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iron overload in haemoglobinopathies
Dr Farrukh ShahConsultant haematologist
Joint Red cell disorders unitWhittington hospital and UCLH
Why?
Erythron
MacrophagesHepatocytes & other
parenchymaTransferrin
Transfusion
20-30mg/day(0,4 mg/kg/day)
NTBI
20-30mg/day
Iron turnover in transfusional overload
Gut
Sources of iron overload in haemoglobinopathy patients
• Dietary iron overload– Thalassaemia intermedia patients– Thalassaemia trait patients given oral iron to
correct anaemia • Intermittent transfusion
– Sickle cell anaemia– Thalassaemia intermedia
• Regular transfusion therapy
-Transfusional Iron Overload
– Normal total body iron (TBI) 3-5g – Transfusional iron overload
without chelation
• 1 unit of Packed Red Blood Cells (PRBC)= 200 mg Fe
• A patient receiving 2-4 units/month receives 4 to 10 grams of iron per year
• Porter JP. Br J Haematol. 2001;115:239-252.
Consequences of iron overload
Organ Systems Affected byIron Overload
Pituitary gland
Heart
Liver
Pancreas
Gonadal
• Iron overload results in non–transferrin-boundiron in the plasma
• Increased iron uptake into selective organs
• Generation of free hydroxyl radicals
Tissue damage
Fatal Complications of iron overload
• Cardiac– Dysrhythmias– Heart failure
• Infections• Liver
– iron overload, cirrhosis– viral hepatitis– failure
non fatal complications of iron overload
• Growth failure• Sexual development & fertility• Diabetes• Hypothyroidism• Hypoparathydroidism• Osteoporosis
Complication-free survival of Italian β-thalassaemia major patients
Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-93.
Surv
ival
pro
babi
lity
p < 0.000050
1.00
0.75
0.50
0.25
0 5 10 15 20 25 30
Age (years)
Birth cohort
1960–19641965–19691970–19741975–19791980–19841985–1997
HR = hazard ratio.
Monitoringiron overload
Why monitor
• For adequacy of treatment– Transfusion– Chelation
• For complications of chelation
Monitoring iron overload
• Tissue iron estimation– Ferritin– Liver iron– Cardiac iron
• Effects of iron overload on function– Heart– Endocrine
• Pituitary damage• Diabetes• Hypothyroidism• Hypoparathyroidism
Serum ferritin reflects
• Iron stores• Recent chelation and type of chelation• Inflammation • Tissue damage• Ascorbate status
Serum ferritin underestimates iron burden in β-thalassaemia intermedia
Origa R, et al. Haematologica. 2007;92:583-8.Taher A, et al. Haematologica. 2008;93:1584-5.
0 5 10 15 20 25 30 35
LIC (mg/g dry wt)
Ser
um
fer
riti
n (
μg
/L)
2,000
4,000
6,000
8,000
10,000
12,000
14,000
0
β-Thalassaemia intermedia
β-Thalassaemia major
Ser
um
fer
riti
n (
μg
/L)
0 5 10 15 20 25 30 35 40 45 50
LIC (mg/g dry wt)
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
9,000
10,000
0
β-Thalassaemia intermedia
β-Thalassaemia major
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
car
diac
failu
re
Follow-up time (days)
< 6 ms
6–8 ms
8–10 ms
> 10 ms
Chelator effect on ferritin
Ang, Ai leen et al ASH 2010
N=84 DFO DFX DFP Median LIC (mg/kg dw) 5 (1.2-30.6) 4.8 (0.8-36.5) 5 (0.5-34.9) Median SF (µg/L) 1927 (1378-
5182) 1713 (312-6085)
1142 (133-2897)
Median SFaverage (µg/L) 2147 (950-6063) 2006 (773-7290)
1240 (230-2734)
Median SF/LIC (µgL-1/µgg-1)
523 (120-1562) 403 (52-1188) 181 (56-910)
Predicted LIC (95% confidence interval) (mg/kg dw) at: - SF 1000 µg/L - SF 2000 µg/L - SF 4000 µg/L
1.9 (0-4.9) 4.4 (2.8-5.9) 9.3 (5.1-13.5)
2.8 (1.9-3.7) 5 (4.2-5.8) 9.5 (7.3-11.6)
5.1 (3.2-6.9) 9.4 (6.8-12.0) 18 (11.1 -24.9)
Why is measurement of liver iron concentration (LIC) important?
• A patient’s LIC value is the best measure of total body iron stores
• A patient’s LIC value enables better informed decisions on when to
– Initiate chelation therapy– Increase chelation dose– Decrease chelation dose– Change mode of chelator delivery (e.g. iv mode)
Bo
dy
iro
n s
tore
s (m
g/k
g)
300
250
200
150
100
50
0
0 5 10 15 20 25
Hepatic iron concentration (mg/g dry wt)
Body iron (mg/kg) = 10.6 x hepatic iron concentration (mg/g dry wt)
Sample < 1 mg dry wt (n = 23)
Angelucci E, et al. N Engl J Med. 2000;343:327-31.
Liver iron concentration predicts total body iron stores
r = 0.83
Bo
dy
iro
n s
tore
s (m
g/k
g)
300
250
200
150
100
50
0
0 5 10 15 20 25
Hepatic iron concentration (mg/g dry wt)
r = 0.98
Sample > 1 mg dry wt (n = 25)
Example: FerriScan® measurements to monitor iron chelation therapy
Before chelation therapy intervention
Mean LIC = 16.0
After 12 months of chelation therapy intervention
Mean LIC = 1.6
Cardiac monitoring in Iron Overload
• Functional– LVEF
• Echo, MUGA, MRI
– Rhythmicity• Resting/Exercise ECG• 24h ECG
• Iron loading:• Low cardiac t2* associated with low LVEF
Severe cardiac ironMinimal liver iron.
Severe liver ironMinimal cardiac iron.
Discordance of liver and heart iron
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].
Mortality rates per cohort
Patie
nts
(%)
Hepatitis C complicationsOther/unknownMalignancyInfectionBMT complicationAnaemiaIron overload
1950–19591960–19691970–19791980–19891990–19992000–2003Th
is cohort
BMT = bone marrow transplantation;CMR = cardiac magnetic resonance imaging
Absence of cardiac siderosis despite elevated LIC and serum ferritin in
Lebanese patients with SCD
Inati A, et al. Eur J Haematol. 2009;83:565-71.
50
45
40
35
30
25
20
15
10
5
0
0 1,000 2,000 3,000 4,000
Serum ferritin (µg/L)
High serum ferritin
Normal T2*
Card
iac
T2*
(mse
c)
p = NS
Sample size: 23 patients (17 SS, 6 ST)
Normal T2*
p = NS
Management of iron overload
Chelators in clinical use
• Desferrioxamine– 20- 40mg/kg/day 8-10h 5-6 x/week– start at 3y or ferritin ≥ 1000µg/L
• Deferiprone – (L1) 75 mg/kg/day in 3 divided doses
• Exjade (ICL670)– 20-30mg/kg/day once daily
• FSB0701 in phase 2
Effect of DFO IV infusion on removal and return of NTBI
( Porter et al, Blood 1996 )
544842363024181260- 6-
-1
0
1
2
3
4
5
6
7
NTBPI (µM)
DFO (µM)
Time (h)
NT
BI
or D
FO
(µ
M)
Compliance with deferoxamine and its impact on survival
Gabutti V, Piga A. Acta Hematol .1996;95:26-36.
50
0–20%
30 40
25
75
100
Cum
ulati
ve %
sur
viva
l
2010
20–40%
40–60%
60–80%
80–100%
Time (years)
300–365225–300150–22575–1500–75
Infusions/year
Complications of Desferrioxamine
• Immediate– Local skin reactions– Allergy
• Infection: yersinia, other G-• Dose related:
– Hearing problems– Eye complications– Growth retardation– Skeletal changes– rare
Deferiprone (Ferriprox®, L1)
● Indication (Europe)– ‘Treatment of iron overload in
patients with thalassaemia major when DFO therapy is contraindicated or inadequate’1
● Oral three times a day (short plasma half life)
● Decreases serum ferritin when baseline levels high
● Variable effects on liver iron
1. Ferriprox [package insert]. Apotex Europe Ltd, 20042. Pennell et al, Blood 2006 Vol 107; 3738-3744
Pharmacokinetics of deferiprone(Kontoghiorghes et al, 1990)
0 100 200 300 400
140
120
100
80
60
40
20
0
Time (minutes)
Glucuronide Deferiprone
Con
cent
ratio
n (µ
M)
t1/2 1.52 hours
Side effects
• Neutropenia: 3.9%• Agranulocytosis: 0.5-0.9%• Gastrointestinal: 3-33%• liver: 1-3% • Joint pains: 4-15%• Neurological complications in high doses
• High drop out rate:
– Ceci study 124/532
– Cohen study 103/187
Cardioprotective effect61patients DFO 43mg/kg/day for 5.7 days vrs DFP 92mg/kg/dayT2* and EF improved more in the DFP group
Pennell et al; Blood, 1 May 2006, Vol. 107, No. 9, pp. 3738-3744.
deferasirox Nick H, Current Medicinal Chemistry. 2003; 10: 1065-1076
• Tridentate iron chelator (high specificity)
• High therapeutic safety in animal data
• Lipophilic but protein bound
• Renal target in animal toxicology
• Long plasma half life in humans
• Excreted in faeces only
• Given as once daily drink
(dispersible tablet)
NNNN
NN
OHOHHOHO
OHOHOO
Safety profile over time in patients with β-thalassaemia major
Cappellini MD, et al. Blood. 2011;118:884-93.
Pat
ien
ts (
%)
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.
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 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)
Geo
met
ric m
ean
T2*
± 95
% C
I (m
s)
> 5–< 10 ms 10–< 20 ms All patients
0
5
10
20
30
15
25
17.1‡
15.6‡
13.9‡
12.0
Impact of monitoring on outcomes
A decade of cardiac monitoring at the UCLH/Whittington Hospital
• Cohort of 132 patients received first CMR 1999–2000
• 109 of these available for long-term CMR follow-up‒ follow-up median 9.2 years (range 7.0–10.6)‒ minimum CMR follow-up of 7 years‒ median age at first CMR 27.9 years (range 7.7–49.5)‒ 58 females, 51 males
Thomas AS, et al. Blood. 2010;116:[abstract 1011]. UCLH = University College London Hospital.
Cohort of 132 patients from UCLH/Whittington hospital
BaselineMedian 9 years follow-up
Pro
po
rtio
n o
f p
atie
nts
(%
)
70
50
30
10
0
60
40
20
T2* ≤ 20 ms T2* < 10 ms
60
23
17
7
p < 0.001
p < 0.001
Thomas AS, et al. Blood. 2010;116:[abstract 1011].
The proportion of patients with cardiac iron overload decreased 3-fold in a
decade
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].
Mortality rates per cohort
Pat
ien
ts (
%)
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
coho
rtBMT = bone marrow transplantation;CMR = cardiac magnetic resonance imaging
Ferriscan liver iron monitoringWhittington audit
• Ferriscan part of routine monitoring from December 2007
• 94 TM patients with at least 2 scans between January 2008-December 2011
Long term
Patient 1
• 30 year old TM• Arrives in UK as a highly skilled migrant • Heavy iron overload in arrival in 2008
– Marked skin deposition – Ferriscan liver iron >43mg/g/dw– No myocardial iron loading– Spontaneous puberty
• Initial treatment is deferiprone, agrees to start deferasirox
Patient 1
• Spontaneous conception on exjade! Around 9 months post arrival in UK!
• Immediately stops deferasirox• Healthy baby delivered in 2009• restarts deferasirox at 40mg/kg/day• Almost fully compliant initially
•In 2011 compliance becomes a challenge•Ferriscan bought forwards