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

48
EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon

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

Page 1: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

EHA & WFHHIGHLIGHTS

July 30-31, 2010Rest House Tyr

Lebanon

Page 2: 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

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THALASSEMIA INTERMEDIA REVISITED

Part I

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● “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

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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.

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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

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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.

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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

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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.

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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.

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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.

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TREATMENT OPTIONS

Part I

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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.

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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

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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.

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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.

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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.

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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)

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• 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.

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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

Page 21: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 22: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 23: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 24: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

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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.

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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.

Page 27: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 28: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

≤ 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

Page 29: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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

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

↑ 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.

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

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.

Page 32: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

Recommendations for iron chelation therapy in TI

Taher A, et al. Br J Haematol .2009;147:634-40.

Page 33: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 34: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 35: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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

Page 36: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 37: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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).

Page 38: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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

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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

Page 39: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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

Page 40: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 41: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 42: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 43: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 44: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 45: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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.

Page 46: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

OPTIMAL CAREMultimodality therapy

Mean numberof complications

Iron chelation

Transfusion

Hydroxyurea

Taher AT, et al. Blood. 2010 ;115:1886-92.

Page 47: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.

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

Page 48: EHA & WFH HIGHLIGHTS July 30-31, 2010 Rest House Tyr Lebanon.