Iron Chelation Basics
John B. Porter, MA, MD, FRCP
Professor
Department of Haematology
University College London
London, United Kingdom
1
Goals of Chelation Treatment

Iron balance with “safe” tissue iron levels
–
–
–
–

0.4–0.5 mg/kg day excretion1
Slow process2
Finite chelatable iron pools2
Prevention of heart and endocrine damage
Detoxification of iron
– Extracellular (NTBI)
– Intracellular (LIP)
– Iron-chelate complex
NTBI = non–trasnsferrin-bound iron; LIP = labile iron pools.
1. Porter J. Hematol/Oncol Clinics. 2005;19:7.
2. Porter JB. Am J Hematol. 2007;82:1136.
2
The Challenge of Iron Chelation—
A Question of Balance

Uncoordinated iron

Uncoordinated chelator

Free-radical generation


Organ damage
Inhibition of
metalloenzymes

Growth failure

Neurotoxicity

Organ failure

Growth failure

Cardiac death

Bone marrow toxicity
Too much iron
Too much chelator
3
Properties of an Ideal Chelator

To control body iron
– High chelating efficiency
– High and specific affinity for Fe3+

To minimize iron toxicity
– 24-hour coverage
– Slow metabolism and elimination rate
– Good tissue penetration with stable iron complex

Acceptable toxicity-efficacy profile
– Clear drug-dose relationship to efficacy and toxicity
– No iron redistribution


Simplicity and ease of monitoring
Patient acceptance/compliance
– Oral bioavailability
– Suitable for monotherapy
4
How Chelators Bind Iron
Deferasirox (DFS)
Desferrioxamine (DFO)
Hexadentate
Tridentate
O
O
O
O
O
Bidentate
O
Fe
O
Deferiprone (DFP)
O
O
Fe
O
O
O
O
O
Adapted from Porter JB, et al. Baillieres Clin Haematol. 1989;2:257.
O
Fe
O
O
O
5
Chelatable Iron Pools

For iron balance
– Plasma iron turnover pools
– Intrahepatic pools

For iron detoxification
– Plasma iron toxic pools (NTBI)
– Intraparenchymal iron toxic pools
eg, heart, liver, endocrine, joints
NTBI = non–transferrin-bound iron.
6
Chelatable Pools
and Excretion Pathways with DFO
Plasma
Bile
Storage Fe
Labile Fe
Fe
Fe
Fe
Fe
Fe
Hepatocyte
Macrophage
Fe
Fe Fe Fe
Fe
Fe
Fe
Fe
Kidney
Fe
Faeces
Fe
Urine
DFO = desferrioxamine.
With permission from Cohen AR, Porter JB. In: Steinberg MH, et al, editors. Disorders of hemoglobin:
genetics, pathophysiology, and clinical management. Cambridge: Cambridge University Press; 2001.
7
Decreasing Cellular Toxicity
with Chelators
Nontransferrin
iron
Ferritin
Labile
iron pool
Lysosomal
degradation
Transferrin
iron
Free-radical generation
Iron
proteins
Organelle damage
LVDCC = L-type voltage-dependent calcium channel.
With permission from Porter JB. Am J Hematol. 2007;82:1136.
8
Chelatable Iron Pools
Prevention of Accumulation More Efficient
than Removal of Stored Iron
Transferrin
saturation occurs
due to frequent
blood transfusions
Normal: No
NTBI produced
100%
Subsequent
formation of
NTBI in
plasma
Uncontrolled
iron loading of
organs, such as:
Iron overload
Fe
Fe
Fe
Fe
Fe
Fe
30%
Fe
Chelators may
prevent iron
uptake
into and
theseinefficient
tissues
Chelation
of storage
iron
is slow
Courtesy of Dr. J. Porter.
9
Chelation Therapy Removes Liver Iron
Faster than Heart Iron*
Myocardial
T2* (ms)
Liver T2*
(ms)
Liver Iron
(mg/g dw)
LVEF (%)
>20
>19
<1.6
61–81
Baseline
5.1 ± 1.9
1.8 ± 1.0
9.6 ± 4.3
52 ± 7.1
3 months
6.9 ± 2.1
3.4 ± 1.8
6.0 ± 5.6
61 ± 8.1
6 months
7.5 ± 2.5
6.9 ± 5.3
2.9 ± 1.9
62 ± 7.9
12 months
8.1 ± 2.8
10.3 ± 9.2
2.1 ± 1.5
63 ± 6.4
.003
.01
.001
.03
Normal range
P-value
* Desferrioxamine Data
dw = dry weight; LVEF = left ventricular ejection fraction.
With permission from Anderson LJ, et al. Br J Haematol. 2004;127:348.
10
Desferrioxamine Therapy for Iron
Overload

Available for > 3 decades with improving survival

Hexadentate molecule not absorbed from gut

Short half-life (20 min), so must be given by
continuous infusion
– 8 –12 h/d, 5 – 7 d/w (40–50 mg/kg SC)

Commenced after 15–20 transfusions or when
ferritin >1000 µg/L

Audiometric, retinopathic, and growth effects at high
doses and low iron loading

Compliance often is poor, leading to variable
outcome
Porter JB, Huehns CR. Baillieres Clin Haematol. 1989;2:459.
Courtesy of Dr. J. Porter
11
DFO–Control of Plasma NTBI Levels
Intravenous continuous infusion
7
NTBI or DFO (µM)
6
DFO (µM)
5
4
3
2
1
NTBI (µM)
0
-1
-6
0
6
12
18
24 30
36
42
48
54
Time (hours)
DFO = desferrioxamine, NTBI = non–transferrin-bound iron.
Reprinted from Porter JB, et al. Blood. 1996;88:705, with permission from the American Society of
Hematology.
12
Efficacy of DFO - early history
Sephton Smith
Barry
1962
IM bolus— Urine Fe excretion inc. with dose, no oral effect
1964
Fe excretion inc. with Tf sat, age, transfusions
1974
Daily IM bolus reduces mortality,
stabilises hepatic iron & fibrosis
Propper, Hussain
1976
Iron balance with 24-h SC infusions using portable devices
Pippard
1978
Iron balance achievable with 12-h SC infusions
Pippard
1982
Faecal excretion important (≥50%)
Freeman
1983
SC therapy improves asymptomatic cardiac disease
Marcus
1984
Intensive IV therapy reverses symptomatic cardiac failure
Wolfe
1985
Long-term SC therapy reduces incidence of cardiac disease
Zurlo
1989
Survival improved in TM cohorts if SC therapy started early
1990
SC therapy started before age 10 y reduces hypogonadism
Olivieri
1994
Long-term control of ferritin reduces heart disease
Brittenham
1994
Compliance long-term protects against diabetes mellitus,
cardiac disease and mortality
BronspiegelWeintrob
Davis BA, Porter JB. Adv Exp Med Biol. 2002;509: 91.
13
DFO–Improved Survival in TM
Survival Probability
1.00
0.75
Birth cohort
1985–1997
1980–1984
1975–1979
1970–1974
1965–1969
1960–1964
0.50
0.25
P < .00005
0
0
5
10
15
20
25
30
Age (years)
DFO = desferrioxamine; TM = thalassaemia major.
Reprinted from Borgna-Pignatti C, et al. Haematologica. 2004;891:187, with permission from the
Ferrata Storti Foundation, Pavia, Italy.
14
DFO–Decline in Complications
Patients with thalassaemia major born after 1960 (n = 977)
Birth 1970-1974*
Birth 1980-1984†
5%
1%
Hypogonadism
64.5%
14.3%
Diabetes
15.5%
0.8%
Hypothyroidism
16.7%
4.9%
Death at age 20 years
*DFO IM, 1975; †DFO SC, 1980.
In 1995, 121 patients switched to deferiprone (censored at this time).
DFO = desferrioxamine.
With permission from Porter JB. Am J Hematol. 2007;82:1136.
15
Iron Balance Over 1 Year with DFO SC x 5/Week
Initial DFO dose (mg/kg/d)
<25
25 to <35
35 to <50
≥50
100%
Increase
0%
.
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Decrease
100%
<0.3
0.3–0.5
>0.5
Iron Intake (mg/kg/d)
With permission from Cohen AR, et al. Blood. 2008;111:583.
16
Unwanted Effects of Desferrioxamine

Effect

Contributing factor
– Retinopathy
– Dose
– Ototoxicity
– Dose, ferritin, therapeutic index
– CNS, coma
– Iron status, other drugs
– Growth retardation
– Dose, age <3 y, ferritin <1000
ug≠L
– Bony changes
– Age, dose, ferritin
– Yersinia infection
– Natural siderophore
– Sensitivity
– Intermittent use
– Misc (pulmonary fibrosis)
– Very high dose (short term)
Desferal [package insert]. East Hanover, NJ: Novartis Pharmaceuticals, 2006.
Porter JB, Huehns ER. Bailliere’s Clin Haematol.1989;2:459.
17
How to Minimize Desferrioxamine’s
Unwanted Effects?

Avoid >40 mg/kg mean daily dose when growing1

Avoid >50 mg/kg mean daily dose in routine use

Avoid starting too early

Dose adjustment as ferritin falls
– Adjust mean daily dose downwards
– Try NOT to reduce frequency of treatment
– Keep therapeutic index <.025 (dose mg/kg / ferritin µg/L)

Monitor regularly for toxic effects
1. Desferal [Package insert]. East Hanover, NJ: Novartis Pharmaceuticals, 2006.
18
Desferrioxamine
Summary of Advantages and Disadvantages

Advantages
– Recognized first-line treatment in iron overload
– Long-term experience and data—reduced morbidity and mortality
– Effective in maintaining near-normal iron stores
 Specific affinity for iron with high chelating efficiency
 Achieves negative iron balance
– Reversal of cardiac disease with intensive therapy

Disadvantages
–
–
–
–
–
–
Requires maximum exposure for optimal outcome
Not absorbed from GI tract
Rapidly eliminated—30-minute half-life requires prolonged infusions
Requires parenteral infusion
Challenges—compliance
Dose-dependent adverse events limit achievable goals
 Ear, eye, bone toxicity
19
Deferiprone

History
– Patented 1982; licensed in EU 1999

OH
Pharmacology
– Bidentate, short plasma half-life — given TID
– Rapidly glucuronidated, low efficiency (7%)
– Urine excretion

O
N
CH3
CH3
Efficacy
– Indicated for treatment of iron overload in patients with thalassaemia major
when desferrioxamine therapy is contraindicated or inadequate1
– May be less effective than desferrioxamine in reducing LIC
– Possible cardioprotective effect 2

Side effects
– Neutropaenia/agranulocytosis (weekly neutrophil count recommended1)
– Nausea, vomiting, abdominal pain
– Arthralgia and arthritis (variable 6%–39%)
EU = European Union; LIC = liver iron concentration.
1. Ferriprox® [Summary of Product Characteristics]. Apotex Europe Ltd. 1999.
2. Anderson LJ, et al. Lancet. 2002;360:516.
20
Percentage Deferiprone Patients with Liver Iron
>7 or >15 mg/g DW After 1-4 Years of Treatment
FU
LIC
LIC
Publication
n
Years
% >7
% >15
Olivieri, 19951
21
3
52
10
Olivieri, 19982
19
4.6
65
39
Tondury, 19983
7
8
53
18
Del Vecchio, 20004
13
1
64
11
Mazza,19985
20
1–3
85
65
Hoffbrand,19986
51(17)
2–4
88
53
DW = dry weight; FU = follow-up; LIC = liver iron concentration.
1. Olivieri N, et al. N Engl J Med. 1995;332:918.
2. Olivieri N, et al. N Engl J Med. 1998;339:417.
3. Töndury P, et al. Br J Haematology. 1998;101:413.
4. Del Vecchio GC, et al. Acta Haematologica. 2000;104:99.
5. Mazza P, et al. Haematologica. 1998;83:496.
6. Hoffbrand AV, et al. Blood. 1998;91:295.
21
Cardioprotective Effect of
Deferiprone Monotherapy?
Author
n
Data
Piga, 2003 1
54
DFP more effective than DFO in
preventing cardiac disease (retrospective)
Anderson, 2002 2
15
DFP more effective than DFO in reducing
cardiac T2* (retrospective control)
Maggio, 2002 3
71
Similar decrease in cardiac MRI by both
drugs
Hoffbrand, 1998 4
51
4 died of cardiac causes
Ceci, 2002 5
532 9 died of heart failure
1.
2.
3.
4.
5.
Piga A, et al. Haematologica. 2003;88:489.
Anderson LJ, et al. Lancet. 2002;360:516.
Maggio A, et al. Blood Cell Mol Dis. 2002;28:196.
Hoffbrand AV, et al. Blood. 1998;91:295.
Ceci A, et al. Br J Haematol. 2002;118:330.
22
Prospective Comparison of DFO vs DFP
Effect on Myocardial T2*


DFP 92 mg/kg orally
DFO 43 mg/kg x 5.7 SC
Myocardial T2*
(geometric mean ± SEM)
18
17
DFP (delta 3.5 ms; n = 29)
16
DFO (delta 1.7 ms; n = 32)
15
14
13
12
Baseline
6 Months
12 Months
DFO = desferrioxamine; DFP = deferiprone; SEM = standard error of the mean.
Reprinted from Pennell DJ, et al. Blood. 2006;107:3738, with permission from the
American Society of Hematology
23
How to Minimize Deferiprone’s
Unwanted Effects

Frequent monitoring of white count (1–2 weeks)
– Avoid exposure if stem cell disorder or neutropaenia



Monitor liver function, liver iron, and histology
Monitor serum zinc
Avoid exceeding recommended dose?
– Is agranulocytosis dose related?



Avoid exposure at young age?
Role of dose adjustment?
Use of other chelators concomitantly?
24
Deferiprone
Summary of Advantages and Disadvantages

Advantages
– Orally active
– Enhanced removal of cardiac iron
– Increased effectiveness when combined with desferrioxamine

Disadvantages
– Short plasma half-life and rapid inactivation by metabolism
– Administered 3 times daily—may negatively impact patient compliance
and outcome
– May not achieve negative iron balance at 75 mg/kg/day
– Risk of agranulocytosis and need for weekly blood counts
– Limited data
 Data in thalassaemia patients but limited use for other indications
 Relationship of dose to tolerability and efficacy
 Effects of combined therapy on tolerability
– Second-line therapy in thalassaemia major
25
Potential Value of 24-Hour Chelation

Minimizes exposure to labile iron
– In tissues
– In plasma

Continuous capture of iron released from
– Red cell catabolism in macrophages
– Ferritin catabolism (mainly in liver)

Minimizes new cellular uptake of NTBI
26
Effects of Monotherapy and Combined
Therapy on LPI

DFO 40 mg/kg/d given at night
– Effectively removes LPI at night
– No protection during the day

DFP 75 mg/kg/d given during the day
– Intermittent decrease in LPI during the day
– Rebound effect at night

DFO 40mg/kg/d given at night + DFP 75 mg/kg/d
given during the day
– Provides 24 hour protection against LPI
Cabantchik ZI, et al. Best Pract Res Clin Hematol. 2005;18:277.
27
Combinations of DFO and DFP
Center
Year
N
Months DFP dose
(mg/kg/d)
Design
Days
DFO
Ferritin
(μg/L)
LIC
(Total Excretion)
88–110
2–6
1/5 ≥ 2500 final
Not done
London1
1998
5
Obs
Turkey2
1999
7
Obs
6
75
(4/7)
2
30% decrease
4/7 ≥ 2500 final
LIC 19% decrease
6/7 ≥ 15 mg/g
Malaysia3
2000
9
Obs
12
75–85
2
7/9 ≥ 2500
No significant fall
7/9 ≥ 15 mg/g
Lebanon4
2003
14
11
Rand
30
Rand
12
75
5
2
Fall in both
6/11 ≥ 2500 final
Not done
12
75
75
5
2
-
Max decrease
NS from DFO
Less decrease
Not done
India5
2004
6–15
Obs = observational; Rand = randomised.
1. Wonke B, et al. Br J Haematol. 1998;103:361. 2. Aydinok Y, et al. Acta Haematol. 1999;102:17.
3. Balveer K, et al. Med J Malaysia. 2000;55:493. 4. Mourad FH, et al. Br J Haematol. 2003;121:187.
5. Gomber S, et al. Indian Pediatrics. 2004;41:21.
28
Combinations of DFO and DFP
Center
Year
N Design
Months
Regimen
DFP Dose
(mg/kg)
DFO Dose mg/kg
Duration
Ferritin LIC
Sardinia1
2005
79 Obs ±
Simul
31 mean
25 TID x 7
40
Ferritin fall from
high*
LIC not done
Greece2
2006
50 Obs
Simul
12
3
Centres3
2006
30
30
Rand
Seq
Greece4
2006
42
Obs
Seq
(x2-6)/7d, 8-24 h
Other
4% agranulocytosis
8% neutropaenia
Improved LVEF Echo*
25 mg TID x 4/7
25mg BID x 3/7
30-55, 3/7 d 8 h
Ferritin fall*
LIC not done
4 agranuloytosis/100 pt y
T2 heart improved
LV shortening fraction
incr
12
25mg TID x 7
33 x 5/7 d, 8 h
33 x 2/7 d, 8 h
Ferritin ± decr same
LIC ± decr same
7% AEs
24% AEs
2 neutropaenia
3-4 y
25-30mg TID
20-40 x 2-6 d
8-12 h
Ferritin fall*
Liver MRI improve*
AEs not reported
Improved GTT*
Improved insulin secr*
*Significant
Obs = observational; Simul = simultaneous; Seq = sequential.
1. Origar, et al. Haematologica. 2005;90:1309. 2. Kattamis A, et al. Blood Cells Mol Dis. 2006;36:21.
3. Galanello R, et al. Haematologica. 2006;91:1241. 4. Farmaki K, et al. Br J Haematol. 2006;134:438.
29
Prospective Randomized Comparison of
DFO Monotherapy vs Combination Therapy with DFP
Design
65 adult patients with TM
Mild to moderate T2* shortening (8–20 ms)
Pretreatment with SC DFO 30–40 mg/kg/night x5
Randomised to
• SC DFO monotherapy 43 mg/kg x5/week
• Placebo or deferiprone 75 mg/kg/day
Outcome
Improvement better in combined arm for
T2* (see graph)
Ferritin (-233 vs -976 µg/L)
Change in Heart T2* (ms)
Normal heart function (LVEF >56%)
8
7
6
Combined
Desferrioxamine
Between groups:
P = .02
5
4
3
2
1
0
0
6
12
Months
LV function (0.6% vs 2.6%)
DFO = desferrioxamine; DFP = deferiprone; TM = thalassaemia major; LVEF = left ventricular ejection fraction.
With permission from Tanner M, et al. Circulation. 2007;115:1876.
30
Deferasirox (ICL670)










Tridentate iron chelator (high specificity)1
High therapeutic safety in animal data
Lipophilic but protein bound1
Renal target in animal toxicology
Long plasma half-life in humans1
Primarily excreted in faeces1
Given as once-daily drink1
Prospective 1-y phase II/III studies in wide range of
anaemias, including (TM2,4,5, SCD3, MDS4, DBA4)
Randomised 1-y comparison with DFO in adult TM2
(n = 586), children with TM2,3, and adults and children
with SCD3 (n = 195)
Licensed in US, EU for treatment of iron overload,
including children
OH
O
N N
N
OH HO
1. EXJADE [Package Insert]. East Hanover, NJ:Novartis Pharmaceuticals 2007
2. Cappellini MD, Blood. 2006;107:3455.
3. Vichinsky E, Br J Haematol. 2007;136:501.
4. Porter J. Eur J Haematol. 2008; 80: 168.
5. Piga A. Haematologica. 2006; 91:873.
31
Plasma Concentration Iron-Free
Deferasirox (µmol/L)
24-Hour Chelation Coverage After
Repeated Daily Dosing
Steady-state levels with daily deferasirox
100
80
60
40
20
Degree of constant chelation coverage with 20 mg/kg dose
0
0
4
8
12
16
20
Time Postdose with Deferasirox 20 mg/kg/day (hours)
24
Mean values of measurements taken on weeks 2, 4, 8, and 12 are presented
With permission from Piga A, et al. Haematologica. 2006;91:873.
32
LPI After Single and Multiple Deferasirox
Dosing in β-thalassaemia
2.0
Predose (n = 13)
2 hours postdose (n = 13)
Mean LPI (µmol/L)
1.8
20 mg/kg/day
1.6
1.4
1.2
1.0
0.8
0.6
0.4
P < .0001*
P = .0119*
P = .1948*
0.2
0
P = .0187
Washout
P = .0007
Baseline
Week 4
Week 16
Once-daily administration of deferasirox provides 24-hour chelation
coverage and cumulative reduction in peak LPI with multiple dosing
*Vs predose
Adapted from Daar S, et al. Haematologica. 2006;91:13, with permission from the
Ferrata Storti Foundation, Pavia, Italy.
33
Efficiency of Chelation Therapy

Definition
– Proportion of administered drug that is eliminated in iron-bound forms

How calculated
– Formal iron balance studies
– Iron excretion or change in body iron (LIC) relative to dose and
transfusion rate

Desferrioxamine: 13% (10%–17%) efficient when given at 25–50 mg/kg over
8–10 hours, 5 times per week1

Deferiprone: 4% of administered dose eliminated in urine bound to iron
at 25 mg/kg/day, 3 times daily2

Deferasirox: 27% of drug eliminated in iron-bound form when given at
10–30 mg/kg/day, once daily1
1. Porter J, et al. Blood. 2005;106:abstr 2690.
2. Hoffbrand V, et al. Blood. 2003;102:17.
34
Deferasirox Dosing Effects
Dose-dependent change in ferritin predicts change in LIC,
with zero change at dose of 10 mg/kg/day
Deferasirox, mg/kg/day
5
10
20
0
1250
30
Change in LIC (mg Fe/g dw)
20
15
10
n = 325; R = 0.63
5
0
-5
-10
-15
-20
-25
-30
-7500
-6250
-5000
-3750
-2500
-1250
2500
3750
5000
Change in Ferritin (µg/mL)
Novartis data on file.
35
Mean Total Body Iron Excretion ± SD
(mg Fe/kg/d)
Iron Excretion and Dose
Comparison over 1 Year with DFO
Deferasirox
DFO
0.8
Thalassaemia major, n=541
0.7
0.6
0.5
0.4
Average transfusional iron
intake in thalassemia
0.3
Average transfusional
iron
intake in MDS 12
Averaget ransfusional iron
intake in SCD 11
0.2
0.1
0
Actual doses, mg/kg/d
0
5
10
15
20
25
30
Deferasirox
0
10
20
30
40
50
60
DFO, on 5 d/wk
With permission from Cohen AR, et al. Blood. 2008;111;583.
36
Iron Intake, Dose, and Outcome
with Deferasirox
Proportion of patients with increase or decrease of LIC
Deferasirox dose (mg/kg/d)
5
10
20
30
63
1
100%
Increase
0%
n=
3
14
16
11
44
42
10
19
17
28
Decrease
100%
<0.3
0.3–0.5
>0.5
(<2 units/mo)
(2–4 units/mo)
(>4 units/mo)
Iron Intake (mg/kg/d)
Reprinted from Cohen AR, et al. Blood. 2008;111;583, with permission from the
American Society of Hematology.
37
Change in Cardiac T2* in Studies 0107 and
0108 in UCLH Patients at Doses
10, 20, 30 mg/kg/day (n = 22)
P = .0026
50
16 thalassaemias
40
6 other anaemias
26.4
±2.8
(gm = 23.1)
30
20
10
0
20.0
±2.0
gm = 18.0
1
Cardiac T2* ms
60
Pre
Post 1 y
9 thalassaemia major patients randomized to DFO arm; T2* pre = 18.1, post = 21.1 (not shown)
With permission from Porter JB, et al. Blood. 2005;106: abstr 3600.
38
Tolerability and Unwanted Effects of Deferasirox in
Adults and Children During Prospective Studies

Generally well tolerated over a range of transfusion-dependent anaemias1,2,3,4

Most common treatment-related adverse events were mild to moderate, transient
gastrointestinal disturbances and skin rash1,2,3

No drug-induced agranulocytosis, neutropaenia, or arthralgia

Mild, nonprogressive, dose-dependent elevations in serum creatinine (>33% above
baseline in 36% of patients, in 10% managed by dose adjustment)1,2,3
–
No increase of incidence or progression in extension studies

2 cases of suspected drug-related hepatitis1

Cataract/lens opacities: 2 patients discontinued — 2 with DFO also1

30 mg/kg/day generally well tolerated in children as young as 2 years4

Sexual and physical development proceeded within normal parameters4
1. Cappellini MD, Blood. 2006;107:3455. (Study 107, randomised vs DFO in TM, n= 586).
2. Vichinsky E, Br J Haematol. 2007;136:501. (Study, 108…randomised vs DFO in sickle, n= 195)
3. Porter J. Eur J Haematol, 2008;80:168. (Study 109… n TM n= 85, MDS n=47, DBA n=30, other=22)
4. Piga A. Haematologica, 2006;91:873. (Study 106…randomised vs DFO in TM paediatric, n=71)
39
Deferasirox
Summary of Advantages and Disadvantages

Advantages
– Orally active with long plasma half-life
– Generally well tolerated over a range of transfusion-dependent anaemias
– Once-daily administration
 Ease of administration, 24-h chelation, increased chelation efficiency
–
–
–
–
–

Clear dose response effect on iron balance
Demonstrated equivalency to desferrioxamine at higher doses
Prospective studies in MDS, thalassaemia, SCD, other anaemias
Ferritin trend follows trend in LIC and hence iron balance
Licensed as first-line treatment in iron overload
Disadvantages
–
–
–
–
Long-term data less than 5 years follow-up
Need to monitor renal function
Limited data on cardiac effects
Not all patients achieve negative iron balance at highest recommended dose
40
Conclusions

Most of body iron is not directly available for chelation

Chelatable iron pools result from continuous turnover of
– Catabolised red cells (in macrophages)
– Catabolised storage iron (ferritin and haemosiderin, mainly in hepatocytes)

Toxic (labile) iron pools are small, transient, and constantly turned over

Iron chelation protects by
– Decreasing absolute levels of storage iron (slow)
– Detoxifying labile iron in cells or plasma (fast)
– Preventing continuous distribution of iron to key tissues via plasma NTBI

Chelation must detoxify iron without producing chelator toxicity

4 decades of clinical experience show chelation is an effective modality

Extensive clinical experience with 3 chelators now available
41