
Serum ferritin underestimates iron burden in TI
Taher A, et al. Haematologica. 2008;93:1584-86.
LIC correlated with serum ferritin levels in patients with TI (R = 0.64; p < 0.001)
0
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.
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.
Recommendations for iron chelation therapy in TI
Taher A, et al. Br J Haematol .2009;147:634-40.
Complication Parameter RR 95% CI p-value
EMH Splenectomy 0.44 0.26-0.73 0.001Transfusion 0.06 0.03-0.09 <0.001Hydroxyurea 0.52 0.30-0.91 0.022
Pulmonary hypertension
Age > 35 yrs 2.59 1.08-6.19 0.032Splenectomy 4.11 1.99-8.47 <0.001Transfusion 0.33 0.18-0.58 <0.001Hydroxyurea 0.42 0.20-0.90 0.025Iron chelation 0.53 0.29-0.95 0.032
Heart failure Transfusion 0.06 0.02-0.17 <0.001Thrombosis Age > 35 yrs 2.60 1.39-4.87 0.003
Hb ≥ 9 g/dl 0.41 0.23-0.71 0.001Ferritin ≥ 1000 ng/ml 1.86 1.09-3.16 0.023Splenectomy 6.59 3.09-14.05 <0.001Transfusion 0.28 0.16-0.48 <0.001
Cholelithiasis Age > 35 yrs 2.76 1.56-4.87 <0.001Female 1.96 1.18-3.25 0.010Splenectomy 5.19 2.72-9.90 <0.001Transfusion 0.36 0.21-0.62 <0.001Iron chelation 0.30 0.18-0.51 <0.001
Abnormal liver function
Ferritin ≥ 1000 ng/ml 1.74 1.00-3.02 0.049
In the OPTIMAL CARE studyChelated patients: 336/584
Taher AT, et al. Blood. 2010 ;115:1886-92.
Complication Parameter RR 95% CI p-value
Leg Ulcers Age > 35 yrs 2.09 1.05-4.16 0.036Splenectomy 3.98 1.68-9.39 0.002Transfusion 0.39 0.20-0.76 0.006Hydroxyurea 0.10 0.02-0.43 0.002
Hypothyroidism Splenectomy 6.04 2.03-17.92 0.001Hydroxyurea 0.05 0.01-0.45 0.003
Osteoporosis Age > 35 yrs 3.51 2.06-5.99 <0.001Female 1.97 1.19-3.27 0.009Splenectomy 4.73 2.72-8.24 <0.001Transfusion 3.10 1.64-5.85 <0.001Hydroxyurea 0.02 0.01-0.09 <0.001Iron chelation 0.40 0.24-0.68 0.001
Hypogonadism Female 2.98 1.79-4.96 <0.001Ferritin ≥ 1000 ng/ml 2.63 1.59-4.36 <0.001Transfusion 16.13 4.85-52.63 <0.001Hydroxyurea 4.32 2.49-7.49 <0.001Iron chelation 2.51 1.48-4.26 0.001
In the OPTIMAL CARE studyChelated patients: 336/584
Taher AT, et al. Blood. 2010 ;115:1886-92.
• Iron chelathion therapy was protective for hypogonadism, PHT, cholelithiasis, and osteoporosis.
• Iron chelathion therapy was protective for hypogonadism, PHT, cholelithiasis, and osteoporosis.
1Cossu P, et al. Eur J Pediatr. 1981;137:267-71. 2Pootrakul P, et al. Br J Hematol. 2003;122:305-10.
● 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
UIE = urinary iron excretion.
Iron chelation therapy
Reduction in iron burden with deferasirox at year 1 in patients with TI
Mean cardiac T2* and LVEF (both normal at baseline), serum creatinine, and cystatin C did not significantly change after 12 months of treatment with deferasiroxMean cardiac T2* and LVEF (both normal at baseline), serum creatinine, and cystatin C did not significantly change after 12 months of treatment with deferasirox
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 .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
Deferasirox can effectively reduce iron burden in patients with TI
Voskaridou E, et al. Br J Haematol 2010;148:332-4.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
● 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 baselineSerum ferritin at 1 yearSerum ferritin at 2 years
LIC at baselineLIC at 1 yearLIC at 2 years
With permission from Ladis V, et al. Haematologica. 2009;94(suppl 2):509(abstr 1279).
0
1000
2000
3000
Ser
um
Fer
riti
n L
evel
s (n
g/m
L)
PatientsPatients0
10
20
40
LIC
(m
g F
e/g
dry
wei
gh
t)
30
PatientsPatients
● 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):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
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.
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 transfusion-
independent – 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 β-globin genotype may be predictive of a good response to hydroxycarbamide; Hb E/β-thalassemia 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 studyPatients on hydroxyurea: 202/584
Complication Parameter RR 95% CI p-value
EMH Splenectomy 0.44 0.26-0.73 0.001Transfusion 0.06 0.03-0.09 <0.001Hydroxyurea 0.52 0.30-0.91 0.022
Pulmonary hypertension
Age > 35 yrs 2.59 1.08-6.19 0.032Splenectomy 4.11 1.99-8.47 <0.001Transfusion 0.33 0.18-0.58 <0.001Hydroxyurea 0.42 0.20-0.90 0.025Iron chelation 0.53 0.29-0.95 0.032
Heart failure Transfusion 0.06 0.02-0.17 <0.001Thrombosis Age > 35 yrs 2.60 1.39-4.87 0.003
Hb ≥ 9 g/dl 0.41 0.23-0.71 0.001Ferritin ≥ 1000 ng/ml 1.86 1.09-3.16 0.023Splenectomy 6.59 3.09-14.05 <0.001Transfusion 0.28 0.16-0.48 <0.001
Cholelithiasis Age > 35 yrs 2.76 1.56-4.87 <0.001Female 1.96 1.18-3.25 0.010Splenectomy 5.19 2.72-9.90 <0.001Transfusion 0.36 0.21-0.62 <0.001Iron chelation 0.30 0.18-0.51 <0.001
Abnormal liver function
Ferritin ≥ 1000 ng/ml 1.74 1.00-3.02 0.049
Taher AT, et al. Blood. 2010 ;115:1886-92. EMH = extramedullary hematopoiesis.
Complication Parameter RR 95% CI p-value
Leg Ulcers Age > 35 yrs 2.09 1.05-4.16 0.036Splenectomy 3.98 1.68-9.39 0.002Transfusion 0.39 0.20-0.76 0.006Hydroxyurea 0.10 0.02-0.43 0.002
Hypothyroidism Splenectomy 6.04 2.03-17.92 0.001Hydroxyurea 0.05 0.01-0.45 0.003
Osteoporosis Age > 35 yrs 3.51 2.06-5.99 <0.001Female 1.97 1.19-3.27 0.009Splenectomy 4.73 2.72-8.24 <0.001Transfusion 3.10 1.64-5.85 <0.001Hydroxyurea 0.02 0.01-0.09 <0.001Iron chelation 0.40 0.24-0.68 0.001
Hypogonadism Female 2.98 1.79-4.96 <0.001Ferritin ≥ 1000 ng/ml 2.63 1.59-4.36 <0.001Transfusion 16.13 4.85-52.63 <0.001Hydroxyurea 4.32 2.49-7.49 <0.001Iron chelation 2.51 1.48-4.26 0.001
In the OPTIMAL CARE study Patients on hydroxyurea: 202/584
Taher AT, et al. Blood. 2010 ;115:1886-92.
• Hydroxyurea treatment was protective for EMH, PHT, leg ulcers, hypothyroidism, and osteoporosis.
• Hydroxyurea treatment was protective for EMH, PHT, leg ulcers, hypothyroidism, and osteoporosis.
OPTIMAL CAREMultimodality therapy
Mean numberof complications
Iron chelation
Transfusion
Hydroxyurea
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 are recently receiving increasing attention in TI
● 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
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