EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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)

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

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.

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

• 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

0 10 30 60 90 120 150

Time (seconds)

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 (%)

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.

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.

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 .

• 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 .

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.

Ferritin ≥ 1000 ng/ml 1.74 1.00-3.02 0.049

In the OPTIMAL CARE study Occasionally-regularly transfused patients: 445/584

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

Age (years)

Non-transfused

Occasionally transfused

Age (years)

No. of abnormalities0 > 11

10 15 20 25 30 35 40 45 50 55 600.1

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

• 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)

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)

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.

Ferritin ≥ 1000 ng/ml 1.74 1.00-3.02 0.049

In the OPTIMAL CARE studyChelated patients: 336/584

• 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).

PatientsPatients0

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.

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

Ferritin ≥ 1000 ng/ml 1.74 1.00-3.02 0.049

Taher AT, et al. Blood. 2010 ;115:1886-92. EMH = extramedullary hematopoiesis.

In the OPTIMAL CARE study Patients on hydroxyurea: 202/584

• Hydroxyurea treatment was protective for EMH, PHT, leg ulcers, hypothyroidism, and osteoporosis.

OPTIMAL CAREMultimodality therapy

Mean numberof complications

Iron chelation

Transfusion

Hydroxyurea

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

EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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