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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
Taher A et al. Eur J Hematol 2011;87(4):355-65.
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
Taher A et al. Eur J Hematol 2011;87(4):350-55.
Creatinine ALT
Creatinine levels remain stable over the study
ALT levels significantly decreased over the study
Growth proceeds normally with deferasirox
Taher A et al. Eur J Hematol 2011;87(4):350-55.
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
Taher A et al. Acta Haematol 2010;123:220–225
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
)
Taher A et al. Acta Haematol 2010;123:220–225
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
Pennell DJ et al. Presented at ASH 2010 [Blood 2010;116(21):abst 4276]
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
Pennell DJ et al. Presented at ASH 2010 [Blood 2010;116(21):abst 4276]
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
creatinine Nausea Rash Vomiting Diarrhea Abdominal
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
creatinine Nausea Rash Vomiting Diarrhea Abdominal
pain Abdominal
pain (upper)
Year 1 Year 2 Year 3 Year 4
Cappellini et al. Blood. 2011;118:884-893
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
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
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 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