thalassaemia Professor John Porter Red Cell Disorders Unit University College London Hospitals and UCL jporteruclacuk Professor John Porter Red Cell Disorders Unit University College London ID: 139663
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Slide1
Monitoring and treatment iron overload in thalassaemia
Professor John Porter
Red Cell Disorders Unit
University College London Hospitals and UCL
j.porter@ucl.ac.ukSlide2
Professor John Porter
Red Cell Disorders Unit
University College London
Hospitals
and UCL j.porter@ucl.ac.uk
M
onitoring and treatment
iron
overload
in
thalassaemiaSlide3
OutlineWhat are the treatment and monitoring options available for iron overload in Thalassaemia MajorOn what are guidelines about ferritin targets based and should we be more ambitious?What are the goals of chelation treatment ?How can monitoring help to achieve these goals?
What can be achieved ?- a personal perspectiveSlide4
Monitoring options
Iron loading rateSerum ferritinLiver Iron concentrationCardiac evaluation – function & T2* Endocrine evaluation – growth, function & MRIAdherence and quality of lifeSlide5
Highly variable iron
excretion is required to balance
transfusional iron loading in Thalassaemia Major
Iron accumulation from transfusion in TM
(n = 586)
233mls/kg/y blood (if
Hct
0.6)
about 40 units/year for a 70 kg person
0.4 ± 0.11 mg/kg/day (mean) of iron
< 0.3mg /kg day 19% of patients
0.3-0.5 mg/kg/day 61%
> 0.5 mg/kg/day
20
%
Cohen,Glimm and Porter. Blood 2008;111:583-7Slide6
Dosing to balance iron transfusional rate
Deferasirox
Deferasirox
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0
5
10
15
20
25
30
Mean total body iron excretion
± SD (mg Fe/kg/day)
Actual doses (mg/kg/day)
0
10
20
30
40
50
60
D
eferoxamine
Studies 107 and 108
Deferoxamine (5 days/week)
Average transfusion iron intake SCD
Average transfusion iron intake
thalassaemia
Cohen AR, et al. Blood. 2008;111:583-7.Slide7
Change in LIC at low defarasirox doses in NTDT
mean loading rate 0.01 mg/kg/day (primarily from increased GI absorption)Taher
, Porter,. et al Blood (2012) , 120, 970-7,
But at 10mg/kg/day, the mean LIC increased at 1y in TM with mean loading rate 0.4mg/kg/day
Cappellini
et al,
Blood
. 2006;107:3455-
3462
LIC change
(mg/g dry wt) from baseline
Ferritin change
(
ng
/ml) from baselineSlide8
Use serum ferritin measures to achieve harmless body iron levels?Clear evidence linking long-term ferritin control to outcome
Convenience and low cost Permit frequent repeated measurements Allows early trend recognition Ferritin trend is increasing; focus on adherenceconsider dose increase
chelator regime changeFerritin trend decreasing If rapid, dose adjust to minimise risks of over chelation for ‘soft landing’If levels already low- dose reduction to allow maintenance of current level
Slide9
Limitations of just using serum ferritin ? Variability in LIC accounts for only 57% of variability in serum ferritin
1 Raised by inflammation or tissue damage Lowered by vitamin C deficiency 2 Origin of serum ferritin differs above values of 4K 3 Relationship of ferritin to body iron (LIC) varies in
different diseases Low relative to LIC in Thal Intermedia 4 (hepatocellular > macrophages)
Higher and variable in SCD 5 Relationship of ferritin to LIC differs with different chelators,6,7
Brittenham et al, Am J Hematol 1993;42:81-5
Chapman et al, J
Clin
Pathol
1982;35:487-91.
Worwood
, M. 1980 Br J
Haematol
46,409-16
Origa
,
Hamatologica 2007, 92 5835. Porter & Huehns, Acta
Haematologica
Fischer et al. Brit J
Haem
2003, 121 938-948
Ai
Leen
Ang
, et al, Blood, 201, 116, Abstract 4246.
Slide10
Why monitor & control liver iron ?
Ferritin alone may not reflect true body iron and chelation trendsLIC predicts total body storage iron in TM1Absence of pathology heterozygotes
of HH where liver levels < 7 mg/g dry weightLiver pathology abnormal ALT if LIC > 17 mg/g dry weight2liver fibrosis progression if LIC > 16 mg/
g dry weight3Cardiac pathology at high levels
Increased LIC linked to risk of cardiac iron in unchelated patients 2,6LIC >15 mg/g dry weight association with cardiac deathall of 15/53 TM patients who died4improvement of subclinical cardiac dysfunction with venesection alone post-BMT
5
Angelucci
E, et al. N
Engl
J Med. 2000;343:327-
31.
Jensen
PD, et al. Blood. 2003;101:91-6.
Angelucci
E, et al. Blood. 2002;100:17-21
.
Brittenham
GM, et al. N
Engl
J Med. 1994;331:
567-73.
Mariotti
E, et al.
Br J Haematol
. 1998;103:916-21.
Buja LM, Roberts WC. Am J Med. 1971;51:209-21
ALT = alanine aminotransferase;
BMT = bone marrow transplantation. Slide11
Low Heart
T2* inreases risk of low LVEF
LVEF = left ventricular ejection fraction.
Anderson et al.
Eur Heart J
. 2001;22:2171
.
Heart T2* (ms)
LVEF (%)
90
80
70
60
50
40
30
20
10
0
0
20
40
60
80
Severe cardiac iron
Minimal liver iron
Severe liver iron
Minimal cardiac ironSlide12
Relationship between cardiac T2* and cardiac failure
Kirk P, et al. Circulation. 2009;120:1961-8.
0
0.1
0.2
0.3
0.4
0.5
0.6
0
30
60
90
120
150
180
210
240
270
300
330
360
Proportion of patients developing cardiac failure
Follow-up time (days)
< 6 ms
6–8 ms
8–10 ms
> 10 msSlide13
Other Approaches to assessing Iron overload
Effects on specific organsOther Organs
Endocrine screening- assessment of functionGrowth monitoring, bone ageRole of MRI screening of pancreas 1, 2 ?Measurement of NTBI/
LPIPredictive value of response 3
Au WY, et al. Haematologica. 2008;93:785. Noetzli
LJ, et al. Blood. 2009;114:4021-6
.
3.
Aydinok
Y, et al.
.
Haematologica
, 2012, 97,6, 835-
41Slide14
MRI and assessment of endocrine complications in Thalassaemia Major
Au WY, et al. Haematologica
. 2008;93:785.
Cardiac
MRI T2*
correlates with endocrine dysfunction
Pancreatic T2* poor correlation with diabetes
Pituitary T2 correlates with multiple endocrine dysfunctions
Age
Ferritin
Cardiac T2*
Hepatic T2*
Pan T2*
Pit T2
Pit SIR
Pit T2*
Heart failure (n = 34)
NS
NS
< 0.001
NS
0.001
0.013
0.017
0.009
Diabetes
(
n = 44)
< 0.001
(0.001)
NS
< 0.001
(0.004)
NS
NS
0.015
0.001
0.055
Hypogonadism
(n = 84)
< 0.001 (0.001)
NS
< 0.001 (0.049)
NS
0.057
< 0.001
< 0.001 (0.05)
NS
Hypothyroid
(n=36)
0.061
<0.001
< 0.001
NS
NS
< 0.001
< 0.001 (0.023)
NS
Hypoparathyroid
(n = 16)
0.001 (0.008)
NS
< 0.001 (0.006)
NS
NS
0.062
0.003
0.058
–
= not analysed; EF = ejection fraction; NS = not significant; Pan = pancreatic; Pit = pituitary; SIR = signal intensity ratio of pituitary to muscle.
*p < 0.05; **p < 0.01; ***p < 0.001
. n=180Slide15
Assessment – when?
Iron intake rate Each transfusionChelation dose & frequency 3
monthlyGrowth & sexual development 6 monthly children
Liver function 3 monthly
Sequential ferritin 3 monthlyGTT, thyroid, Ca metab Yearly in adults
Liver
iron Yearly from age 8-10
Heart
function Yearly from age 8-10
Heart iron (T2*
) Yearly from age 8-10
Observation Frequency
ExpenseSlide16
Prevention of iron mediated damageBalance input and output - iron balanceAchieve harmless levels of body iron safelyRescue
patients with high levels of body ironpatients with high levels of cardiac ironpatients with heart dysfunction
Goals of chelation therapySlide17
Licensed iron chelators
Property
DFO
Deferiprone
Deferasirox
Route
Sc
, iv
(8–12 hours,
5 days/week)
Oral
3 times daily
Oral
Once daily
Half-life
20–30 minutes
3–4 hours
8–16 hours
Excretion
Urinary,
fecal
Urinary
Fecal
Main adverse effects
in PI
Local reactions, ophthalmologic, auditory, growth retardation, allergic
Gastrointestinal disturbances, agranulocytosis/ neutropenia, arthralgia, elevated liver enzymes
Gastrointestinal disturbances, rash, mild non-progressive
creatinine
increase, elevated liver enzymes, ophthalmologic, auditory
Usual dose (mg/kg/day)
25–60
75–100
20–30Slide18
Chelation regimes
DFO monotherapySc 8-12hcontinuous (sc or iv)Deferiprone monotherapypo 3 x dailyCombined Deferiprone and DFO
Deferiprone daily with DFO nocte n x weekDeferiprone daily + DFO at same timeDeferasirox monotherapyNew combinations and drugsSlide19
‘Harmless body iron levels’ ?what are guidelines based on ?
Experience with thalassaemia major
Experience with DFOControl of ferritin and LIC links to risk of cardiac diseaserisk of under and over chelationSlide20
Guidelines with DFO therapy
Begin after 10–20 blood transfusionsor when serum ferritin > 1,000 µg/LDose adults 40-60mg/kg 8-12h nocte
minimum 5x/wkMaintainserum ferritin < 2,500 µg/L (1,000 µg/L recommended)LIC < 7 mg/g dry weight
Intensify dose or frequency ifif severe iron overloadHigh ferritin values persistently > 2,500 µg/L
High liver iron > 15 mg/g dry weight or significant cardiac diseaseSignificant cardiac dysrhythmias Evidence of failing ventricular functionEvidence of severe cardiac iron loading Reduce dose ifFerritin <1000µg/L
Ratio of mean daily dose (mg/kg) / ferritin >0.025Slide21
Guidelines based on
Risks of over-chelation with DFO
Risks of starting too early
effects on growtheffects on bones, especially < 3 years of age1,2
Risks of too high a dosegrowth affected: > 70 mg/kg/day, normalized ≤ 40 mg/kg/day3skeletal/bones: > 70 mg/kg in children1eyes: visual symptoms > 80 mg/kg/day
4
otoxicity
4,5
Risks at low iron loads
effects on growth: patients had mean ferritin of 1,300 µg/L
3
otoxicity
: with serum ferritin < 2,000 µg/L or when ratio dose/ferritin
too high
5
neurotoxicity in non-iron-overloaded RA patients at low doses
6ocular toxicity in dialysis patient7
1.
Olivieri
NF, et al. Am J
Pediatr
Hematol
Oncol
. 1992;14:48-56.
2. Brill PW, et al.
Am.J.Roentgenol
. 1991;156:561-5. 3.
Piga
A, et al.
Eur
J
Haematol
.
1998;40:380-1.
4.
Olivieri
NF, et al. N
Engl
J Med
.
1986;314:869-73. 5. Porter JB, et al. Br J Haematol
. 1989;73:403-9.6. Blake DR, et al. Q J Med. 1985;56:345-55. 7. Rubinstein M, et al. Lancet. 1985;325:817-8.Slide22
Survival probability
Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-93.
(
p < 0.00005)
0
1.00
0.75
0.50
0.25
0
5
10
15
20
25
30
Age (years)
Birth cohort
1960–1964
1965–1969
1970–1974
1975–1979
1980–1984
1985–1997
DFO Chelation
therapy
has improved
patient
survival in TMSlide23
Decline in complications with
iron chelation
Birth 1970–1974*
Birth 1980–1984
†
Death at 20 years
6.3%
1%
Hypogonadism
64.5%
14.3%
Diabetes
15.5%
0.8%
Hypothyroidism
16.7%
4.9%
Patients with
β
-thalassaemia major
born after 1960 (N = 977)
*DFO i.m., 1975;
†
DFO s.c., 1980.
In 1995, 121 patients switched to deferiprone (censored at this time)
Borgna-Pignatti C, et al.
Haematologica. 2004;89:1187-93.Slide24
Is
there a risk of over-chelation with other chelation regimes
?How low can we go?
How is risk of chelator toxicity related toAbsolute chelator dose
Dose in relation toBody iron load Transfusional iron loading rateRate of decrease of load with chelationSlide25
Do DFP doses >75mg/kg/d
affect tolerability?
Unwanted Effect Dose dependence?
GI distrurbances 3-24% at 75mg/kg (1-3)
66% at 100mg/kg
(n=29)
(4)
Neutropaenia insufficient human numbers
Agranulocytosis insufficient human numbers
Thrombocyopenia age <6y (7/44) ? dose effect
(5)
Arthropathy ? improved arthropathy at 50mg/kg
(6)
Neurotoxicity Yes with unintended large doses
1. Al Rafae Brit J Haematol, 1995;
91:224-9.2. Ceci A, et al.
Br J Haematol. 2002;118: 330-6.
3. Cohen AR, et al. Br J Haematol.
2000;108:305-12.
4. Pennell DJ, et al. Blood. 2006;107:3738-44
5. Naithani et al, Eur J Haematol. 2005 ;74:217-20
6. Lucal et a, Ceylon Med, 45, 71-4.J 2000
.Slide26
Low serum ferritin without toxicity with long-term combined therapy
53 patients 5-7y on DFO 20-60mg/kg/day and deferiprone 75mg/kg/day ‘individually tailored’Ferritin
bl 3421µg/L - 87 µg/L at 5-7y T2* bl 28ms
- 38 ms at 5-7yLIC
bl 12.7 - 0.8mg/g dry wt at 5-7yGTT normal bl 23% - 64% at 5-7y
Thyroxine
replacement
bl
34% - 20% at 5-7y
Secondary amen
bl
19/26
- 3/19 spontaneous ovulation No toxicity
Farmaki et al presentation at ITC 2008 FC07 Pg. 92
Farmaki et al Br J Haematol, 466-75 (2010)Slide27
Porter JB, et al. Blood. 2008;112:[abstract 5423].
Experience
with serum ferritin
< 1,000
μg/L
174 adult and paediatric patients (out of 474) were chelated to serum ferritin levels < 1,000
μ
g/L
% of patients achieving serum ferritin < 1,000 µg/L
Year 1
Year 2
Year 3
Year 4
Year 5
The incidence of drug-related AEs did not appear to increase during the periods after serum ferritin levels first decreased < 1,000 μg/L
YearsSlide28
Safety profile of serum ferritin <1000
μg/L
Investigator-assessed d
rug-related adverse events (n 5%)
, n (%)
Serum ferritin
< 1,000
μ
g/L
(n = 174)
≥ 1,000
μ
g/L
(n = 300)
Nausea
26 (14.9)
38 (12.7)
Diarrhoea
17 (9.8)
42 (14.0)
Vomiting
14 (8.0)
25 (8.3)
Abdominal pain
12 (6.9)
32 (10.7)
Rash
9 (5.2)
16 (5.3)
Upper abdominal pain
6 (3.4)
20 (6.7)
The incidence of drug-related adverse events did not appear to increase during the periods after serum ferritin levels first decreased < 1,000
μ
g/L
Safety profile
was similar to patients with serum ferritin levels > 1,000
μ
g/L
No increase in the proportion of patients with creatinine increases > 33% above baseline and ULN or with ALTs > 10 x ULN
Porter JB, et al. Blood. 2008;112:[abstract 5423].
ALT = alanine transaminase.Slide29
Duration of therapy: 52 weeks
Deferasirox 20–30 mg/kg/day
DFO 35–50 mg/kg/infusion infused 3–7 days/week
Combined chelation therapy with DFX and DFO in transfusion-dependent thalassaemia
Lal
, Porter,
et al. Blood. 2010;116:[abstract 4269].
Aim: to explore safety and efficacy of combined
deferasirox
and DFO in patients with transfusion-dependent
thalassaemia
who had failed standard chelation therapy with single drug (US24T)
15 patients enrolled and randomized into 3 equally sized groups
Group A
Adults
LIC <15 mg/g dry
wt
Group B
Adults
LIC >15 mg/g dry
wt
Group C
8–18 years
LIC >5 mg/g drywtSlide30
DFX + DFO:improvements in iron overload
Cardiac improvements (in three patients who had T2* < 20 ms at baseline)T2* < 20 ms at baseline (6.5–19.5 ms): improved +2.43 ms (8.8–21.3 ms) (p = 0.027)
LVEF < 60% at baseline (47.4–58.1%): improved to 60.6–64.4%Median LPI decreased: 0.87 µM to 0.05 µM (p = 0.004)
Median LIC (mg/g)
Median plasma NTBI (µM)
DFO
DFO + deferasirox
p < 0.001
Median serum ferritn (
μ
g/L)
BL 1 year
48%
(p = 0.003)
43%
(p = 0.008)
BL 1 year
LIC
Serum ferritin
NTBI
0
500
1,000
1,500
2,000
0
5
10
15
0
1
2
3
Lal A, et al. Blood. 2010;116:[abstract 4269].
LPI = labile plasma iron.Slide31
DFX + DFO:improvements in iron overload
Lal
, Porter et al Blood.Cells Mol Dis. 2012 in press.Slide32
DFP + DFX?A patient case34-year-old female with TM, 2 units of packed red blood cells, every 20 days
Deferoxamine – failed to comply T2* liver 1.1 ms, cardiac T2* 9.4 msserum ferritin > 2,800 µg/LDeferasirox, 20 mg/kg for 12 months
liver T2* 3.33 ms, cardiac T2* 10.6 ms Deferasirox 30 mg/kg for 24 months liver 7.
81 ms, cardiac T2* 13.8 ms serum ferritin 2,080 µg/LDeferasirox 30 mg/kg/day + deferiprone 75 mg/kg/day
for 12 months serum ferritin 397 μg/Lliver T2* 15.3 ms, cardiac T2* 21.1 ms
Voskaridou E, et al. Br J Haematol. 2011;154:654-6.
Combination
Cardiac
Liver
Year
MRI T2* (ms)
2005
2006
2007
2008
2009
2010
25
15
5
0
20
10
Year
Serum ferritin (µg/L)
2005
2006
2007
2008
2009
2010
3,000
1,500
500
0
2,000
1,000
2,500
Serum ferritinSlide33
DFP + DFX
Farmaki, et al. Blood Cells Mol Dis. 2011;47;33-40.
GTT = glucose tolerance test.
* p < 0.001
Patient selection
16 TM > 20 years old
Either intolerance to DFO or
‘inconvenience to DFO’
Serum ferritin > 500 µg/L
> 1 iron overload complication
(clinical or laboratory)
Treatment:
up to 2 years of
DFX (20–25 mg/kg/day)
+ DFP (75–100 mg/kg/day)
Outcome
Reversal of cardiac dysfunction in 2/4
Mean LVEF increased significantly
GTT improved in 2/8 with impaired GTT
Improvement in gonadal function
Tolerability
No serum
creatinine
> ULN
No
agranulocytosis
, neutropenia, thrombocytopenia
3/15 (20%) minor GI disturbance
Baseline
After
Serum ferritin (µg/L)
581±346
103±60
LIC (mg/g dry wt)
1.6±1.1
1.0±0.2
Cardiac T2* (ms)
34.1±5.8
36.9±5.6*
LVEF (%)
61±6.0
65±7.6*
2-hour GTT (mg/dL)
150±87
111±24
Creatinine (mg/dL)
0.9
1.0Slide34
Approaches to LIC measurementBiopsyPatient safety and acceptanceSample size (4mg wet wt)
Inhomogeneity of distributionMeasurements not standardisedSQUIDOnly 4 machinesVery expensive to run and maintainNot
standardisedMRIT2* calibration underaseimates LIC by two foldR2* (= 1/T2*) R2 (ferriscan) standardised
, easy to introduceSlide35
How has chelation therapy and monitoring impacted on outcome in transfusion dependent thalassaemia
- a local perspective in UKSlide36
Treatment of Thalassaemia
Major in the UK
1960 → 1970 → 1980 → 1990 → 2005
1980 – SC desferoxamine standard of care
1964 – IM desferoxamine
1984 – Bone marrow transplant initiated
1987 – Deferiprone
1999 – CMR
Deferasirox
Cardiac failure secondary to cardiac iron overload is reported as the leading cause of death amongst patients with
TM
Survival substantially improved with introduction of iron chelation therapy but despite this by 2000, 50% UK patients died before the age of 35 in 2000
1
.
CMR introduced in London 1999 – what impact has this had
Cohort of 121 patients monitored and treated at UCLH/
Whittinton
since 1999Slide37
DFO
DFP
DFP + DFO
DFO
DFP
DFP + DFO
DFX
2010
Chelation regimes
DFP + DFO
DFP
DFXSlide38
Impact of a decade of cardiac MRI assessment on cardiac T2*
Cohort of 132 patients from UCLH/Whittington hospitals
Thomas AS, et al. Blood. 2010;116:[abstract 1011].
Baseline
Median 9 years follow-up
Proportion of patients (%)
70
50
30
10
0
60
40
20
T2* ≤ 20 ms
T2* < 10 ms
60
23
17
7
p < 0.001
p < 0.001Slide39
MortalityTotal of 8 deaths amongst 132 patients:
2 female, 6 malemedian age at death 35.6 years (range 27.3-48.4)None directly related to myocardial ironMortality rate 1.65 / 1000 patient y (95% CI 0.71-3.24
)Previous reports from UK thalassaemia registry:1980-1999: 12.7 deaths / 1000 patient y 2
2000-2003: 4.3 deaths / 1000 patient y 3
1. Thomas
AS, et al. Blood. 2010;116:[abstract 1011
]
2 Modell
et al , Lancet 355:2051-2, 2000
3. Modell
et al , J.
Cardiovas
Magnetic Resonance, 2008Slide40
Causes of Death and cardiac MRI
Cardiac MRI at death, n = 8
T2* > 20ms 3 pt with hepatitis C complications 1 sudden deathT2* 10-20ms
1 pt with meningitis 1
pt with cancerT2* < 10ms 2 pt with sepsisSlide41
Chelator regime at death
DFO (n= 4)DFP (n= 2)Combination DFP + DFO ( n= 1)DFX ( n= 1)Slide42
0
10
20
30
40
50
60
70
80
90
100
Causes of death in
β
-
thalassaemia
major in the UK
Adapted from UK Thalassaemia Registry data from Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42.
Thomas AS, et al. Blood. 2010;116:[abstract 1011].
Use of modern iron chelation therapy and regular CMR monitoring has dramatically reduced the iron overload-related mortality in the Red-cell Disorders Unit
Mortality rates per cohort
Patients (%)
Hepatitis C
complications
Other/unknown
Malignancy
Infection
BMT complication
Anaemia
Iron overload
1950–1959
1960–1969
1970–1979
1980–1989
1990–1999
2000–2003
This cohort
BMT = bone marrow transplantation;
CMR = cardiac magnetic resonance imagingSlide43
Optimal Outcome - What else
do we need ?Recognition that chronic diseases pose special challenges which require targeted resourcesRapid
access to free careStaff with expert knowledge & experience Continuity of care (especially staff)
Systems organized to allow best care with minimum disruption
to ordinary life Identity (a ‘unit’) for patients allowing a focus for care but not isolated from hospital Multidisciplinary team with integrated clinics & investigations
Optimal
monitoring and intensification for high risk
patients
ANDSlide44
ConclusionsWith modern chelation regimes, used alone or in combination and when applied with modern monitoring techniques, excellent survival can be obtainedThe challenge over the next decade will to be to improve quality of life in an ageining population by;
Further decreasing morbidities associated with thalassaemia and iron overloadFurther improving infrastructure and delivery of care to thalassaemia patients inside and outside treatment ‘centres’Slide45
Then
and
Now
What can be achieved with transfusion, chelation and optimal monitoringSlide46
ThankyouSlide47
A decade of cardiac monitoring with modern
chelation therapies for TM, UCLH/Whittington
Cohort of 132 patients received 1
st CMR 1999-2000109 of these available for long term CMR FU
Follow up median 9.2 years (range 7.0-10.6)Minimum CMR follow up of 7 yMedian age at 1st CMR 27.9 years (range 7.7-49.5)
58 female, 51 maleSlide48
Variables studied
% Patients with evidence of myocardial ironAt 1st CMRAt latest CMRSurvival in cohort with baseline CMR 1999-2000
Cause of deathT2* at deathModes of chelation
At baselineAt latest follow upAt death
Number of switches in chelatorSlide49
Causes of Death by cardiac MRI
Cardiac MRI at death, n = 8
T2* > 20ms 3 pt with hepatitis C complications 1 sudden deathT2* 10-20ms
1 pt with meningitis
1 pt with cancerT2* < 10ms 2 pt with sepsisSlide50
Changes in Chelation
69% changed chelator at least once based on:Iron assessmentFerritin trend
LIC trendm T2* trendSide effects/tolerabilityAdherence or patient preference
Availability of new chelators: trials/funding decisionsSlide51
Impact of monitoring and comprehensive support on outcomeSlide52
Survival (%)
0
60
80
50
40
30
20
10
70
90
100
0
28
26
24
22
20
18
16
14
12
10
8
6
4
2
30
32
34
36
38
40
Years
300
–
3
65
225
–
3
00
150
–
2
25
75
–
1
50
0
–
7
5
Frequency of
DFO chelation
and survival in
T
halassaemia
M
ajor
Gabutti V, Piga A. Acta Haematol. 1996;95:26-36.
Infusions/yearSlide53
Survival in UK as a whole and UCLH
- a question of optimal care?Modell et al1
200050% of thalassaemia major patients in
UK die < the age 35y Modell et al., Lancet 2000; 9220:2051-2
Davis et al, 2001, UCLH experience N=103, 78% survival at 40yrsNo death in cohorts after 1971
Porter & Davis Best
Pract
Res
Clin
Haematol
, 15, 328-68 2002Slide54
Crude mortality rates in
thalassaemia major
Birth cohort
UK as a whole
UCLH
1955-1964
1964-1974
1975-1984
1985-1994
1995-2000
56%
34%
14%
3%
2%
29%
15%
0%
0%
0%
Overall
24%
Porter & Davis Best Pract Res Clin Haematol, 15, 328-68 2002
11.7%
Slide55
Reasons for better outcome?
Experience of clinicians - large clinic ?Different patient group ?Different Chelation regimen ?Better monitoring and intervention ?
Better Patient support of compliance adherence ?Slide56
DELIVERY OF THALASSAEMIA CARE IN UK as a
WHOLE807 patients cared for by 164 physicians nationwide71 physicians 1 patient77 physicians 2-9 patients
12 physicians 10-30 patients4 physicians 50 or more
Modell et al., Lancet 2000; 9220:2051-2Slide57
UK National Guidelines for Thalassaemia
Transfusion and other care locally butAt least yearly review in specialist centre
UK Thalassaaemia SocietySlide58
Thalassaemia
Major management in the UK
1960 → 1970 → 1980 → 1990 →
2005
1980 – SC desferoxamine standard of care
1964 – IM desferoxamine
1984 – Bone marrow transplant initiated
1987 – Deferiprone
1999
– CMR
Deferasirox
Cardiac failure secondary to cardiac iron overload is reported as the leading cause of death amongst patients with TM
Survival substantially improved with introduction of iron chelation therapy but despite this by 2000, 50% UK patients died before the age of 35 in 2000
1
.
1 Modell et al, Lancet 2000 355:2051-2Slide59
A decade of cardiac monitoring with modern
chelation therapies for TM, UCLH/Whittington
Cohort of 132
patients received 1st CMR 1999-2000
109 of these available for long term CMR FUFollow up median 9.2 years (range 7.0-10.6)Minimum
CMR
follow up
of 7 y
Median age at 1
st
CMR 27.9 years (range 7.7-49.5)
58 female, 51 maleSlide60
Impact of a decade of cardiac MRI assessment on cardiac T2*
Cohort of 132 patients from UCLH/Whittington hospitals
Thomas AS, et al. Blood. 2010;116:[abstract 1011].
Baseline
Median 9 years follow-up
Proportion of patients (%)
70
50
30
10
0
60
40
20
T2* ≤ 20 ms
T2* < 10 ms
60
23
17
7
p < 0.001
p < 0.001Slide61
MortalityTotal of 8 deaths amongst 132 patients:
2 female, 6 malemedian age at death 35.6 years (range 27.3-48.4)Mortality rate 1.65 / 1000 patient y (95% CI 0.71-3.24)
Previous reports from UK thalassaemia registry:
1980-1999: 12.7 deaths / 1000 patient y 12000-2003: 4.3 deaths / 1000 patient y 2
1 Modell et al , Lancet 355:2051-2, 2000
2
Modell et al , J.
Cardiovas
Magnetic Resonance, 2008Slide62
Causes of Death and cardiac MRI
Cardiac MRI at death, n = 8
T2* > 20ms 3 pt with hepatitis C complications 1 sudden deathT2* 10-20ms
1 pt with meningitis 1
pt with cancerT2* < 10ms 2 pt with sepsisSlide63
Chelator regime at death
DFO (n= 4)DFP (n= 2)Combination DFP + DFO ( n= 1)DFX ( n= 1)Slide64
Changing Causes of death in TMSlide65
Optimal Care for chronic anaemias - What do we need ?
Optimal monitoring technigues - yes but also need…….Setting to optimise treatment adherence
Recognition that chronic diseases pose special challenges which require targeted resourcesRapid access to free careStaff with expert knowledge & experience
Continuity of care (especially staff)Systems organized to allow best care with minimum disruption to ordinary life
Identity (a ‘unit’) for patients allowing a focus for care but not isolated from hospital Multidisciplinary team with integrated clinics & investigationsSlide66
SummaryIron toxicity occurs in tissues where
excess storage iron accumulates though NTBI uptakeDistribution of excess iron differs in transfusional and non transfusional iron overloadDistribution also differs depending on underling disorder (e.g. Thal vs sickle)
Heart and endocrine tissues more sensitive to excess iron than liverNo single measure assesses risk of iron overload equally in all clinical conditionsAssessment of iron overload needs to estimate both;
The degree of body iron overloadThe distribution of iron excess (extra-hepatic vs hepatic)Transferrin saturation- good screening tool – less useful for monitoring
Ferritin is a useful marker of iron overload with prognostic significanceLIC assessment can estimate total body iron storesMyocardial T2* by MRI, validated with prognostic significance MRI other tissuesPlasma iron speciation and quantitationSlide67
1960
1970
1980
1990
200020102020
1980 – SC desferoxamine standard of care
1964 – IM desferoxamine
1984 – Bone marrow transplant initiated
1987 – Deferiprone trials
1999 - CMR
1980-1999: 12.7 deaths per 1000 patient years
2000-2003: 4.3 deaths per 1000 patient years
1999-2010: 1.65 deaths per 1000 patient years
??Exjade Trails
The future for thalassaemia care……..Slide68
Special challenges in treating haemoglobin disorders?
Challengers for the carersLife-long conditions do not fit comfortably with a hospital environmentProviding sustained support throughout life is rarely possible for one doctor
Challenges of knowledge and/or experience of rare conditionsChallenges of minimising the problems of transitioning from childhood to adolescence department or hospital
Challenges of operating within an ocology domiated environmentSlide69
Summary - MonitoringIron toxicity occurs in tissues where
excess storage iron accumulates though NTBI uptakeDistribution of excess iron differs in transfusional and non transfusional iron overloadDistribution also differs depending on underling disorder (e.g. Thal vs sickle)
Heart and endocrine tissues more sensitive to excess iron than liverNo single measure assesses risk of iron overload equally in all clinical conditionsAssessment of iron overload needs to estimate both;
The degree of body iron overloadThe distribution of iron excess (extra-hepatic vs hepatic)
Transferrin saturation- good screening tool – less useful for monitoringFerritin is a useful marker of iron overload with prognostic significanceLIC assessment can estimate total body iron storesMyocardial T2* by MRI, validated with prognostic significance MRI other tissuesPlasma iron speciation and quantitationSlide70
Long term use of deferoxamine is associated with falling cardiac mortality
Age (years)
0
10
20
30
40
0
0.25
0.50
0.75
1.00
1955-64 (n=21)
1965-74 (n=39)
1975-97 (n=42)
Davis and Porter.
Adv Exp Med Biol
. 2002;509:91.
Survival probability
Patients With
Beta
-Thalassemia Major (N=103)
Survival by Birth Cohort at
University College London Hospitals
Analysis September 2000Slide71
Falling Cardiac and other complications with Deferoxamine
Borgna-Pignatti, 2004
Thal Major born after 1960, n=977
Birth 1970-74* Birth 1980-84^
Death at 20 5% 1%
Hypogonadism 64.5% 14.3%
Diabetes 15.5% 0.8%
Hypothyroidism 17.7% 0. 0%
* IM DFO 1975 ^ sc DFO 1980
1995 121 switched to L1 (censored at this time)Slide72
Rescue With Continuous IV DFO
for Cardiac DiseaseRationaleContinuous chelation because labile chelatable iron pools (NTBI) re-emerge rapidlyHigh doses may not be necessary
Outcome at 16y follow-upLVEF improvement within 6-8monthsReversal of arrhythmias in 6/6 (24h-6 mo)Good long term survival if chelation subsequently maintained
20
30
40
50
60
70
LVEF (%)
Pre–IV DFO
Post–IV DFO
6-8 mo
Mean 49%
Mean 36%
P
=0.002
LVEF = left ventricular ejection fraction; DFO = deferoxamine.
Davis and Porter.
Blood.
2000;95:1229.Slide73
New developments in chelation
Deferasirox monotherapyNew combinationsCombination studies with desferrioxamine (3)Tolerability at low ferritinFerrokinDesferrithiocin derivative
Phase 2 study results submitted for publicationSlide74
Deferasirox:recent publicationsLong-term cardiac effects
Liver effectsLong-term efficacy and tolerabilitySafety and efficacy of dose escalationTolerability at low levels of iron loadEffect of administration regime on efficacy and tolerabilityUse in combination with other chelators
Use in conditions other than transfusion-dependent thalassaemiaSlide75
5-year follow-up in patients with β-thalassaemia major: changes in serum ferritin
(n)
(422)
(433)
(375)
(343)
(286)
(253)
(244)
(220)
(154)
Cappellini MD, et al. Blood. 2008;112:[abstract 5411].
Studies 105–108: 4.5-year data
3,000
2,500
2,000
1,500
1,000
500
0
Time (months)
Median serum ferritin (
μ
g/L)
Mean deferasirox dose (mg/kg/day)
30
25
20
15
10
5
0
Deferasirox dose
Serum ferritin
BL 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Mean actual daily dose of DFX:
22.1
± 6.4 mg/kg/day (range (6–37)
N = 472 at
baseline (BL)
Core
(DFO)
Extension (deferasirox)Slide76
Porter JB, et al. Blood. 2008;112:[abstract 5423].
Experience
with serum ferritin
< 1,000
μg/L
174 adult and paediatric patients (out of 474) were chelated to serum ferritin levels < 1,000
μ
g/L
% of patients achieving serum ferritin < 1,000 µg/L
Year 1
Year 2
Year 3
Year 4
Year 5
The incidence of drug-related AEs did not appear to increase during the periods after serum ferritin levels first decreased < 1,000 μg/L
YearsSlide77
Safety profile over time in patients with β-thalassaemia major
Cappellini MD, et al. Blood. 2011;118:884-93.
Patients (%)
Adverse event
10
8
6
4
2
0
9
7
5
3
1
Increased blood
creatinine
Abdominal
pain*
Nausea
Vomiting
Rash
Diarrhoea
Year 1 (n = 296)
Year 2 (n = 282)
Year 3 (n = 234)
Year 4 (n = 213)
Year 5 (n = 196)
* Reports of abdominal pain and abdominal pain are combined
and presented as abdominal pain.Slide78
Stable creatinine clearance in children and adults with β-thalassaemia major over 5 years
Adapted from: Cappellini MD, et al. Blood. 2011;118:884-93.
37 (6.7%) patients with a normal serum creatinine at baseline
had 2 consecutive values > 33% and > ULN
Creatinine clearance (mL/min)
400
200
0
300
100
BL
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
60
Deferasirox
Crossover
Time (months)
Core
Extension
ULN = upper limit of normal.Slide79
Patients, n
< 10 ms
24
24
24
24
10–< 20 ms
47
47
47
44
All patients
71
71
71
68
Cardiac iron reduction with deferasirox: continued improvement in cardiac T2*
Pennell D, et al.
Haematologica. 2012 Jan 22. [Epub ahead of print].
CI = confidence interval; LOCF = last observation carried forward.
†
p = 0.0012 versus baseline;
‡
p < 0.001 versus baseline
Dashed line indicates normal cardiac T2* of ≥
20 ms
10.5
‡
7.7
8.6
†
9.4
‡
15.0
17.7
‡
20.3
‡
22.3
‡
Baseline
12
24
36
Time (months)
Geometric mean T2*
± 95% CI (ms)
> 5
–< 10 ms
10
–< 20 ms
All patients
0
5
10
20
30
15
25
17.1
‡
15.6
‡
13.9
‡
12.0Slide80
CORDELIA: RCT deferasirox vs DFOObjective: to prospectively compare the efficacy of deferasirox to DFO in patients with a MRI-measured LVEF of
56% but with evidence of cardiac iron deposition depicted by a myocardial T2* of 20 ms
Screening
23 days
1-year study Rx in core study
96 patients* deferasirox
96 patients* DFO
1-year study Rx in extension study
96 patients deferasirox
96 patients DFO
Randomize eligible patients
(1:1 ratio)
Followed by 5-day washout
Screening
23 days
End core / start extension
End
extension
* = Patients with β-thalassaemia major or Diamond-Black anaemia or sideroblastic anaemia on chronic transfusion therapy.Slide81
82.6% of patients experienced either stabilization or improvement in fibrosis stagingImprovements in fibrosis staging were observed in patients who met the LIC response criteria and in those who did not
Figure 1
Deugnier Y, et al. Gastroenterology. 2011;141:1102-11.
Improvement in liver pathology with at least 3 years of deferasirox treatmentSlide82
Combination Tharapies
Desferrioxamine + Deferiprone
Desferrioxamine + Deferasirox
Deferiprone + DeferasiroxSlide83
Deferasirox + DFO metabolic iron balance studies
Grady et al, 2010 116: Abstract 5163
Introduction: Deferasirox (Exjade, ICL670) is an orally effective iron chelating agent approved for use in patients 2 years of age and older with transfusional iron overload. While it is effective as a single agent, there are patients who do not attain net negative
iron balance despite being at the upper limit of approved dosing (40 mg/kg/day). Deferiprone (Ferriprox, L1) is another orally effective iron chelator. Through a series of metabolic iron balance studies we were able to demonstrate that various regimens
involving the combined use of deferiprone and deferoxamine (Desferal, DFO) were capable of placing all patients into net negative iron balance with the potential to adjust dosing schedules and the ratio of drugs to maximize effectiveness while minimizing toxicity. A variety of such regimens are now in widespread clinical use. We have taken the same approach in order to optimize the use of deferasirox.Methods: Six patients with thalassemia major were enrolled in a 34-day
metabolic iron balance study wherein
deferasirox
and deferoxamine
were evaluated alone and in combination, each patient serving
as his/her own control. Deferoxamine (40 mg/kg) was administered
on days 5 – 10 as an 8-hour subcutaneous infusion during
the night. On days 15 – 20, deferasirox (30 mg/kg) was given orally, 30 minutes prior to breakfast. Both drugs were given on days 25 – 30, the same doses and dosing schedules being employed. Non drug days allowed for washout of stool iron induced by the previous treatment. The patients consumed a fixed low-iron diet consisting of four individualized meal plans. Daily collections of urine and stool were made and their iron content determined by atomic absorption, a correction being made for all uneaten food.Results: As in previous studies, there was significant patient to patient variability in terms of the amount of drug-induced iron excretion. Combination therapy placed all patients into iron balance exceeding
200% (206% - 270%, mean 251%). The combination was synergistic
in two patients (35% and 57%), additive in three patients, and
less than additive in one patient. Where iron excretion was
more than additive, all of the excess appeared in the urine
(a 2.1- and 3.4-fold increase). Deferasirox proved to be less effective than deferoxamine in all six patients (relative iron
excretion: 23% - 59%, mean 42%), stool iron excretion in response
to the respective drugs being 94% -100% (mean 98%) and 49% - 74% (mean 59%). Net negative iron balance was achieved in 2/6 patients when on deferasirox (iron balance 28% - 129%, mean
72%) and 6/6 patients when infusing deferoxamine (iron balance 125% - 219%, mean 167%).Discussion: These results suggest that chelation therapy can be tailored
to the individual needs of each patient, selectively removing iron from different pools while minimizing any side effects. Deferasirox appears to shuttle iron to deferoxamine for excretion
in the urine, not unlike the situation when deferiprone and deferoxamine are combined, although the source of the iron may be somewhat different. It is hoped that these results will provide patients with further options to optimize their chelation regimens
.
Patients: - 6 with TM
- 34-day metabolic iron balance study - each patient serving as his/her own control
- fixed low-iron diet consisting of four individualized meal plansDosing: - Deferoxamine
(40 mg/kg) days 5 – 10 as an 8-hour sc nocte - Deferasirox (30 mg/kg) days 15 – 20, 30 minutes prior to breakfast. - Washout - then both drugs
were given on days 25 – 30Results: - Combination – Mean -
ve iron balance -251%,( range 206% - 270%) - Combination > additive 2 patients (35% and 57%) - additive in three patients
< additive in one patient Slide84
Duration of therapy: 52 weeks
Deferasirox 20-30 mg/kg/dayDFO 35-50 mg/kg/infusion infused 3-7 days/week
Combined Chelation Therapy with Deferasirox
and Deferoxamine in Transfusion-Dependent Thalassemia
Lal A, et al.
Blood.
2010;116: Abstract 4269.
Aim: To explore safety and efficacy of combined
deferasirox
and DFO in patients with transfusion-dependent thalassemia who had failed standard chelation therapy with single drug (US24T)
15 patients enrolled and randomized into 3 equally sized groups
Group A
Adults
LIC <15 mg/g dw
Group B
Adults
LIC >15 mg/g dw
Group C
8–18 years
LIC >5 mg/g dwSlide85
Improvements in Iron Overload
Median LIC (mg/g)
Cardiac improvements (in three patients who had T2* <20
ms
at baseline)
T2* <20
ms
at baseline (6.5 to 19.5
ms
): improved +2.43
ms
(8.8 to 21.3
ms
) [
p
=.027]
LVEF <60% at baseline (47.4 to 58.1%): improved to 60.6 to 64.4%Median labile plasma iron (LPI) decreased: 0.87 µM to 0.05 µM (P = .004)
Median plasma NTBI (µM)
DFO
DFO + deferasirox
P
<.001
Median SF (ng/mL)
BL 1 year
48%
(
P
= .003)
43%
(
P
= .008)
BL 1 year
LIC
Serum ferritin
Non-transferrin-
bound iron (NTBI)
0
500
1000
1500
2000
0
5
10
15
0
1
2
3
Lal A, et al.
Blood.
2010;116: Abstract 4269.Slide86
Deferiprone + Deferasirox ?34yo female TM, 2 units of packed red blood cell, every 20 dDeferoxamine - failed to comply
- T2* liver 1.1ms, cardiac T2* 9.4ms - serum ferritin > 2800 lg/lDeferasirox, 20 mg/kg for 12 mo liver T2* 3.33 ms,
Cardic T2* 10.6 ms Deferasirox 30 mg/kg, 24mo Liver 7.81ms, cardiac T2* 13.
8 ms, SF 2080 lg/l Deferasirox 30 mg/kg/d
+ deferiprone 75 mg/kg/d for 12 mo - Serum ferritin (397 lg/l), - Liver T2* 15.3, Cardiac 21.1 ms
Voskaridou,, et al. (2011).
Brit. J Haematol
154
(5): 654-656.
combination
Cardiac
LiverSlide87
Berdoukas et al , Blood. Blood 2010 116
Abstract 2064
Deferiprone + Deferasirox
Patient selection
4 case reports - adult patients with TM Reduced LVEF + either severe allergy or intolerance to DFOHigh liver iron concentrations (LIC)
Previous treatments DFX or DFO
Treatment
DFX (15–40 mg/kg/day ) + DFP (75–100 mg/kg/day), 6 - 60
mo
(mean 18 )
Outcome
Cardiac T2* improved
from 5.8 ±1.5 to 7.0 ± 1.5
ms
(mean) (p=0.15).
LVEF 52.8% to 58.9% (p=0.02). Ferritin fell from a mean of 5826 to 5544 ng/L (p=0.86).LIC increased from 20.7 to 28.1 mg/g dry weight (p=0.36)Tolerability No drug-related neutropenia, agranulocytosis or arthralgia No significant proteinuria and mean
creatinine
levels were unchanged.
ALT's showed fluctuations
Compliance
Highly variable
Conclusions
Well tolerated, prospective studies neededSlide88
Deferiprone + Deferasirox
Patient selection
16 TM >20yo either intolerance to DFO or ‘Inconvenience to DFO’
Ferritin >500µg/L >1 IOL complication (clinical or laboratory)Treatment; up to 2years of DFX (20–25 mg/kg/day ) + DFP (75–100 mg/kg/day )OutcomeReversal of cardiac dysfunction in 2/4
Mean LVEF increased significantly.
GTT improved in 2/8 with impaired GTT
Improvement in gonadal function (1)
Tolerability
No serum
creatinine
>ULN
No
agranulocytosis,neutropenia
thrombocytopenia
3/15(20%) minor GI disturbance______________________________ Baseline After______________________________Ferritin(µg/L)
581
±346
103
± 60
LIC
(mg/g
dw
)
1.6
±1.1 1.0 ± 0.2cT2* ms 34.1 ± 5.8
36.9 ±5.6 *LVEF (%) 61
± 6.0 65 ± 7.6 *2h GTTmg/dl
150 ± 87 111 ± 24Creatinine(mg/dl) 0.9 1.0
_______________________________*p<0.001
Farmaki et al, Blood Cells, Mol, and Dis 47 (2011) 33–40
cT2* = cardiac T2, GTT glucose tolerance test,
ULN upper limit normal, IO: iron overlloadSlide89
Desferrithiocin and derivatives
Desferrithiocin
Bergeron RJ, et al. Biometals. 2011;24:239-58.
Tridentate chelator
Renal toxicity is a class
effect but minimized by
derivatization in animal
studies
Numerous analogues
synthesized
Def
erritrin, nephrotoxic in clinical studies
Deferitrin (1)
CH
3
CO
2
H
N
S
OH
HO
(
S
)-3′-(HO)-DADFT-PE (9)
OH
CH
3
CO
2
H
OCH
3
N
S
O
O
O
By replacing the 4
′
-(HO) of 1 with a 3,6,9-trioxadecyloxy group nephrotoxicity could be controlledSlide90
Phase 1b dose-escalation study: safety, tolerability, and pharmacokinetics16 adult patients with transfusional overloaded Once daily for 7 days at doses up to 32 mg/kg
Well tolerated at all dose levelsPharmacokinetics showed dose-proportionalityCmax at 60–90 min
Rapidly distributed at the predicted therapeutic dosesPlasma t1/2 – approximately 19 hours
Clinical studies witha desferrithiocin
derivative FBS0701Rienhoff HY Jr, et al. Haematologica. 2011;96:521-5.Slide91
51 patients, stratified by transfusional iron intake FBS0701 at 14.5 or 29 mg/kg/day p.o. once daily49 patients (96%) completed the studyNo AEs showed dose-dependency Commonest AE was increased transaminases (16%, n = 8)
Mean serum creatinine did not change significantlyΔLIC mean at 14.5 mg/kg/day was +3.1 mg/g (dry wt) 29% achieved a decrease in LICΔLIC mean at 29 mg/kg/day was −0.3 mg/g (dry wt) 44% achieved a decrease in LIC
24-week multicentre phase 2 studywith FBS0701
Neufeld EJ, et al. Blood. 2012 Jan 17;[Epub ahead of print].Slide92
Conclusions
Cardiac iron overload is no longer the leading cause of mortality in Thal major patients if treated with full range of chelator options and monitored (including MRI) and supported
appropraitelyAll chelator regimes remove cardiac iron; choice of regime depends on severity of loading and heart functionLiver disease is becoming a serious issue in undertreated patients especially SCD
New combinations of chelators
are at early stage of assessment but may provide useful treatment options in future for difficult patientsFBS entering Phase III , when efficacy/toxicty will be scrutinisedSlide93
Treatment of Iron overloadWhich conditions ?Transfusion dependent Thalassaemia MajorMulti transfused SCDDBASideroblastic
Aplastic AnaemiaIron loaded NTDTMDSSlide94
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, fecal
Urinary
Fecal
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
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.Slide95
Univariate analysis of biochemical, virological, and histological features associated with severe fibrosis
Di Marco V, et al. Haematologica. 2008;93:1243-6.
The majority of HCV-RNA negative patients with low iron load did not develop liver fibrosis, while hepatitis virus C-RNA positive patients infected with genotype 1 or 4 and iron overload more frequently developed advanced fibrosis
Fibrosis stage
0–1–2
(104 patients)
Fibrosis stage
3–4
(22 patients)
p value
Age, mean ± SD
16.8±8.7
19.7±9.2
0.2
Gender, M/F
50/54
17/5
0.01
ALT, mean ± range
69.1±80.1
112.5±61.2
< 0.001
Serum ferritin, median (range)
1,583 (141–5,952)
2,115 (188–5,503)
0.3
HCV-RNA positive
39 (37.5%)
19 (86.4%)
< 0.001
LIC, median (range)
2.3 (0.3–22)
2.9 (0.4–11.8)
0.3
Histological inflammation (grading)
Grade 0
23 (22%)
0
Grade 1/Grade 2
79 (76%)
22 (100%)
Grade 3
2 (2%)
0
0.2Slide96
Rate of fibrosis progression in transfusion-dependent β-thalassaemia patients
Patients (n)
Rate of fibrosis progression
(per year)
Expected duration for progression to cirrhosis (years)
All patients
117
0.087
(0.077–0.107)
57
(47–65)
HCV RNA+
80
0.101
(0.083–0.120)
49
(42–60)
HCV RNA−
37
0.075
(0.058–0.111)
67
(45–85)
Prati D, et al. Haematologica.
2004;89:1179-86
.Slide97
LIC Increases With Time in the Absence of Effective Chelation
Adapted from Olivieri NF, et al. N Engl J Med. 1999;341:99-109.
Homozygoushemochromatosis
Estimate for
NTDT
Age (years)
Non-chelated thalassemia major
0
0
10
20
30
40
50
Hepatic Iron (mg/g of liver, dry weight
)
Increased risk of iron-related morbidity
Normal hepatic iron concentration
Homozygous hemochromatosis
10
20
30
40
50Slide98
labile
iron
Cell death
Fibrosis
Organelle
damage
TGF-
β
1
ROS
Lipid peroxidation
Lysosomal
fragility
Enzyme leakage
Collagen synthesis
NF-
к
B
activation
DNA damage
Genomic Instability
Caspase
activation
Anti-
-apoptotic
Blood
Transfusion
+
Iron
Chelation
-
Neoplasia
High Iron
absorption
Infection
storage
iron
Pathophysiology of Iron OverloadSlide99
Organs susceptible to iron overload
Diabetes
Pancreas
Hypogonadotrophic Hypogonadism
Gonads
Cirrhosis, carcinoma
Liver
Cardiomyopathy
Heart
Hypoparathyoidism
Parathyroid
Hypothyroidism
Thyroid
Hypogonadotrophic Hypogonadism
Pituitary
Consequences
Organ