Monitoring and treatment
iron overload in thalassaemia
Professor John Porter
Red Cell Disorders Unit
University College London Hospitals and UCL
j.porter@ucl.ac.uk
Monitoring and treatment iron
overload in thalassaemia
Professor John Porter
Red Cell Disorders Unit
University College London Hospitals and UCL
j.porter@ucl.ac.uk
Outline
• What are the treatment and monitoring options
available for iron overload in Thalassaemia Major
• On 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 perspective
Monitoring options
•
•
•
•
•
•
Iron loading rate
Serum ferritin
Liver Iron concentration
Cardiac evaluation – function & T2*
Endocrine evaluation – growth, function & MRI
Adherence and quality of life
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;111:583-7
Dosing to balance iron transfusional rate
Mean total body iron excretion
± SD (mg Fe/kg/day)
Studies 107 and 108
0.8
Deferasirox
Deferoxamine
0.7
0.6
0.5
Average transfusion iron intake
thalassaemia
0.4
0.3
Average transfusion iron intake SCD
0.2
0.1
Actual doses (mg/kg/day)
0
0
5
10
15
20
25
30
Deferasirox
0
10
20
30
40
50
60
Deferoxamine (5 days/week)
Cohen AR, et al. Blood. 2008;111:583-7.
Change in LIC
at low defarasirox doses in NTDT
Ferritin change (ng/ml) from baseline
LIC change (mg/g dry wt) from baseline
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
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 adherence
– consider dose increase
–
•
chelator regime change
Ferritin 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
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
1.
2.
3.
4.
5.
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, 92 583
Porter & Huehns, Acta Haematologica
Fischer et al. Brit J Haem 2003, 121 938-948
Ai Leen Ang, et al, Blood, 201, 116, Abstract 4246.
Why monitor & control liver iron ?
• Ferritin alone may not reflect true body iron and chelation trends
• LIC predicts total body storage iron in TM1
• Absence of pathology
– heterozygotes of HH where liver levels < 7 mg/g dry weight
• Liver pathology
– abnormal ALT if LIC > 17 mg/g dry weight2
– liver fibrosis progression if LIC > 16 mg/g dry weight3
• Cardiac pathology at high levels
Increased LIC linked to risk of cardiac iron in unchelated patients 2,6
– LIC >15 mg/g dry weight association with cardiac death
–
• all of 15/53 TM patients who died4
• improvement of subclinical cardiac dysfunction with venesection
alone post-BMT5
1. Angelucci E, et al. N Engl J Med. 2000;343:327-31.
ALT = alanine aminotransferase;
BMT = bone marrow transplantation.
2. Jensen PD, et al. Blood. 2003;101:91-6.
3. Angelucci E, et al. Blood. 2002;100:17-21.
4. Brittenham GM, et al. N Engl J Med. 1994;331:567-73.
5. Mariotti E, et al. Br J Haematol. 1998;103:916-21.
6. Buja LM, Roberts WC. Am J Med. 1971;51:209-21
Low Heart T2* inreases risk of low LVEF
90
80
70
60
Severe cardiac iron
Minimal liver iron
LVEF (%)
50
40
30
20
10
0
0
20
40
60
Heart T2* (ms)
Severe liver iron
80 Minimal cardiac iron
LVEF = left ventricular ejection fraction.
Anderson et al. Eur Heart J. 2001;22:2171.
Relationship between cardiac T2* and
cardiac failure
0.6
< 6 ms
Proportion of patients
developing cardiac failure
0.5
0.4
6–8 ms
0.3
8–10 ms
0.2
0.1
> 10 ms
0
0
30
60
90 120 150 180 210 240 270 300 330 360
Follow-up time (days)
Kirk P, et al. Circulation. 2009;120:1961-8.
Other Approaches
to assessing Iron overload
• Effects on specific organs
– Other Organs
• Endocrine screening- assessment of function
• Growth monitoring, bone age
• Role of MRI screening of pancreas 1, 2 ?
• Measurement of NTBI/LPI
– Predictive value of response 3
1.
2.
3.
Au WY, et al. Haematologica. 2008;93:785.
Noetzli LJ, et al. Blood. 2009;114:4021-6.
Aydinok Y, et al. . Haematologica, 2012, 97,6, 835-41
MRI and assessment of endocrine
complications in Thalassaemia Major
Age
Ferritin
Cardiac
T2*
Hepatic
T2*
Pan T2*
Pit T2
Pit SIR
Pit T2*
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
0.061
<0.001
< 0.001
NS
NS
< 0.001
< 0.001
(0.023)
NS
0.001
(0.008)
NS
< 0.001
(0.006)
NS
NS
0.062
0.003
0.058
Heart failure (n = 34)
Hypothyroid
(n=36)
Hypoparathyroid
(n = 16)
– = 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=180
•
Cardiac MRI T2* correlates with endocrine dysfunction
•
Pancreatic T2* poor correlation with diabetes
•
Pituitary T2 correlates with multiple endocrine dysfunctions
Au WY, et al. Haematologica. 2008;93:785.
Assessment – when?
Observation
Frequency
Iron intake rate
Each transfusion
Chelation dose & frequency
3 monthly
Growth & sexual development
6 monthly children
Liver function
3 monthly
Sequential ferritin
3 monthly
GTT, 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
Expense
Goals of chelation therapy
• Prevention of iron mediated damage
– Balance input and output - iron balance
– Achieve harmless levels of body iron safely
• Rescue
– patients with high levels of body iron
– patients with high levels of cardiac iron
– patients with heart dysfunction
Licensed iron chelators
Property
DFO
Deferiprone
25–60
75–100
20–30
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
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)
Route
Main adverse
effects
in PI
Deferasirox
Chelation regimes
• DFO monotherapy
– Sc 8-12h
– continuous (sc or iv)
• Deferiprone monotherapy
– po 3 x daily
• Combined Deferiprone and DFO
– Deferiprone daily with DFO nocte n x week
– Deferiprone daily + DFO at same time
• Deferasirox monotherapy
• New combinations and drugs
‘Harmless body iron levels’ ?
what are guidelines based on ?
• Experience with thalassaemia major
• Experience with DFO
• Control of ferritin and LIC
– links to risk of cardiac disease
– risk of under and over chelation
Guidelines with DFO therapy
• Begin
– after 10–20 blood transfusions
– or when serum ferritin > 1,000 µg/L
– Dose adults 40-60mg/kg 8-12h nocte minimum 5x/wk
• Maintain
– serum ferritin < 2,500 µg/L (1,000 µg/L recommended)
– LIC < 7 mg/g dry weight
• Intensify dose or frequency if
– if severe iron overload
• High ferritin values persistently > 2,500 µg/L
• High liver iron > 15 mg/g dry weight
– or significant cardiac disease
• Significant cardiac dysrhythmias
• Evidence of failing ventricular function
• Evidence of severe cardiac iron loading
• Reduce dose if
– Ferritin <1000µg/L
– Ratio of mean daily dose (mg/kg) / ferritin >0.025
Guidelines based on
Risks of over-chelation with DFO
• Risks of starting too early
– effects on growth
– effects on bones, especially < 3 years of age1,2
• Risks of too high a dose
–
–
–
–
growth affected: > 70 mg/kg/day, normalized ≤ 40 mg/kg/day3
skeletal/bones: > 70 mg/kg in children1
eyes: visual symptoms > 80 mg/kg/day4
otoxicity4,5
• Risks at low iron loads
– effects on growth: patients had mean ferritin of 1,300 µg/L3
– otoxicity: with serum ferritin < 2,000 µg/L or when ratio dose/ferritin
too high5
– neurotoxicity in non-iron-overloaded RA patients at low doses6
– ocular 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.
DFO Chelation therapy
has improved patient survival in TM
1985–1997
1.00
1970–1974
0.75
Survival probability
1980–1984
1975–1979
Birth cohort
0.50
1965–1969
1960–1964
0.25
(p < 0.00005)
0
0
5
10
15
20
25
30
Age (years)
Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-93.
Decline in complications with
iron chelation
Patients with β-thalassaemia major born after 1960 (N = 977)
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%
*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.
Is there a risk of over-chelation
with other chelation regimes?
How low can we go?
• How is risk of chelator toxicity related to
– Absolute chelator dose
– Dose in relation to
• Body iron load
• Transfusional iron loading rate
• Rate of decrease of load with chelation
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
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 5-7y
• LIC
bl 12.7
- 0.8mg/g dry wt at 5-7y
• GTT normal
bl 23%
- 64% at 5-7y
• Thyroxine replacement bl 34%
- 20% at 5-7y
• Secondary amen
- 3/19 spontaneous ovulation
bl 19/26
• No toxicity
Farmaki et al presentation at ITC 2008 FC07 Pg. 92
Farmaki et al Br J Haematol, 466-75 (2010)
Experience with serum ferritin
< 1,000 μg/L
% of patients achieving serum ferritin < 1,000 µg/L
Year 1
Year 2
Year 3
Year 4
Year 5
Years
The incidence of drug-related AEs did not appear to increase during the periods
after serum ferritin levels first decreased < 1,000 μg/L
174 adult and paediatric patients (out of 474) were chelated to serum
ferritin levels < 1,000 μg/L
Porter JB, et al. Blood. 2008;112:[abstract 5423].
Safety profile
of serum ferritin <1000 μg/L
Investigator-assessed drug-related
adverse events (n  5%), n (%)
Serum ferritin
< 1,000 μg/L
(n = 174)
≥ 1,000 μg/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 μg/L
• Safety profile was similar to patients with serum ferritin levels > 1,000 μg/L
• No increase in the proportion of patients with creatinine increases > 33% above baseline
and ULN or with ALTs > 10 x ULN
ALT = alanine transaminase.
Porter JB, et al. Blood. 2008;112:[abstract 5423].
Combined chelation therapy with DFX and DFO in
transfusion-dependent thalassaemia
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
Group B
Adults
Group C
8–18 years
LIC <15 mg/g dry wt
LIC >15 mg/g dry wt
LIC >5 mg/g drywt
Duration of therapy: 52 weeks
Deferasirox 20–30 mg/kg/day
DFO 35–50 mg/kg/infusion infused 3–7 days/week
Lal , Porter, et al. Blood. 2010;116:[abstract 4269].
DFX + DFO:
improvements in iron overload
LIC
5
0
BL
1 year
2,000
43%
(p = 0.008)
1,500
1,000
500
0
BL
1 year
Median plasma NTBI (µM)
48%
(p = 0.003)
Median serum ferritn (μg/L)
Median LIC (mg/g)
15
10
NTBI
Serum ferritin
3
p < 0.001
2
1
0
DFO
DFO +
deferasirox
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)
LPI = labile plasma iron.
Lal A, et al. Blood. 2010;116:[abstract 4269].
DFX + DFO:
improvements in iron overload
Lal , Porter et al Blood.Cells Mol Dis. 2012 in press.
DFP + DFX?
A patient case
25
• Deferoxamine – failed to comply
– T2* liver 1.1 ms, cardiac T2* 9.4 ms
– serum ferritin > 2,800 µg/L
20
MRI T2* (ms)
• 34-year-old female with TM, 2 units of
packed red blood cells, every 20 days
Combination
0
2005
– liver T2* 3.33 ms, cardiac T2* 10.6 ms
3,000
Serum ferritin (µg/L)
– serum ferritin 397 μg/L
– liver T2* 15.3 ms, cardiac T2* 21.1 ms
Cardiac
Liver
2006
2007
2008
2009
2010
2008
2009
2010
Year
• Deferasirox 30 mg/kg for 24 months
• Deferasirox 30 mg/kg/day +
deferiprone 75 mg/kg/day
for 12 months
10
5
• Deferasirox, 20 mg/kg for 12 months
– liver 7.81 ms, cardiac T2* 13.8 ms
– serum ferritin 2,080 µg/L
15
Serum ferritin
2,500
2,000
1,500
1,000
500
0
2005
2006
2007
Year
Voskaridou E, et al. Br J Haematol. 2011;154:654-6.
DFP + DFX
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
0.9
1.0
Creatinine (mg/dL)
GTT = glucose tolerance test.
* p < 0.001
Farmaki, et al. Blood Cells Mol Dis. 2011;47;33-40.
How has chelation therapy and
monitoring impacted on outcome in
transfusion dependent thalassaemia
- a local perspective in UK
Treatment of Thalassaemia Major in the UK
1960 → 1970 → 1980 → 1990 → 2005
1964 – IM
desferoxamine
1980 – SC
desferoxamine
standard of care
1987 –
Deferiprone
1984 – Bone
marrow
transplant
initiated
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 20001.
• CMR introduced in London 1999 – what impact has this had
– Cohort of 121 patients monitored and treated at UCLH/Whittinton
since 1999
Chelation regimes
DFP + DFO
DFX
DFX
9%
DFP
28%
21%
32%
DFO
DFO
70%
18%
DFP
DFP ++ DFO
DFO
1999-2000
22%
DFP
DFP
2010
Impact of a decade of cardiac MRI
assessment on cardiac T2*
Cohort of 132 patients from UCLH/Whittington hospitals
p < 0.001
Proportion of patients (%)
70
60
60
Baseline
Median 9 years follow-up
50
40
30
p < 0.001
23
20
17
10
7
0
T2* ≤ 20 ms
T2* < 10 ms
Thomas AS, et al. Blood. 2010;116:[abstract 1011].
Mortality
• Total of 8 deaths amongst 132 patients:
– 2 female, 6 male
– median age at death 35.6 years (range 27.3-48.4)
– None directly related to myocardial iron
• 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 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, 2008
Causes of Death and cardiac MRI
• Cardiac MRI at death, n = 8
• T2* > 20ms
– 3 pt with hepatitis C complications
– 1 sudden death
• T2* 10-20ms
– 1 pt with meningitis
– 1 pt with cancer
• T2* < 10ms
– 2 pt with sepsis
Chelator regime at death
• DFO (n= 4)
• DFP (n= 2)
• Combination DFP + DFO ( n= 1)
• DFX ( n= 1)
Patients (%)
Causes of death in
β-thalassaemia major in the UK
100
90
80
70
60
50
40
30
20
10
0
Hepatitis C
complications
Other/unknown
Malignancy
Infection
BMT complication
Anaemia
Iron overload
Mortality rates per cohort
Use of modern iron chelation therapy and regular CMR monitoring has dramatically reduced the
iron overload-related mortality in the Red-cell Disorders Unit
BMT = bone marrow transplantation;
CMR = cardiac magnetic resonance imaging
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].
Optimal Outcome
- What else do we need ?
• Optimal monitoring and intensification for high risk patients
AND
• Recognition that chronic diseases pose special challenges which
require targeted resources
• Rapid access to free care
• Staff 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
Conclusions
• With modern chelation regimes, used alone or in
combination and when applied with modern
monitoring techniques, excellent survival can be
obtained
• The 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 overload
– Further improving infrastructure and delivery of care
to thalassaemia patients inside and outside treatment
‘centres’
What can be achieved with transfusion,
chelation and optimal monitoring
Then
and
Now
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 FU
• Follow up median 9.2 years (range 7.0-10.6)
• Minimum CMR follow up of 7 y
• Median age at 1st CMR 27.9 years (range 7.7-49.5)
• 58 female, 51 male
Variables studied
• % Patients with evidence of myocardial iron
– At 1st CMR
– At latest CMR
• Survival in cohort with baseline CMR 1999-2000
– Cause of death
– T2* at death
• Modes of chelation
–
–
–
–
At baseline
At latest follow up
At death
Number of switches in chelator
Causes of Death by cardiac MRI
• Cardiac MRI at death, n = 8
• T2* > 20ms
– 3 pt with hepatitis C complications
– 1 sudden death
• T2* 10-20ms
– 1 pt with meningitis
– 1 pt with cancer
• T2* < 10ms
– 2 pt with sepsis
Changes in Chelation
69% changed chelator at least once based on:
- Iron assessment
- Ferritin trend
- LIC trend
- m T2* trend
- Side effects/tolerability
- Adherence or patient preference
- Availability of new chelators: trials/funding
decisions
Impact of monitoring
and comprehensive support
on outcome
Frequency of DFO chelation
and survival in Thalassaemia Major
300–365 Infusions/year
100
225–300
90
80
Survival (%)
70
60
150–225
50
40
30
75–150
20
0–75
10
0
0 2
4
6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Years
Gabutti V, Piga A. Acta Haematol. 1996;95:26-36.
Survival in UK as a whole and UCLH
- a question of optimal care?
• Modell et al1 2000
– 50% 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 40yrs
– No death in cohorts after 1971
Porter & Davis Best Pract Res Clin Haematol, 15, 328-68 2002
Crude mortality rates in thalassaemia major
Birth cohort
UK as a whole
UCLH
1955-1964
56%
29%
1964-1974
34%
15%
1975-1984
14%
0%
1985-1994
3%
0%
1995-2000
2%
0%
Overall
24%
11.7%
Porter & Davis Best Pract Res Clin Haematol, 15, 328-68 2002
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
?
DELIVERY OF THALASSAEMIA
CARE IN UK as a WHOLE
• 807 patients cared for by 164 physicians nationwide
• 71 physicians
1 patient
• 77 physicians
2-9 patients
• 12 physicians
10-30 patients
• 4 physicians
50 or more
Modell et al., Lancet 2000; 9220:2051-2
UK National Guidelines
for Thalassaemia
• Transfusion and other care locally but
• At least yearly review in specialist centre
UK Thalassaaemia Society
Thalassaemia Major management in the UK
1960 → 1970 → 1980 → 1990 → 2005
1964 – IM
desferoxamine
1980 – SC
desferoxamine
standard of care
1987 –
Deferiprone
1984 – Bone
marrow
transplant
initiated
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 20001.
1 Modell et al, Lancet 2000 355:2051-2
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 FU
• Follow up median 9.2 years (range 7.0-10.6)
• Minimum CMR follow up of 7 y
• Median age at 1st CMR 27.9 years (range 7.7-49.5)
• 58 female, 51 male
Impact of a decade of cardiac MRI
assessment on cardiac T2*
Cohort of 132 patients from UCLH/Whittington hospitals
p < 0.001
Proportion of patients (%)
70
60
60
Baseline
Median 9 years follow-up
50
40
30
p < 0.001
23
20
17
10
7
0
T2* ≤ 20 ms
T2* < 10 ms
Thomas AS, et al. Blood. 2010;116:[abstract 1011].
Mortality
• Total of 8 deaths amongst 132 patients:
– 2 female, 6 male
– median 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 1
– 2000-2003: 4.3 deaths / 1000 patient y 2
1 Modell et al , Lancet 355:2051-2, 2000
2 Modell et al , J. Cardiovas Magnetic Resonance, 2008
Causes of Death and cardiac MRI
• Cardiac MRI at death, n = 8
• T2* > 20ms
– 3 pt with hepatitis C complications
– 1 sudden death
• T2* 10-20ms
– 1 pt with meningitis
– 1 pt with cancer
• T2* < 10ms
– 2 pt with sepsis
Chelator regime at death
• DFO (n= 4)
• DFP (n= 2)
• Combination DFP + DFO ( n= 1)
• DFX ( n= 1)
Changing Causes of death in TM
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 resources
– Rapid access to free care
– Staff 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
Summary
•
•
•
•
•
•
•
•
•
•
•
•
Iron toxicity occurs in tissues where excess storage iron accumulates though NTBI uptake
Distribution of excess iron differs in transfusional and non transfusional iron overload
Distribution also differs depending on underling disorder (e.g. Thal vs sickle)
Heart and endocrine tissues more sensitive to excess iron than liver
No single measure assesses risk of iron overload equally in all clinical conditions
Assessment of iron overload needs to estimate both;
• The degree of body iron overload
• The 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 significance
LIC assessment can estimate total body iron stores
Myocardial T2* by MRI, validated with prognostic significance
MRI other tissues
Plasma iron speciation and quantitation
1960
1964 – IM desferoxamine
The future for thalassaemia
care……..
1970
1980 – SC desferoxamine
standard of care
1984 – Bone marrow
transplant initiated
1987 – Deferiprone
trials
1999 - CMR
1980
1990
2000
1980-1999: 12.7 deaths per
1000 patient years
2000-2003: 4.3 deaths per
1000 patient years
??Exjade Trails
2010
2020
1999-2010: 1.65 deaths per
1000 patient years
Special challenges in treating
haemoglobin disorders?
• Challengers for the carers
– Life-long conditions do not fit comfortably with a
hospital environment
– Providing sustained support throughout life is rarely
possible for one doctor
– Challenges of knowledge and/or experience of rare
conditions
– Challenges of minimising the problems of
transitioning from childhood to adolescence
department or hospital
– Challenges of operating within an ocology domiated
environment
Summary - Monitoring
•
•
•
•
•
•
•
•
•
•
•
•
Iron toxicity occurs in tissues where excess storage iron accumulates though NTBI uptake
Distribution of excess iron differs in transfusional and non transfusional iron overload
Distribution also differs depending on underling disorder (e.g. Thal vs sickle)
Heart and endocrine tissues more sensitive to excess iron than liver
No single measure assesses risk of iron overload equally in all clinical conditions
Assessment of iron overload needs to estimate both;
• The degree of body iron overload
• The 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 significance
LIC assessment can estimate total body iron stores
Myocardial T2* by MRI, validated with prognostic significance
MRI other tissues
Plasma iron speciation and quantitation
New developments in chelation
• Deferasirox monotherapy
• New combinations
– Combination studies with desferrioxamine (3)
– Tolerability at low ferritin
• Ferrokin
– Desferrithiocin derivative
– Phase 2 study results submitted for publication
Deferasirox:
recent publications
• Long-term cardiac effects
• Liver effects
• Long-term efficacy and tolerability
• Safety and efficacy of dose escalation
• Tolerability at low levels of iron load
• Effect of administration regime on efficacy and tolerability
• Use in combination with other chelators
• Use in conditions other than transfusion-dependent
thalassaemia
5-year follow-up in patients with
β-thalassaemia major: changes in serum ferritin
N = 472 at baseline (BL)
3,000
30
Median serum ferritin (μg/L)
25
Deferasirox dose
2,000
20
1,500
15
Serum ferritin
1,000
10
Mean actual daily dose of DFX:
22.1 ± 6.4 mg/kg/day (range (6–37)
500
Core
(DFO)
0
BL
3
6
5
Mean deferasirox dose (mg/kg/day)
2,500
Extension
(deferasirox)
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
0
Time (months)
(n)
Studies 105–108: 4.5-year data
(422)
(433)
(375)
(343)
(286)
(253)
(244)
(220)
(154)
Cappellini MD, et al. Blood. 2008;112:[abstract 5411].
Experience with serum ferritin
< 1,000 μg/L
% of patients achieving serum ferritin < 1,000 µg/L
Year 1
Year 2
Year 3
Year 4
Year 5
Years
The incidence of drug-related AEs did not appear to increase during the periods
after serum ferritin levels first decreased < 1,000 μg/L
174 adult and paediatric patients (out of 474) were chelated to serum
ferritin levels < 1,000 μg/L
Porter JB, et al. Blood. 2008;112:[abstract 5423].
Safety profile over time
in patients with β-thalassaemia major
10
Year 1 (n = 296)
Year 2 (n = 282)
Year 3 (n = 234)
Year 4 (n = 213)
Year 5 (n = 196)
9
8
Patients (%)
7
6
5
4
3
2
1
0
Increased blood
creatinine
Abdominal
pain*
Nausea
Rash
Vomiting
Diarrhoea
Adverse event
* Reports of abdominal pain and abdominal pain are combined
and presented as abdominal pain.
Cappellini MD, et al. Blood. 2011;118:884-93.
Stable creatinine clearance in children and
adults with β-thalassaemia major over 5 years
Creatinine clearance (mL/min)
400
Deferasirox
Crossover
300
200
100
Core
Extension
0
BL
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Time (months)
37 (6.7%) patients with a normal serum creatinine at baseline
had 2 consecutive values > 33% and > ULN
ULN = upper limit of normal.
Adapted from: Cappellini MD, et al. Blood. 2011;118:884-93.
Cardiac iron reduction with deferasirox:
continued improvement in cardiac T2*
> 5–< 10 ms
Geometric mean T2* ± 95% CI (ms)
30
10–< 20 ms
All patients
25
22.3‡
20.3‡
20
17.7‡
15.6‡
15.0
13.9‡
15
12.0
10
5
8.6†
7.7
17.1‡
9.4‡
10.5‡
†p
= 0.0012 versus baseline; ‡p < 0.001 versus baseline
Dashed line indicates normal cardiac T2* of ≥ 20 ms
0
Baseline
12
24
36
24
47
71
24
44
68
Time (months)
Patients, n
< 10 ms
10–< 20 ms
All patients
24
47
71
CI = confidence interval; LOCF = last observation carried forward.
24
47
71
Pennell D, et al. Haematologica. 2012 Jan 22. [Epub ahead of print].
CORDELIA: RCT deferasirox vs DFO
Screening
23 days
1-year study Rx in core
study
1-year study Rx in
extension study
96 patients*
deferasirox
96 patients
deferasirox
96 patients*
DFO
96 patients
DFO
Randomize eligible patients
(1:1 ratio)
Followed by 5-day washout
End core / start
extension
End
extension
• Objective: 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
* = Patients with β-thalassaemia major or Diamond-Black anaemia or sideroblastic anaemia on chronic transfusion therapy.
Figure 1
Improvement in liver pathology with at
least 3 years of deferasirox treatment
•
•
82.6% of patients experienced either stabilization or improvement in fibrosis staging
Improvements in fibrosis staging were observed in patients who met the LIC
response criteria and in those who did not
Deugnier Y, et al. Gastroenterology. 2011;141:1102-11.
Combination Tharapies
• Desferrioxamine + Deferiprone
• Desferrioxamine + Deferasirox
• Deferiprone + Deferasirox
Deferasirox + DFO
metabolic iron balance studies
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 plans
Dosing: - 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 – 30
Results: - Combination – Mean -ve iron balance -251%,( range 206% - 270%)
- Combination
> additive 2 patients (35% and 57%)
- additive in three patients
< additive in one patient
Grady et al, 2010 116: Abstract 5163
-
Combined Chelation Therapy with Deferasirox and
Deferoxamine in Transfusion-Dependent Thalassemia
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
Duration of therapy: 52 weeks
Deferasirox 20-30 mg/kg/day
DFO 35-50 mg/kg/infusion infused 3-7 days/week
Lal A, et al. Blood. 2010;116: Abstract 4269.
Group C
8–18 years
LIC >5 mg/g dw
Improvements in Iron Overload
48%
(P = .003)
10
5
0
BL
1 year
43%
(P = .008)
1500
1000
500
0
BL
3
Median plasma NTBI (µM)
2000
Median SF (ng/mL)
Median LIC (mg/g)
15
Serum ferritin
LIC
Non-transferrinbound iron (NTBI)
P<.001
2
1
0
1 year
DFO
DFO +
deferasirox
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)
Lal A, et al. Blood. 2010;116: Abstract 4269.
Deferiprone + Deferasirox ?
• 34yo female TM, 2 units of packed red blood cell,
every 20 d
• Deferoxamine - failed to comply
- T2* liver 1.1ms, cardiac T2* 9.4ms
- serum ferritin > 2800 lg/l
• Deferasirox, 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
Liver
Deferiprone + Deferasirox
Patient selection
4 case reports - adult patients with TM
Reduced LVEF + either severe allergy or intolerance to DFO
High 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 needed
Berdoukas et al , Blood. Blood 2010 116 Abstract 2064
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 )
Outcome
• Reversal 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 ± 0.2
cT2* ms
36.9 ±5.6 *
LVEF (%)
34.1 ± 5.8
61 ± 6.0 65 ± 7.6 *
2h GTTmg/dl 150 ± 87
111 ± 24
Creatinine(mg/dl) 0.9
1.0
_______________________________
cT2* = cardiac T2, GTT glucose tolerance test,
ULN upper limit normal, IO: iron overlload
*p<0.001
Farmaki et al, Blood Cells, Mol, and Dis 47 (2011) 33–40
Desferrithiocin and derivatives
O
O
O
• Tridentate chelator
OH
HO
OH OH
• Renal toxicity is a class
CH
N
OCH3
N 3CH3
N
N
CH3
effect but minimized by
COOH
CO2H
S
S
derivatization in animal
CO2H
S
(S)-3′-(HO)-DADFT-PE (9)
studies
(22)
Desferrithiocin
Deferitrin (1)
• Numerous analogues
synthesized
● Deferritrin,
nephrotoxic in clinical studies
● By replacing the 4′-(HO) of 1 with a 3,6,9trioxadecyloxy group nephrotoxicity could
be controlled
Bergeron RJ, et al. Biometals. 2011;24:239-58.
Clinical studies with
a desferrithiocin derivative FBS0701
• Phase 1b dose-escalation study: safety, tolerability, and
pharmacokinetics
• 16 adult patients with transfusional overloaded
• Once daily for 7 days at doses up to 32 mg/kg
• Well tolerated at all dose levels
• Pharmacokinetics showed dose-proportionality
• Cmax at 60–90 min
• Rapidly distributed at the predicted therapeutic doses
• Plasma t1/2 – approximately 19 hours
Rienhoff HY Jr, et al. Haematologica. 2011;96:521-5.
24-week multicentre phase 2 study
with FBS0701
• 51 patients, stratified by transfusional iron intake
• FBS0701 at 14.5 or 29 mg/kg/day p.o. once daily
• 49 patients (96%) completed the study
• No AEs showed dose-dependency
• Commonest AE was increased transaminases (16%, n = 8)
• Mean serum creatinine did not change significantly
• ΔLIC mean at 14.5 mg/kg/day was +3.1 mg/g (dry wt)
– 29% achieved a decrease in LIC
• ΔLIC mean at 29 mg/kg/day was −0.3 mg/g (dry wt)
– 44% achieved a decrease in LIC
Neufeld EJ, et al. Blood. 2012 Jan 17;[Epub ahead of print].
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 appropraitely
• All chelator regimes remove cardiac iron; choice of regime depends
on severity of loading and heart function
• Liver 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 patients
• FBS entering Phase III , when efficacy/toxicty will be scrutinised
Treatment of Iron overload
• Which conditions ?
– Transfusion dependent Thalassaemia Major
– Multi transfused SCD
– DBA
– Sideroblastic
– Aplastic Anaemia
– Iron loaded NTDT
– MDS
Overview of Iron Chelators
Property
Usual dose
Route
Half-life
Excretion
Adverse
effects
Approved
indications
Deferoxamine (DFO)
Deferiprone (DFP)
Deferasirox
25-60 mg/kg/day
75 mg/kg/day
20-40 mg/kg/day
s.c., i.v.
8-12 h, 5 days/week
p.o.
3 times daily
p.o.
once daily
20-30 min
3-4 h
8-16 h
Urinary, fecal
Urinary
Fecal
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
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.
Univariate analysis of biochemical,
virological, and histological features associated with
severe fibrosis
Fibrosis stage
0–1–2
(104 patients)
Fibrosis stage
3–4
(22 patients)
p value
16.8±8.7
19.7±9.2
0.2
50/54
17/5
0.01
69.1±80.1
112.5±61.2
< 0.001
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
Grade 0
23 (22%)
0
Grade 1/Grade 2
79 (76%)
22 (100%)
2 (2%)
0
Age, mean ± SD
Gender, M/F
ALT, mean ± range
Serum ferritin, median (range)
Histological inflammation (grading)
Grade 3
0.2
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
Di Marco V, et al. Haematologica. 2008;93:1243-6.
Rate of fibrosis progression in transfusiondependent 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.
LIC Increases With Time in the Absence of
Effective Chelation
Normal hepatic iron concentration
Increased risk of iron-related morbidity
Hepatic Iron (mg/g of liver, dry weight)
50
Non-chelated thalassemia major
40
Homozygous hemochromatosis
Homozygous
hemochromatosis
30
20
10
Estimate for NTDT
0
0
10
20
Age (years)
Adapted from Olivieri NF, et al. N Engl J Med. 1999;341:99-109.
30
40
50
Pathophysiology of Iron Overload
storage iron
Iron
Chelation
Neoplasia
Blood
Transfusion
-
Anti-apoptotic
labile iron
NF-кB
activation
ROS
High Iron
absorption
Infection
Lipid peroxidation
DNA damage
Genomic
Instability
+
Caspase
activation
Organelle
damage
TGF-β1
Lysosomal fragility
Collagen synthesis
Enzyme leakage
Cell death
Fibrosis
Organs susceptible to iron overload
Organ
Consequences
Pituitary
Hypogonadotrophic Hypogonadism
Thyroid
Hypothyroidism
Parathyroid
Hypoparathyoidism
Heart
Cardiomyopathy
Liver
Cirrhosis, carcinoma
Pancreas
Diabetes
Gonads
Hypogonadotrophic Hypogonadism