monitoring and treatment iron overload in thalassaemia
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Monitoring and treatment iron overload in thalassaemia. Professor John Porter Red Cell Disorders Unit University College London Hospitals and UCL [email protected]. M onitoring and treatment iron overload in thalassaemia. Professor John Porter Red Cell Disorders Unit - PowerPoint PPT PresentationTRANSCRIPT
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Monitoring and treatment iron overload in thalassaemia
Professor John PorterRed Cell Disorders Unit
University College London Hospitals and UCL [email protected]
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Professor John PorterRed Cell Disorders Unit
University College London Hospitals and UCL [email protected]
Monitoring and treatment iron overload in thalassaemia
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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
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Monitoring options
• Iron loading rate• Serum ferritin• Liver Iron concentration• Cardiac evaluation – function & T2* • Endocrine evaluation – growth, function & MRI• Adherence and quality of life
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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
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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
Mea
n to
tal b
ody
iron
excr
etion
±
SD (m
g 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.
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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/dayCappellini et al, Blood. 2006;107:3455-3462
LIC
chan
ge (m
g/g
dry
wt)
from
bas
elin
e
Ferr
itin
chan
ge (n
g/m
l) fr
om b
asel
ine
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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
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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. Brittenham et al, Am J Hematol 1993;42:81-52. Chapman et al, J Clin Pathol 1982;35:487-91.3. Worwood, M. 1980 Br J Haematol 46,409-164. Origa, Hamatologica 2007, 92 5835. Porter & Huehns, Acta Haematologica 6. Fischer et al. Brit J Haem 2003, 121 938-9487. Ai Leen Ang, et al, Blood, 201, 116, Abstract 4246.
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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;343:327-31.2. 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
ALT = alanine aminotransferase; BMT = bone marrow transplantation.
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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
00 20 40 60 80
Severe cardiac ironMinimal liver iron
Severe liver ironMinimal cardiac iron
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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
Prop
ortio
n of
pati
ents
de
velo
ping
card
iac
failu
re
Follow-up time (days)
< 6 ms
6–8 ms
8–10 ms
> 10 ms
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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. Au WY, et al. Haematologica. 2008;93:785.2. Noetzli LJ, et al. Blood. 2009;114:4021-6.3. Aydinok Y, et al. . Haematologica, 2012, 97,6, 835-41
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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=180
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Assessment – when?
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
Observation Frequency Expense
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• 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
Goals of chelation therapy
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Licensed iron chelatorsProperty DFO Deferiprone Deferasirox
Route Sc, iv(8–12 hours, 5 days/week)
Oral3 times daily
OralOnce 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 20–30
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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
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‘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
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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
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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.
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Surv
ival
pro
babi
lity
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 30Age (years)
Birth cohort
1960–1964
1965–1969
1970–1974
1975–19791980–1984
1985–1997
DFO Chelation therapy has improved patient survival in TM
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Decline in complications withiron 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.
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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
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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 doses1. 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;107:3738-445. Naithani et al, Eur J Haematol. 2005 ;74:217-206. Lucal et a, Ceylon Med, 45, 71-4.J 2000.
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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 bl 19/26 - 3/19 spontaneous ovulation
• No toxicity Farmaki et al presentation at ITC 2008 FC07 Pg. 92Farmaki et al Br J Haematol, 466-75 (2010)
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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 μg/L
% of patients achieving serum ferritin < 1,000 µg/L
Year 1Year 2Year 3Year 4Year 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
Years
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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 ULNPorter JB, et al. Blood. 2008;112:[abstract 5423].ALT = alanine transaminase.
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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 AAdultsLIC <15 mg/g dry wt
Group BAdultsLIC >15 mg/g dry wt
Group C8–18 yearsLIC >5 mg/g drywt
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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)
Med
ian
LIC
(mg/
g)
Med
ian
plas
ma
NTB
I (µM
)
DFO DFO + deferasirox
p < 0.001
Med
ian
seru
m fe
rritn
(μg/
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.
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DFX + DFO:improvements in iron overload
Lal , Porter et al Blood.Cells Mol Dis. 2012 in press.
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DFP + DFX?A patient case
• 34-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 ms– serum ferritin > 2,800 µg/L
• Deferasirox, 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/L
• Deferasirox 30 mg/kg/day + deferiprone 75 mg/kg/day for 12 months
– serum ferritin 397 μg/L– liver 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
Seru
m fe
rriti
n (µ
g/L)
2005 2006 2007 2008 2009 2010
3,000
1,500
500
0
2,000
1,000
2,500
Serum ferritin
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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 functionTolerability• 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 1.0
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How has chelation therapy and monitoring impacted on outcome
in transfusion dependent thalassaemia
- a local perspective in UK
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Treatment of Thalassaemia Major in the UK
1960 → 1970 → 1980 → 1990 → 20051980 – 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 20001.
• CMR introduced in London 1999 – what impact has this had– Cohort of 121 patients monitored and treated at UCLH/Whittinton
since 1999
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70%
21%
9%
1999-2000
DFO
DFP
DFP + DFO
DFO
DFPDFP + DFO
DFX
2010
Chelation regimes
DFP + DFODFP
DFX
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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].
BaselineMedian 9 years follow-up
Prop
ortio
n of
pat
ient
s (%
)
70
50
30
10
0
60
40
20
T2* ≤ 20 ms T2* < 10 ms
60
23
17
7
p < 0.001
p < 0.001
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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
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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
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Chelator regime at death
• DFO (n= 4)
• DFP (n= 2)
• Combination DFP + DFO ( n= 1)
• DFX ( n= 1)
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0102030405060708090
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
Patie
nts
(%)
Hepatitis C complicationsOther/unknownMalignancyInfectionBMT complicationAnaemiaIron overload
1950
–195
919
60–1
969
1970
–197
919
80–1
989
1990
–199
920
00–2
003
This co
hort
BMT = bone marrow transplantation;CMR = cardiac magnetic resonance imaging
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Optimal Outcome - What else do we need ?
• 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
• Optimal monitoring and intensification for high risk patients
AND
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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’
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Then and Now
What can be achieved with transfusion, chelation and optimal monitoring
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Thankyou
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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
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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
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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
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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
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Impact of monitoring and comprehensive support
on outcome
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Surv
ival
(%)
0
60
80
50
40
30
20
10
70
90
100
0 282624222018161412108642 30 32 34 36 38 40
Years
300–365
225–300
150–225
75–150
0–75
Frequency of DFO chelation and survival in Thalassaemia Major
Gabutti V, Piga A. Acta Haematol. 1996;95:26-36.
Infusions/year
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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
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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%
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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 ?
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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
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UK National Guidelines for Thalassaemia
• Transfusion and other care locally but
• At least yearly review in specialist centre
UK Thalassaaemia Society
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Thalassaemia Major management in the UK
1960 → 1970 → 1980 → 1990 → 20051980 – 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 20001.
1 Modell et al, Lancet 2000 355:2051-2
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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
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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].
BaselineMedian 9 years follow-up
Prop
ortio
n of
pat
ient
s (%
)
70
50
30
10
0
60
40
20
T2* ≤ 20 ms T2* < 10 ms
60
23
17
7
p < 0.001
p < 0.001
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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
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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
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Chelator regime at death
• DFO (n= 4)
• DFP (n= 2)
• Combination DFP + DFO ( n= 1)
• DFX ( n= 1)
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Changing Causes of death in TM
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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
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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
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1960
1970
1980
1990
2000
2010
2020
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……..
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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
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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
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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
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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
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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)
Med
ian
seru
m fe
rriti
n (μ
g/L)
Mean deferasirox dose (m
g/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)
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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 μg/L
% of patients achieving serum ferritin < 1,000 µg/L
Year 1Year 2Year 3Year 4Year 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
Years
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Safety profile over time in patients with β-thalassaemia major
Cappellini MD, et al. Blood. 2011;118:884-93.
Patie
nts
(%)
Adverse event
10
8
6
4
2
0
9
7
5
3
1
Increased bloodcreatinine
Abdominalpain*
Nausea VomitingRash 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.
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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
Cre
atin
ine
clea
ranc
e (m
L/m
in)
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
DeferasiroxCrossover
Time (months)
Core Extension
ULN = upper limit of normal.
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Patients, n< 10 ms 24 24 24 2410–< 20 ms 47 47 47 44All 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 baselineDashed line indicates normal cardiac T2* of ≥ 20 ms
10.5‡
7.78.6† 9.4‡
15.0
17.7‡
20.3‡
22.3‡
Baseline 12 24 36
Time (months)
Geom
etric
mea
n 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‡
12.0
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CORDELIA: RCT deferasirox vs DFO
• 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
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.
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• 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
Figure 1
Deugnier Y, et al. Gastroenterology. 2011;141:1102-11.
Improvement in liver pathology with at least 3 years of deferasirox treatment
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Combination Tharapies
• Desferrioxamine + Deferiprone
• Desferrioxamine + Deferasirox
• Deferiprone + Deferasirox
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Deferasirox + DFO metabolic iron balance studies
Grady et al, 2010 116: Abstract 5163
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
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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 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 AAdultsLIC <15 mg/g dw
Group BAdultsLIC >15 mg/g dw
Group C8–18 yearsLIC >5 mg/g dw
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Improvements in Iron OverloadM
edia
n LI
C (m
g/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)
Med
ian
plas
ma
NTB
I (µM
)
DFO DFO + deferasirox
P<.001
Med
ian
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.
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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
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Berdoukas et al , Blood. Blood 2010 116 Abstract 2064
Deferiprone + Deferasirox
Patient selection4 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 variableConclusions Well tolerated, prospective studies needed
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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 34.1 ± 5.8 36.9 ±5.6 *
LVEF (%) 61 ± 6.0 65 ± 7.6 *
2h GTTmg/dl 150 ± 87 111 ± 24
Creatinine(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 overlload
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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 analoguessynthesized● Deferritrin, nephrotoxic in clinical studies
Deferitrin (1)
CH3
CO2H
N
S
OHHO
(S)-3′-(HO)-DADFT-PE (9)
OH
CH3
CO2H
OCH3 N
S
OOO
● By replacing the 4 -(HO) of 1 with a 3,6,9-′trioxadecyloxy group nephrotoxicity could be controlled
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• 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
Clinical studies witha desferrithiocin derivative FBS0701
Rienhoff HY Jr, et al. Haematologica. 2011;96:521-5.
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• 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
24-week multicentre phase 2 studywith FBS0701
Neufeld EJ, et al. Blood. 2012 Jan 17;[Epub ahead of print].
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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
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Treatment of Iron overload
• Which conditions ?– Transfusion dependent Thalassaemia Major– Multi transfused SCD– DBA– Sideroblastic– Aplastic Anaemia– Iron loaded NTDT– MDS
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Overview of Iron ChelatorsProperty Deferoxamine (DFO) Deferiprone (DFP) DeferasiroxUsual 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 hExcretion 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.
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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 stage0–1–2
(104 patients)
Fibrosis stage3–4
(22 patients) p valueAge, 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 0.2
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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.
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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
00 10 20 30 40 50
Hepa
tic Ir
on (m
g/g
of li
ver,
dry
wei
ght)
Increased risk of iron-related morbidityNormal hepatic iron concentration
Homozygous hemochromatosis
10
20
30
40
50
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labile iron
Cell death Fibrosis
Organelle damage
TGF-β1
ROSLipid peroxidation
Lysosomal fragility
Enzyme leakageCollagen synthesis
NF-кB activation
DNA damage
Genomic Instability
Caspaseactivation
Anti--apoptotic
Blood Transfusion
+Iron
Chelation
-Neoplasia
High Ironabsorption
Infection
storage iron
Pathophysiology of Iron Overload
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Organs susceptible to iron overload
DiabetesPancreasHypogonadotrophic HypogonadismGonads
Cirrhosis, carcinomaLiverCardiomyopathyHeartHypoparathyoidismParathyroidHypothyroidismThyroid
Hypogonadotrophic HypogonadismPituitary
ConsequencesOrgan