Tahir Clinical Management of · PDF fileAli Taher, MD, FRCP American University of Beirut,...

Ali Taher, MD, FRCP

American University of Beirut, Lebanon Canada - 2011

Clinical Management of Thalassemia: An INTERNATIONAL perspective

Haemolysis Ineffective erythropoiesis

Membrane binding of

IgG and C3

Increased erythropoietin

synthesis

Anaemia

Splenomegaly

Skeletal deformities, osteopenia

Erythroid marrow

expansion

Iron overload

Excess free α-globin chains

Denaturation Degradation

Formation of haem and haemichromes

Iron-mediated toxicity

Removal of damaged red cells

Reduced tissue oxygenation

Increased iron absorption

C3 = complement component 3; IgG = immunoglobulin G. Olivieri N, et al. N Engl J Med. 1999;34:99-109.

Pathophysiology of β-thalassaemia Thalassaemia syndromes are inherited haemoglobin disorders

caused by defective and imbalanced globin production

Management of thalassemia �  Conventional therapy:

� Transfusion therapy (mainly for TM) �  Iron chelation therapy �  Splenectomy �  Supportive therapy/treating complications �  Psychological support

�  Non-conventional therapy: �  Fetal Hb modification � Gene therapy

�  Radical therapy: �  Stem cell transplant

All of which will be discussed throughout this meeting

Demography �  The thalassemia gene confers greater immunity for the

heterozygous individuals against malaria �  It is common in parts of the world where malaria is/was

common: Southeast Asia, China, India, Africa, and the Mediterranean

�  However, thalassemia now is more recognized globally because of ease of travel, etc….

Demography �  However, due to migration, there is virtually no country with

no inhabitants affected with thalassemia

Improvement in survival of -thalassemia major patients with transfusions and chelation therapy

�  Without transfusions: < 5 years �  Regular transfusions with red blood cells: < 20 years �  Chelation therapy in addition to transfusions: > 20 years

Courtesy of Antonio Piga, MD, University of Turin, Italy.

Age (years)

Num

ber

0 2 4 6 8

10 12 14 16 18 20

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

1987

1997 1977

Causes of death in β-thalassemia

All patients (N = 1,073) Patients born after 1970 (n = 720)

6.8

1.8

6.8

4.1

4.1

3.6

3.2

2.7

50.8

6.6

14.8

3.3

3.3

3.3

8.2

9.7

60 0 5 10 15 20 25 30 35 40 45 50 55 65

Cardiac failure

Arrhythmia

Myocardial infarction

Infection

Cirrhosis

Thrombosis

Malignancy

Diabetes

Unknown

Other*

60.2

6.7

%

*Accident, renal failure, HIV/AIDS, familial autoimmune disorder, anorexia, haemolytic anaemia, thrombocytopenia

100 115 Total

1.7 2 Accidental events

0.9 1 Lymphoma

0.9 1 Metabolic disorders

3.5 4 Bone marrow transplantation

3.5 4 Thromboembolism

4.3 5 Liver disease

6.1 7 AIDS

7.8 9 Sepsis

% n Cause

82 Cardiac disease 71.3

Borgna-Pignatti C, et al. Ann N Y Acad Sci. 2005;1054:40-7. Ladis V, et al. Ann N Y Acad Sci. 2005;1054:445-50.

Transfusion therapy in Thalassemia

Transfusion therapy remains the hallmark of thalassemia treatment

Transfusion Programs

�  The recommended treatment for thalassemia major involves lifelong regular blood transfusions, usually administered every two to five weeks, to maintain the pretransfusion hamoglobin level above 9-10.5 g/dl

•  The post-transfusion Hb should not be greater than 14-15 g/dl and should be monitored occasionally

Goals of iron chelation therapy

The primary goals of iron chelation therapy are to remove excess iron and to provide protection from the effects of (labile) toxic iron

Transfusions and iron intake

Iron chelation therapy

Iron stores

Disease-free survival related to body iron levels assessed by serum ferritin

Chelation therapy (years)

0.00

0.50

0.25

0.75

1.00

0 2 4 6 8 10 14 12 16

Prop

orti

on w

itho

ut c

ardi

ac d

isea

se

<33% ferritin measures >2500 ng/mL

33–67% ferritin measures >2500 ng/mL

>67% ferritin measures >2500 ng/mL

Cardiac disease-free survival in patients with:

Olivieri N et al. N Eng J Med 1994;331:574–578. Massachusetts Medical Society,

Survival of patients according to serum ferritin level

Malcovati L, et al. Haematologica. 2006;91:1588-90.

In patients with serum ferritin > 1,000 µg/L, every further increase by 500 µg/L leads to a 30% reduction in survival

RA/RARS/5q− (HR = 1.42; p < 0.001)

Cum

ulat

ive

prop

ortio

n su

rviv

ing

0.0

0.1

0.2

0.3

0.4 0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180 Survival time (months)

Serum ferritin 1,000 µg/L 1,500 µg/L 2,000 µg/L 2,500 µg/L

HR = hazard ratio; RA = refractory anaemia; RARS = RA with ringed sideroblasts.

Clinical sequelae of iron overload

Pituitary impaired growth, infertility

Thyroid hypoparathyroidism

Heart cardiomyopathy, cardiac dysfunction

Liver hepatic cirrhosis

Pancreas diabetes mellitus

Gonads hypogonadism

Organ systems susceptible to iron overload

Iron overload end-organ iron toxicities are inevitable in the absence of intervention therapy

Methods to assess body iron burden

Standard measures of body iron

�  Assessment of Liver Iron

� Accurate reflection of total body iron burden

�  Measurement of serum ferritin levels

�  Indirect measure of body iron burden

Specialist measures of iron levels

�  Evaluation of Heart iron

�  Assessment of “NTBI” …

NTBI assessment only available as a research method today, useful to show effectiveness of chelators over entire 24hr period

Monitoring Iron Overload by MRI

An R2 image of an iron-overloaded human liver superimposed on a T-2 weighted image. Bright areas represent high iron concentration; dark areas represent low iron concentration.

Clark PR, et al. Magn Reson Med. 2003;49:572-575. Image courtesy of T. St. Pierre

Monitoring Iron Overload by MRI

LVEF

(%)

0

50

70

40

30

20

10

60

80

90

0 20 40 60 90 80 100 10 30 50 70

Heart T2* (ms)

Cardiac T2* value of 37 in a normal heart

Cardiac T2* value of 4 in a significantly iron overloaded heart

Relationship between myocardial T2* values and left ventricular ejection fraction (LVEF). Below a myocardial T2* of 20 ms, there was a progressive and

significant decline in LVEF (r=0·∙61, P<0·∙0001)

Anderson LJ et al. Eur Heart J 2001;22:2171–2179, Oxford University Press, with permission

T2* MRI: emerging new standard for cardiac iron

Thresholds for Parameters Used to Evaluate Iron Overload

>250 <250 Alanine aminotransferase, U/L

>0.4 0–0.4 LPI, μM

<1.2 LIC, mg Fe/g dw

>50 20–50 Transferrin saturation, %

Severe Moderate Mild

>20 T2*, ms

<300 Serum ferritin, ng/mL

Iron overloaded state Normal Parameter

>7 3–7

8–14 14–20

>1000 to <2500

Increased risk of complications

>15

<8

>2500

Increased risk of cardiac disease

LPI=labile plasma iron

History of Iron chelation

1962 1967 1972 1977 1982 1987 1992 1999 2002 2007 2011……………

Desferioxamine IM (Sephton -Smith 20 mg/Kg)

Desferioxamine SC (Propper:25-45 mg/Kg)

Deferiprone

Deferasirox

Desferioxamine IV

PROGNOSIS (years)

7-10 16-20 open

Properties of an ideal iron chelator �  Body iron control

�  high and specific affinity for Fe3+

�  high chelating efficiency

�  Iron toxicity minimization �  24-hour coverage �  slow metabolism and elimination rate �  good tissue penetration with stable iron complex

�  Acceptable efficacy–toxicity profile �  clear drug–dose relationship with efficacy and toxicity �  no iron redistribution

�  Simplicity and ease of monitoring

�  Patient acceptance/compliance �  oral bioavailability �  suitable for monotherapy

Available Iron chelators

FeO O

OO

O

O

N

N

NH2N-(H2C)5

Deferoxamine Hexadentate (1:1); high MW

FeH2O OH2

OH2H2O

OH2

OH2

Deferasirox Tridentate (2:1); low MW

FeH2O OH2

OH2H2O

OH2

OH2

FeO OH2

OH2O

OH2

N

N N

-OOC

FeO

OO

N

N

N N

-OOC

N N

COO-

O

Deferiprone Bidentate (3:1); low MW

FeH2O OH2

OH2H2O

OH2

OH2

FeH2O OH2

OH2O

O

OH2

N

FeO OH2

OO

O

OH2

N

NFe

O O

OO

O

O

N

N

N

Overview of iron chelators

Property Deferoxamine (DFO) Deferiprone (DFP) Deferasirox Usual dose 25–60 mg/kg/day 75 mg/kg/day 20–40 mg/kg/day

Route s.c., i.v. 8–12 h, 5 days/week

p.o. 3 times daily

p.o. once daily

Half-life 20–30 min 3–4 h 8–16 h

Excretion Urinary, faecal Urinary Faecal

Adverse effects Local reactions, ophthalmological, auditory, growth retardation, allergic

GI disturbances, agranulocytosis/ neutropenia, arthralgia, elevated liver enzymes

GI disturbances, rash, mild non-progressive creatinine increase, ophthalmological, auditory, elevated liver enzymes

Status Licensed

Licensed in USA or Canada Licensed

Approved indications

Treatment of chronic iron overload due to transfusion-dependent anaemias

Thalassemia major Treatment of chronic iron overload due to frequent blood transfusions

Deferoxamine Prescribing Information. Deferasirox Summary of Product Characteristics. Deferiprone Summary of Product Characteristics. GI = gastrointestinal; i.v. = intravenous; p.o. = per orum; s.c. = subcutaneous.

1Gabutti V & Piga A. Acta Haematol 1996;95:2636

Limitations of DFO therapy

•  Poor oral bioavailability and short plasma half-life

•  Slow subcutaneous infusion 3 – 7 times weekly

•  Needs specialized pumps and equipment not widely available

•  Injection-site reactions and pain

•  Poor compliance

•  Increased mortality1

Practical Issues with Subcutaneous Infusion

Site of infusion  Care must be taken to avoid inserting needles near important

vessels, nerves or organs   The abdomen is generally the best place

  However, because of local reactions such, it is often necessary to ‘rotate’ the sites used for injection   Some patients find that the skin over the deltoid or the lateral aspect of the thigh provides useful additional or alternative sites

Gabutti V, Piga A. Acta Haematol. 1996;95:26-36.

Compliance to chelation improves survival in patients with -thalassaemia major

Surv

ival

(%)

0

60

80

50

40

30

20

10

70

90

100

0 28 24 20 16 12 8 4 32 36 40 Years

300–365 225–300 150–225 75–150 0–75

Infusions/year

Deferiprone

  Standard dose: 75 mg/kg/day in 3 divided dose (up to 100 mg/kg/day, but as yet not enough information)

  Children above 10 years of age

  Vi tamin C concomitant t reatment not recommended

  Weekly blood counts (more frequently if signs of infection)

  Pregnancy – stop treatment

Deferiprone: Safety profile Local side effects no Growth arrest no Bone changes no

Arthropathy yes

Yersinia enteroc. ? Renal toxicity no Loss of high-frequency hearing no GI disturbances yes Impaired renal function no Skin rush no Liver enzymes yes Agranulocytosis yes

ICOC 1995, Olivieri et al. 1995, Maggio et al. 2002, Ceci et al. 2002

Effect of deferiprone therapy on serum ferritin levels

10 studies (11–162 patients); duration 6 –> 58 months

Hoffbrand V, et al. Blood. 2003;102:17-24.

Seru

m fe

rriti

n (µ

g/L)

Car

diac

T2*

(g

eom

etric

mea

n ±

SEM

)

DFP (change 3.5 ms; n = 29; p < 0.001)

DFO (change 1.7 ms; n = 32; p < 0.001)

SEM = standard error of the mean.

DFP 92 mg/kg/day orally

12

13

14

15

16

17

18

Baseline 6 months 12 months

Prospective improvement in cardiac T2* with DFO and deferiprone monotherapy

DFO 43 mg/kg/day x 5.7 s.c.

Time (months)

Pennell DJ, et al. Blood. 2006;107:3738-44.

Ceci A et al. Br J Haematol 2002;118:330336; Cohen AR et al. Br J Haematol 2000;108:305312; Kattamis A. Ann N Y Acad Sci 2005;1054:175182; Al-‐Refaie FN et al. Br J Haematol 1995;91:224229

Cohen study Ceci study Al-Refaie study Kattamis review*

0.9

0.43

0

1

2

3

4

*Combined DFO and DFP therapy

0.5 0.6

0

1

2

3

4 3.8

1.8

0

1

2

3

4 3.8

1.7

0

1

2

3

4

Agranulocytosis

Frequency (%) Incidence (per 100 patient years)

Agranulocytosis

�  Probably an idiosyncratic response �  Frequency: 1.5–2% of thalassemia patients using DFP �  Usually in the first year of treatment �  Rapidly reversible after cessation of therapy �  Treatment with granulocyte colony-stimulating factor may be

warranted �  Usually recurs upon rechallenge �  Requires close surveillance (complete blood count every 7–10

days)

Hof:brand AV et al. Blood 2003;102:1724

Combination Therapy

�  In patients for whom monotherapy with desferrioxamine or deferiprone is not controlling body levels of iron or myocardial iron, some combined regimes offer an alternative that can reduce iron levels in both the liver and heart.

�  Caution: agranulocytosis may be more frequent in combination therapy, especially in simultaneous use.

0

2

4

6

8

10

12

14

16

18

20

0 6 12

DFO alone versus DFO + DFP combination treatment

Liver T2*

Myocardial T2*

p = 0.01

p < 0.001

p < 0.001

p = 0.001

Between groups p = 0.02

Between groups p < 0.001

T2*

(geo

met

ric

mea

n ±

SEM

)

Tanner MA, et al. Circulation. 2007;115:1876-84. Time (months)

DFO (n = 33) Combined (n = 33)

Deferasirox

�  Treatment of iron overload due to blood transfusions in adults and children aged 2 years and older (US) or >6 years (Europe)

Once-daily administration of deferasirox

�  Selected among 700 molecules

�  Highly specific for iron �  The complex iron/chelator

is excreted by feces

Exjade® (deferasirox) Basic Prescribing Information. Novartis Pharma AG.

Deferasirox is administered once daily by dispersing tablets in water, apple juice, or orange juice and swallowing the suspension*

Study 105

0

20

40

60

80

100

0 4 8 12 16 20 24 Time post dose with deferasirox 20 mg/kg/day (hours)

Plas

ma

conc

entr

atio

n ir

on-f

ree

defe

rasi

rox

(µm

ol/L

)

Degree of constant chelation coverage with 20 mg/kg dose

Deferasirox provides 24-hour chelation coverage with once daily dosing

Piga A et al. Haematologica 2006; 91(7):873-879.

Predictable daily response to deferasirox.

Steady-state levels with daily deferasirox

Once-daily administration of deferasirox

EXJADE® (deferasirox) Basic Prescribing Information. Novartis Pharma AG. National Prescribing Information should be followed

Deferasirox is administered once daily by dispersing tablets in water, apple or orange juice and swallowing the suspension

 Recommended dose: ¤ Starting dose 20 mg/kg/day

  After 10-20 transfusions (iron intake 0.3-0.5 mg/kg/day)

¤  If pre-existing iron overload (or iron intake > 0.5 mg/kg/day)   A dose of ≥30 - 40 mg/kg/day is recommended

¤ For patients with low rate of iron loading (<0.3 mg/kg/day)   10-15 mg/kg/day may be sufficient to control iron loading.

 Use in children > 2 (FDA) and >6 (EMEA) years of age

 Contraindicated in renal failure or significant renal dysfunction

 Cannot be given during pregnancy

Deferasirox (Exjade®)

Deferasirox (Exjade®) Patient perspective

Oral Subcutaneous

Once Daily Every 8-12 hrs

EXJADE

DESFERAL

Patient Instructions

 Take deferasirox on an empty stomach at least 30 minutes before food, preferably at the same time everyday

 Do not chew, crush or swallow deferasirox tablets whole  Place the tablets in a glass of water or orange juice

(100-200 ml), do not use carbonated drinks or milk  Stir the mix until a fine suspension is obtained  Drink the mix immediately then add little water or juice

to the same glass to re-suspend remaining residue  Drink again to make sure all of the deferasirox has been

taken

Patient Instructions

 If you miss a dose, take the missed dose as soon as you remember

 However, if it is almost time to take the next dose, skip the dose you missed and take the next regularly scheduled dose as directed. Do not take a double dose

 Consult your physician if you experience any symptom or side effect that is worrying you

 Do not store deferasirox at above 30°C, and keep in original package to protect from moisture

Practical Notes on Safety

  Effective use of deferasirox should be coupled with comprehensive understanding of the associated adverse events and their management

  Our experience so far has proved that deferasirox is well tolerated by most patients

  Adverse events if they exist are usually self limited, or can be easily managed with dose modification and careful monitoring

Managing GI side effects

Diarrhea

1.  Antidiarrheal for up to 2 days + hydration.

2.  Deferasirox could be taken in the evening rather than the morning.

3.  Lactaids or probiotics could be added to the diet

Nausea/vomiting

Patients should drink small, steady amounts of clear liquids, such as electrolyte solutions, and keep hydrated

1.  Patients should sip water or other clear fluids, and avoid solid food for the first few hours.

2.  Avoid narcotics and NSAIDS.

3.  Deferasirox could be taken in the evening rather than the morning.

Abdominal pain

Managing Skin Rash

�  Skin rashes can be successfully managed using the Exjade treatment algorithm

Mild-to-moderate rash Continue treatment without interruption

Severe rash

1.  Interrupt treatment

2.  Reintroduce Exjade at lower dose maybe in combination with oral steroid after resolution of rash

3.  Gradually escalate dose

1.  Interrupt treatment

2.  Reintroduce Exjade at lower dose after resolution of rash

3.  Gradually escalate dose

More severe rash

RENAL CHANGES

Serum creatinine levels should be assessed in duplicate before therapy, then monthly. If patients have additional renal risk factors, serum creatinine levels should be monitored weekly for the first month or after

modification of deferasirox therapy, then monthly

>33% above pretreatment values at two consecutive visits (not attributed to other causes)

Deferasirox dose should be reduced by 10 mg/kg

Progressive increases beyond the ULN Deferasirox should be interrupted, then reinitiated at a lower dose followed by gradual dose escalation if the clinical benefit

outweighs the potential risks

Pediatrics, >33% above pretreatment values and above the age-appropriate ULN at two consecutive visits

Deferasirox dose should be reduced by 10 mg/kg

CHANGES IN LIVER FUNCTION

Liver function should be monitored monthly. Following any severe or persistent elevations in serum transaminase levels, dose modifications should be considered. Deferasirox therapy can be cautiously re-

introduced once transaminase levels return to baseline

Managing Changes in Renal and Liver Function

ULN = upper limit of normal

The ESCALATOR study

�  Prospective, open-label, 1 year, multicenter study conducted in the Middle East

�  Patients who completed

the initial 1-year study were permitted to enter an extension study lasting at least 1 year

Taher A et al. Eur J Haematol 2009;82:458–465

Egypt

Oman

Syria

Saudi Arabia

Lebanon

Deferasirox reduces LIC in previously unsuccessfully chelated patients

LIC by biopsy at core baseline and MRI if LIC by MRI was not done; *P<0.001; **P<0.0001 Taher A et al. Eur J Hematol 2011;87(4):355-65.

Mean absolute change in LIC from baseline

Pediatric Adult All End of 1-yr extension –5.7 ± 9.1** –8.5 ± 9.9** –6.6 ± 9.4*

Age group Mean iron intake (mg/kg/day)

Overall average actual dose (mg/kg/day)

Pediatric patients 0.36 ± 0.10 24.2 ± 3.5

Adult patients 0.28 ± 0.10 25.4 ± 4.6

Mea

n LI

C ±

SD

(mg

Fe/g

dw

)

25

5

–5 Core baseline

35

20

Extension baseline

P<0.001

End of 1st year extension

30

0

10

15

Pediatric patients, n 162 162 143

Adult patients, n 71 71 68

Pediatric patients Adult patients All patients

Deferasirox reduces serum ferritin in previously unsuccessfully chelated patients

Pediatric patients

Median duration of treatment was 2.7 years; *P<0.0001

Taher A et al. Eur J Hematol 2011;87(4):355-65.

Median absolute change in serum ferritin from baseline Pediatric Adult All

End of 1-year extension –853* –1254* –929*

Patients, n

Med

ian

seru

m fe

rriti

n ±

25th

and

75th

pe

rcen

tiles

(ng/

mL)

Time (weeks) 0 8 16 24 40 80 32 56

7000

5000

3000

1000

8000

6000

4000

2000

104 48 64 72 0

40

35

30

25

20

15

10

0

5

Average actual dose ± SD

(mg/kg/

day)

Serum ferritin Deferasirox dose

Mean iron intake = 0.36 ± 0.1 mg/kg/day

96 88

162 162 161 162 162 156 159 161 156 162 150 154 156 156

Adult patients

Patients, n M

edia

n se

rum

ferr

itin

± 2

5th a

nd 7

5th

perc

entil

es (n

g/m

L)

Time (weeks) 0 8 16 24 40 80 32 56

7000

5000

3000

1000

8000

6000

4000

2000

104 48 64 72 0

40

35

30

25

20

15

10

0

5

Average actual dose ± SD

(mg/kg/

day)

Mean iron intake = 0.28 ± 0.1 mg/kg/day

96 88

71 71 71 71 71 69 71 71 69 71 67 59 69 69

Change in LIC and serum ferritin with doses < and ≥ 30 mg/kg/day


Patients with LIC <7 mg Fe/g dw Pa

tient

s (%

) with

LIC

<7

m

g Fe

/g d

w

0

5

10

15

20

25

30

35

40

45

50

Core baseline End of core End of study*

*Median duration of treatment was 2.7 years Taher A et al. Eur J Hematol 2011;87(4):349-54

9.4%

26.2%

39.3%

Deferasirox significantly reduces LPI after one dose

Daar S et al. Eur J Haematol 2009;82:454–457

All tested patients (n=14) experienced a rapid reduction in LPI with deferasirox (20 mg/kg/day)

3.0

2.5

2.0

1.5

1.0

0.5

0

LPI (μm

ol/L

)

Mean = 0.98

Mean = 0.12; P=0.00061

Pre administration 2-hours post administration

Day 1

P=0.0028*

Deferasirox 20 mg/kg/day reduces LPI after single and multiple dosing in patients with β-thalassemia

Pre-administration 2 hours post-administration

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

Baseline Week 4 Week 16 Week 28 Week 40† Week 52‡

Mea

n LP

I + S

D (μ

mol

/L)

P=0.0131*

P=0.0014*

P=0.0217*

P=0.0085*

Once-daily administration of deferasirox provides 24-hour chelation coverage and sustained reduction in peak LPI with multiple dosing

*Versus pre administration at baseline LPI data are taken from 13 patients, except †n=11 and ‡n=12 due to lost samples

Daar S et al. Eur J Haematol 2009;82:454–457

Normal threshold

Investigator-assessed drug-related AEs ≥5% by baseline LIC<7 & ≥7

Taher A et al. Eur J Hematol 2011;87(4):349-54

AE BL LIC <7 (n=22) BL LIC≥7 (n=209)

Core Extension Core Extension

Any AE 11 (50.0) 6 (27.3) 89 (42.6) 49 (23.4)

Vomiting 2 (9.1) 2 (9.1) 18 (8.6) 12 (5.7)

Increased sCr 1 (4.5) 1 (4.5) 8 (3.8) 13 (6.2)

Increased ALT 3 (13.6) 3 (13.6) 10 (4.8) 13 (6.2)

Rash 3 (13.6) 0 15 (7.2) 2 (1.0)

Nausea 0 0 14 (6.7) 4 (1.9)

Increased AST 2 (9.1) 0 4 (1.9) 2 (1.0)

Proteinuria 2 (9.1) 0 4 (1.9) 1 (0.5)

Renal and hepatic safety


Creatinine ALT

Creatinine levels remain stable over the study

ALT levels significantly decreased over the study

Growth proceeds normally with deferasirox


Med

ian

abso

lute

cha

nge

in h

-SD

S fr

om b

asel

ine

1.5

–0.5

–2.5 2–<6 years

2.5

1.0 n=10

2.0

–1.0

0

0.5

Male

Female

–2.0

–1.5

6–<12 years 12–<16 years

n=16

n=41

n=33

n=22

n=27

Satisfaction with deferasirox Pa

tient

s (%

)

0

10

20

30

40

50

60

70

80

90

100

Baseline Week 4 Week 24 End of study

Very satisfied

Satisfied

Taher A et al. Acta Haematol 2010;123:220–225

Convenience of deferasirox Pa

tient

s (%

)

0

10

20

30

40

50

60

70

80

90

100

Baseline Week 4 Week 24 End of study

Very convenient

Convenient


Average time lost due to chelation therapy during the last month

0

10

20

30

40

50

60

70

80

Baseline (n=195)

Week 4 (n=187)

Week 24 (n=222)

End of study (n=196)

Aver

age

time

lost

for

norm

al a

ctiv

ities

+ S

D (h

ours

)


Adverse event Frequency, n (%) Before dose escalation After dose escalation

Median exposure (weeks) 115.4 36.1 Vomiting 17 (7.6) 6 (2.7) Abdominal pain 15 (6.7) 3 (1.3) Abdominal pain upper 3 (1.3) 3 (1.3) Nausea 24 (10.7) 3 (1.3) Rash 19 (8.5) 2 (0.9) Diarrhoea 12 (5.4) 2 (0.9)

Most common drug-related adverse events, as assessed by investigators (observed in > 1 patient after dose escalation to > 30 mg/kg/day)

Adverse events

Taher A, et al. Br J Haematol. 2009;147(5):752-9.

21 countries 142 sites 697 screening failures 1744 enrolled patients

UK, France, Italy, Germany, The Netherlands, Belgium, Greece, Spain, Turkey, Lebanon, Egypt, Switzerland, Austria, Australia, China, Hong Kong, Malaysia, Taiwan, South Korea, Thailand, Israel

EPIC Trial 21 countries, 142 sites, 1744 patients

Change in serum ferritin levels over 1 year in patients with β-thalassaemia major

< 20 mg/kg/day (n = 193) ≥ 20–< 30 mg/kg/day (n = 614) ≥ 30 mg/kg/day (n = 130) All patients (n = 937)

Med

ian

chan

ge fr

om b

asel

ine

in

seru

m fe

rrit

in le

vels

(μ

g/L)

Time (months)

-1000

-800

-600

-400

-200

0

200

Baseline 3 6 9 12

29.0

20.6

21.2 17.8

33.5

23.6

24.0

17.5

36.5

26.2

26.2

17.6

39.0

28.3 18.6 28.1

Cappellini MD, et al. Haematologica. 2010;95:557-66.

EPIC cardiac substudy: 1 year results from the prevention arm

Demographic and baseline patient characteristics Cardiac prevention

(n=78)

Mean age ± SD (range) 20.2 ± 7.5

Age: 10–<16 years, n (%) 26 (33.3)

Age: ≥16 years, n (%) 52 (66.7)

Female:male 43:35

Geometric mean baseline cardiac T2* ± CV%, ms 32.0 ± 25.6

Mean transfusion sessions in the year prior to study entry, ± SD* 15.2 ± 8.5

Mean total amount transfused in the year prior to study entry, mL/kg ± SD 133.7 ± 77.4

Mean baseline liver iron concentration (LIC), mg Fe/g dw ± SD 28.8 ± 10.2

Median baseline serum ferritin, ng/mL (range) 4367 (1627–10528)

*Information on the number of transfusions is only available for the year prior to study entry

Pennell DJ et al. Blood 2010;115:2364–2371

Prevention of cardiac iron accumulation

Time (months)

Mean actual dose (mg/kg/day): 27.6 ± 6.0

Time (months)

Change in LVEF

Geo

met

ric

mea

n ca

rdia

c T2*

(ms)

Cardiac T2*: values represent geometric mean ± 95% CI

Change in myocardial T2*

32 32.5

0

5

10

15

20

25

30

35

40

Baseline 12

Mea

n LV

EF ±

SD

(%)

Mean change = 1.8% P<0.001

69.6

67.7

56 58 60 62 64 66

68 70 72 74 76

Baseline 12

All patients (n = 75)

Pennell DJ et al. Blood 2010;115:2364–2371

Results at 3-years: Myocardial T2*

Pennell DJ et al. Presented at ASH 2010 [Blood 2010;116(21):abst 4276]

*P<0.001 versus baseline; Dashed line indicates normal cardiac T2* of 20 ms

7.7 8.6* 9.4* 10.5*

14.9

17.8*

20.3* 22.3*

17.1* 15.6*

13.9*

11.9

0

5

10

15

20

25

Baseline 12 24 36 Time (months)

Mea

n T2*

(ms)

>5–<10 ms (n=24) 10–<20 ms (n=47) All patients (n=71)

●  LVEF remained stable in the normal range throughout the study

Results at 3-years: Shift in Patients with Severe, Mild-to-moderate and Normalized Myocardial T2*

33.8 21.1

33.8

45.8 8.5

66.2

32.4

50.0

66.2

23.4

46.5

68.1

0

20

40

60

80

100

120

Baseline EOS Baseline EOS Baseline EOS

Prop

ortio

n of

pat

ient

s (%

)

T2* ≥ 20 ms T2* 10 – <20 ms T2* >5 - <10

All patients Baseline T2* >5–<10 ms Baseline T2* 10–<20 ms

4.2


Results at 3-years: Safety �  Of 71 patients who entered the 3rd year, 66 completed 3 years of deferasirox treatment �  No patients died during 211.4 patient-years of deferasirox exposure �  There was one serious cardiac AE (atrial fibrillation) which was not considered deferasirox-related �  Six patients (8.5%) had two consecutive serum creatinine increases >33% above baseline and ULN �  Two patients (2.8%) had two consecutive increases in ALT >10 x ULN �  The incidence of common drug-related AEs ( ≥5%) decreased throughout the study

0

5

10

15

20

25

Increased blood creatinine

Rash Increased alanine aminotransferase

Diarrhea

Prop

ortio

n of

pat

ient

s (%

)

Year 1 (n=114) Year 2 (n=101) Year 3 (n=71) Adverse events over time


Five-year follow-up: Safety �  Drug-related AEs were generally transient, mild-to-moderate in nature and decreased in

frequency each year

●  In the deferasirox and crossover cohorts, respectively: –  26 (8.8%) and 11 (4.2%) patients had 2 consecutive SCr increases >33% above baseline

and >ULN –  3 (1.0%) and 2 (0.8%) patients had 2 consecutive increases in ALT >10 × ULN

Deferasirox cohort Crossover cohort

Abdominal pain

0 1 2 3 4 5 6 7 8 9

10

Increased blood

creatinine Nausea Rash Vomiting Diarrhea Abdominal

pain (upper)

Patie

nts (

%)

Abdominal pain

0 1 2 3 4 5 6 7 8 9

10

Increased blood


pain (upper)

Year 1 Year 2 Year 3 Year 4 Year 5

Increased blood

creatinine

0 1 2 3 4 5 6 7 8 9

10

Nausea Rash Vomiting Diarrhea Abdominal pain

Abdominal pain (upper)

Increased blood


pain Abdominal

pain (upper)

Year 1 Year 2 Year 3 Year 4

Cappellini et al. Blood. 2011;118:884-893

FBS0701

FBS0701

�  Novel iron chelator still in Phase II trial in preparation for clinical use

�  Binds Fe(III) with very high affinity and selectivity over Fe(II) and other biologically important metals

�  Extensive preclinical toxicological studies demonstrated a higher no-observable-adverse-effect level (NOAEL) compared to deferasirox

Reinhoff HY Jr. et al. Haematologica. 2011;96(4):521-5.

FBS0701 �  Phase I: 3 studies

�  16 patients tried the new drug with different doses to study its pharmacokinetic and toxicity profiles

Reinhoff HY Jr. et al. Haematologica. 2011;96(4):521-5.

Deaths in thalassemia patients in the UK

UK Thalassaemia Register Causes of death by 5-year interval

Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42.

0 5

10 15 20 25 30 35 40 45 50

1950-

1954

1955-

1959

1960-

1964

1965-

1969

1970-

1974

1975-

1979

1980-

1984

1985-

1989

1990-

1994

1995-

1999

2000-

2004

Dea

ths i

n 5

year

s

Unknown Other Malignancy Iron overload Infection BMT complication Anaemia

BMT = bone marrow transplantation.

●  50% of UK patients died before the age of 35 years ●  Heart disease was responsible for 71% of the deaths

PREVENTION COMES FIRST! �  Premarital laws �  Prenatal diagnosis �  Preimplantation genetic screening

Specialized Care

•  Several countries have reported improved survival of patients with thalassemia major who are treated at specialized care centers compared to those followed up elsewhere.

•  This has been attributed to:

Forni GL, et al. Am J Hematol 2009;84:317-318.

•  Better transfusion therapy, •  greater availability and precision of

chelation, •  more adequate control of compliance, •  adequate therapy for complications,

especially heart failure and arrhythmias.

Chronic Care Center

Prevention Program

Ministry of Social Affairs

Community Centers,

network of community health workers

Ministry of Education Awarness in Schools, Inclusion of Thalassemia in Curicullum

Ministry of Public Health

Implementation of Premarital Law

The Chronic Care Center

�  The only multidisciplinary center dedicated for the treatment of chronic diseases including thalassemia for free…

�  680 Patients are being closely followed by a team of health professionals consisting of hematologists, endocrinologists, cardiologists, ophthalmolgists…

The Chronic Care Center - Lebanon

•  The Chronic Care Center led to an increase in complication-free as well as overall survival of patients with thalassemia.

•  This has been attributed to •  Earlier diagnosis and initiation of chelation therapy, •  Introduction of new oral iron chelators, •  Better iron overload quantitation methods.

Charafeddine K, et al. Acta Haematol 2008;120:112–116

Treatment �  All Lebanese Thalassemics have access to chelation therapy �  Patients are provided with comprehensive treatment at the

Chronic Care Center in a multidisciplinary approach

1 • Premarital Law

2

•  Awareness Campaigns at the national level •  Around 8000 persons per year are attending these sessions (villages, schools, universities)

3

•  Training of trainers •  Additional 100 professionals are trained as trainers per year to promote awareness in their

community

4

•  Free screening to identify new carriers •  General population (schools, universities) •  High risk group (brothers/sisters, cousins, family members)

5

• Prenatal diagnosis in genetics laboratory • Genetic testing of CVS or amniotic fluid • Pre-implantation genetic diagnosis for beta thalassemia

6 • Updated registry of carriers at the center

7 • Counseling of identified carriers

Public Awareness and Education/ Prevention Program activity •  Collaboration with the Ministry of Education to include

Thalassemia in the Science Curriculum of secondary level.

•  Training of trainers: – Training Area Coordinators from the Ministry of Social Affairs –  additional 100 professionals are trained as trainers per year to

promote awareness in their community (community health workers, nurses, biology teachers)

•  Awareness Campaigns on the national level –  around 7500 persons per year are attending these sessions

Awareness Campaigns in different regions

Year Number of participants/MSA Network

Number of participants/ CCC Team

Total/ year

2008 5400 2087 7487

2009 6839 1864 8703

�  Production and dissemination of Educational material

Several educational material have been prepared, printed and distributed to patients and the public

Prevention Program Activities

The Center celebrates yearly, the International Thalassemia Day on 8th of May :

Some of the media campaigns were : •  “Give blood, give life” to encourage blood donation

•  “Don’t turn your back for premarital testing”

•  “We are alike” to encourage social integration

Celebration of International Thalassemia Day

Lebanese premarital law: “Don’t turn your back on premarital testing”

Mandatory screening of People with MCV < 70 fl

Public Surveillance/ Population Screening

•  Conducting several studies to assess carrier rate which is 2-3 %

•  Identify Carriers in Different group – General population – High risk Groups

•  Relatives of thalassemics registered at CCC •  Siblings and cousins

•  Counseling of the carriers

Targeted screening of High Risk Group: Relative of patients- Extended Family

Village Qaza Number of persons tested

Number of Thala Carriers

%

Bibnin-Akkar North 68 11 16

Berkayel-Akkar North 102 6 6

Mcheick Bekaa 235 41 17

Screening for Siblings and Cousins •  Screening for Cousins

2008-2009 37% carriers

•  Screening for brothers/sisters 2008-2009 44% carriers

For a group of siblings and cousins: Number tested Number of carriers %

279 115 41

Prenatal Diagnosis

�  The practice of prenatal genetic counseling available in Lebanon �  Parents considered “high-risk” (i.e. patients, carriers, close

relatives of patients) offered prenatal diagnosis �  Prenatal Diagnosis for β Thalassemia is only offered in Lebanon at

the Chronic Care Center’s Genetics Laboratory. This test was introduced in 1999.

β thalassemia in Lebanon prenatal diagnosis

Number of amniocentesis done to mothers, of which both the husband and the wife are carriers

β thalassemia in Lebanon Results of the prenatal diagnosis

Abortion in Lebanon �  Abortion is Illegal in Lebanon unless the health of the

mother is in danger .

�  In Lebanon, different opinions concerning abortion exist among different religious sects.

This has its impact on decision made by couples at risk.

How successful were preventive measures in Lebanon? Is the prevention program effective? Can we eradicate Thalassemia ?

Age Distribution of Thalassemics in a country with no prevention

Preven?on of Thalassaemias and other hemoglobin Disorders Vol.1 Thalassemia Interna?onal Publica?ons ( 3)

Pa?ents are mostly infants ( non-‐ preven?on) and children ( early deaths)

Age distribution comparison

Prevention of Thalassaemias and other hemoglobin Disorders Vol.1 Thalassemia International Publications

WHO estimated thalassemic birth rate

Guidelines for the control of hemoglobin disorders Geneva, 1994 unpublished document who/hdp/hb/gl/94.1

46

12

15 14

9

18 17

21

8 10

14 14

11

6

12

9 8

5 6 6

3 5 6

8

9 2

10

5

4

3

5

7 2

5 5

6

4

1 2

1 1

2

0

0

1

2 1

2

0

5

10

15

20

25

30

1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

CCC Thalassemic Patients per year of birth & Diagnosis starting 1986

Alpha Thalassemia

Thalassemia Intermedia

Thalassemia Major

CCC was established in 1993. Premarital Law was implemented in 1994

Significant Decrease in Number of Newborn patients with Thalassemia (n<10/yr) due to Prevention Program and implementation of Premarital Law

CCC was established in 1993. Premarital Law was implemented in 1994

Significant Decrease in Number of Newborn patients with Thalassemia (n<10/yr) due to Prevention Program and implementation of Premarital Law

Success in Decreasing the number of new born with thalassemia

Lebanese Premarital Certificate

Lebanese premarital law pitfalls

�  If MCV < 70, Hemoglobin Electrophoresis is required � Missing carriers with MCV>70

�  Wrong Interpretation of Results �  Marriages accomplished without proper premarital

certificate �  Religious people are sometimes aware of the results

� Personal choice

�  Contradictory message to where results will be sent

Premarital Law implementation •  If MCV < 70, Hemoglobin electrophoresis is required

– Missing carriers with MCV>70

•  Wrong interpretation of results •  Marriages accomplished without premarital certificate •  Religious people are sometimes aware of the results

–  Personal choice

•  The certificate is sometimes photocopied •  Contradictory message to where results will be sent- Report •  No compilation of Data or interpretation

MCV > 70 Missing Carrier

Carriers tested in CCC lab Carriers with MCV>70

Number 385 28

% 100 7.2%

General population

Carrier rate Missed Carrier with actual premarital Law

100 3% 0.216%

100 2.3 % 0.165%

For every 466 persons tested we are missing 1 carrier with MCV > 70

New cases: Reasons

Year Nb. of cases

Lab. Error

MCV>70 Wrong Interpretation of result

Family Decision

No Premarital Test

Married <1994

Outside Leb.

2007 11 0 0 4 1 3 3 0

2008 17 1 3 1 2 1 9 0

2009 16 0 0 5 2 2 5 2

total 44 1 3 10 5 6 17 2

% 2% 7% 23% 11% 14% 39% 5%

Towards a better prevention

�  Proper application of the law �  Mandatory Hemoglobin Testing Electrophoresis/ HPLC ( to

avoid missing carriers) �  Improve Remote Laboratories reliability �  Proper counseling and interpretation of results

Partners in Prevention �  Doctors �  Laboratories �  Ministry of Public Health �  Religious People �  Community Health Workers

After 16 years of work, we realize that despite the achievements we should multiply our efforts to achieve our goal: Eradicating Thalassemia in Lebanon ( a country where abortion is illegal). We hope that with the collaboration of all stakeholders doctors, specialists, health workers, laboratories , governmental institutions, NGOs, religious people , we will soon reach our goal.

Achieving number zero…

Conclusion � Over the past couple of years, the region

gained a big experience in conducting clinical trials

� More collaboration among the different countries

� More awareness among the public and the patients

1925: Cooley description 1880: Cardarelli 1884: Somma 1925: Rietti

1940–1950: Caminopetros, Silvestroni, Bianco

Hb abnormalities, hereditary pattern 1949–1960: Pauling: Hb structure HbS-Mendelian transmission Ceppellini: HbA2

1960–1970: Weatheral and Clegg

Hb chain synthesis 1970–1980: transfusional therapy Iron chelation: deferoxamine

1980–2000: Prenatal diagnosis (Kan)

Bone marrow transplantation (Lucarelli) 2000… new oral iron chelators

Present: Gene therapy?

1935: Miceli

1928: Greppi

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