Slide 1 of 26 Iron Chelator Basics Ali T. Taher, MD Professor of Medicine Haematology-Oncology...

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Iron Chelator Basics

Ali T. Taher, MDProfessor of Medicine

Haematology-Oncology DivisionAmerican University Beirut Medical Center

Beirut, Lebanon

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Outline

• Goals of iron chelator therapies and strategies

• Comparison and contrast between current iron chelators

• Update in efficacy and safety/tolerability of iron chelators– New data on myocardial iron removal

– Update on long-term tolerability of iron chelators

– High-dose (>30 mg/kg/day) efficacy and safety

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Goals of Iron Chelation Therapy

• Maintain iron balance with “safe” tissue iron levels– Prevention

Match transfused iron with chelated (excreted) iron Prevent iron from reaching levels at which tissue damage occurs

– Rescue Remove excess iron—slow process—finite pools Reverse dysfunction

• Detoxification of labile iron—24-hour protection – Extracellular (non–transferrin-bound iron, labile plasma iron)

– Intracellular (labile iron pool)

• Wide therapeutic safety margin of regimen

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Properties of an Ideal Iron Chelator

• To control body iron– High and specific affinity for Fe3+

– High chelating efficiency

• To minimize iron toxicity– 24-hour coverage

– Slow metabolism and elimination rate

– Good tissue penetration with stable iron complex

• Acceptable efficacy–toxicity profile– Clear drug–dose relationship with efficacy and toxicity

– No iron redistribution

• Simplicity and ease of monitoring

• Patient acceptance/compliance– Oral bioavailability

– Suitable for monotherapy

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Decreasing Cellular Toxicity with Chelators

• By inhibiting non–transferrin-bound iron uptake

• By directly chelating labile intracellular iron

• By preventing the incorporation of this iron into new ferritin synthesis

• By intercepting iron derived from lysosomal degradation of ferritin

Porter JB. Am J Hematol. 2007;82:1136-1139.

Effective mechanisms for the action ofchelation therapy

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Overview of Iron ChelatorsProperty Desferrioxamine1 Deferiprone2 Deferasirox3

Usual dose 25–60 mg/kg/d 75 mg/kg/d 20–30 mg/kg/d

Route SC, IV

8–12 h, 5 d/wk

PO

3 times daily

PO

Once daily

Half-life 20–30 min 3–4 h 8–16 h

Excretion Urinary, faecal Urinary Faecal

Adverse effects Local reactions, ophthalmologic, auditory, growth retardation, allergic

GI disturbances, agranulocytosis/neutropenia, arthralgia, elevated liver enzymes

GI disturbances, rash, mild non-progressive creatinine increase, ophthalmologic, auditory, elevated liver enzymes

Status Licensed Not licensed in theUnited States or Canada

Licensed

Approved indications

Treatment of chronic iron overload due to transfusion-dependent anaemias

Thalassaemia major Treatment of chronic iron overload due to frequent blood transfusions

1. Desferrioxamine [PI]. Stein, Switzerland: Novartis Pharma Stein AG; 2007.2. Deferasirox [Summary of Product Characteristics] [PI]. Apotex Europe LTD. 1999. 3. Deferiprone [PI]. West Sussex, UK: Novartis Europharm LT; 2006.

Abbreviations: GI, gastrointestinal; IV, intravenous; PO, by mouth; SC, subcutaneous.

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Thalassaemia International Federation Guidelines for Iron Chelation in -Thalassaemia Major

Treatment Recommendation

Deferasirox • 20 mg/kg/day starting dose in averagely transfused

patients

• 30 mg/kg/day in patients with pre-existing high levels of

iron loading

• 10–15 mg/kg/day for patients with low levels of iron loading

Desferrioxamine • 20–40 mg/kg for children, ≤50–60 mg/kg for adults

• In paediatric patients <3 years of age, recommend reduced

dose and monitoring of growth and bone development

Deferiprone • 75 mg/kg/day

• May be combined with desferrioxamine if desferrioxamine

monotherapy is ineffective

http://www.thalassaemia.org.cy/archive.asp

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Cardiac T2* and Risk of Cardiac DysfunctionLe

ft V

entr

icul

ar E

ject

ion

Fra

ctio

n (%

)

0

50

70

40

30

20

10

60

80

90

0 20 40 60 9080 10010 30 50 70

Cardiac T2* (ms)

Severe cardiac ironSevere cardiac ironMinimal liver ironMinimal liver iron

Severe liver ironSevere liver ironMinimal cardiac ironMinimal cardiac iron

With permission from Anderson LJ, et al. Eur Heart J. 2001;22:2171-2179.

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Cardiac T2* and Risk of Cardiac Dysfunction

Cardiac T2* (ms)

0

50

70

40

30

20

10

60

80

1 3 5 7 10 11 12 13 14 15 16 17 18 199 202 4 6 8

Per

cen

tag

e o

f A

sses

smen

ts w

ith

L

VE

F <

56%

Abbreviation: LVEF, left ventricular ejection fraction.With permission from Westwood MA, et al. J Cardiovasc Magn Reson. 2005;7:46-47.

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Mean Change in LIC and Cardiac T2* During 6 Months of Therapy with

DFSa in TM Patients

6

8

10

12

14

16

18

20

22

Baseline 6 monthsStudy US04, preliminary data.aDosage: 30–40 mg (given over 18 months).Abbreviations: DFS, deferasirox; dw, dry weight; LIC, liver iron concentration; TM, thalassaemia major.With permission from Wood J, et al. Blood. 2007;110:abstr 2781.

Changes in cardiac T2* and LIC (mean ± SE)

Car

dia

c T

2*

(ms

)L

IC (

mg

/g d

w)

Cardiac T2* (P = .0136)LIC (P = .0027)

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Effect on Oxidant-Stress and Inflammation—DFS vs DFO

Mean Decline at 1 Year

Markers DFS DFO P valueTx vs Baseline

P valueDFS vs DFO

Malondialdehyde -21% -25% P = .006 ns

C-reactive protein -51%-27%

+8.6%+34%

NAa

P = .02b

P = .02c

a P values not provided.b Confounded by differences in baseline values and missing baseline data.c Controlled for confounding differences and missing baseline data.Abbreviations: DFO, desferrioxamine; DFS, deferasirox.Walter PB, et al. Haematologica. 2008;93:817-825.

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Effect on Oxidant-Stress and Inflammation—DFS vs DFO Conclusions

• Liver iron concentrations and ferritin declined significantly in both treatment groups, paralleling a significant decline in malondialdehyde

• C-reactive protein decreased significantly only in patients receiving DFS, although this finding should be interpreted with caution

Abbreviations: DFO, desferrioxamine; DFS, deferasirox.Walter PB, et al. Haematologica. 2008;93:817-825.

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Deferasirox—3.5 Years of Data

Trial Patient Population Phase Design N End-Points

106 Paediatric Thal II Single armDFS 10 mg/kg/d

40 1° safety

2° LIC by SQUID

107 Adult, paediatric

Thal III Randomized DFS 530 mg/kg/d vs

DFO 2060 mg/kg/d

586 1° LIC by biopsy or SQUID

2° tolerability

108 Adult,paediatric

Thal, MDS, rare anaemias

II Single arm DFS 530 mg/kg/d

86 thal

98 other

1° LIC by biopsy or SQUID2° tolerability

109 Adult, paediatric

SCD II Randomized DFS1030 mg/kg/d vs

DFO 2060 mg/kg/d

195 1° safety2° LIC by SQUID

• 652 patients have received DFS for a median of 3.4 years (range 0–4.5)

• Extension studies: 312 patients crossed over from DFO to DFS: median of 2.2 years on DFS (range 0–2.9)

• Efficacy analysis based on DFS extension trials: β-thalassaemia: 421; other anaemias: 231

Abbreviations: DFO, desferrioxamine; DFS, deferasirox; LIC, liver iron concentration; SCD, sickle cell disease; SQUID, superconducting quantum interference device; Thal, thalassaemia.. Cappellini MD, et al. ASH 2007. December 8-10, 2007. Poster 967. Porter J, et al. ASH 2007. December 8-10, 2007. Poster 968.

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Median Change in Serum Ferritin Levels from Baseline (By Initial Dose Group)

−1500

−1000

-500

0

500

1000

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42

Time Since Start of Treatment (months)

Med

ian

Ch

ang

e in

Ser

um

Fer

riti

n L

evel

s (µ

g/L

)

0

Core Extension

5–10 (n = 227) 20 (n = 182) 30 (n = 243)Initial deferasirox dose, mg/kg/day

Studies 106–109With permission from Porter J, et al. ASH 2007. December 8-10, 2007. Poster 968.

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Deferasirox—Long-Term Efficacy

• Long-term data highlights– The importance of regularly monitoring serum ferritin levels

– Ensuring that patients receive the appropriate deferasirox dose, based on iron burden and transfusional iron intake to reach therapeutic goal

• In general, serum ferritin levels decreased at deferasirox doses of 30 mg/kg/day and were maintained at doses of 20–25 mg/kg/day

• Treating to a target serum ferritin level of 500 μg/L is a realistic goal

Porter J, et al. ASH 2007; December 8-10, 2007.

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Most Common (> 4% overall) Drug-Related Adverse Events During 3.5 Years of

Treatmenta

Adverse event Frequency, n (%) Severity, n (%)

Mild Moderate Severe

Nausea 99 (10.3) 84 (8.7) 14 (1.5) 1 (0.1)

Diarrhoea 86 (8.9) 68 (7.1) 16 (1.7) 2 (0.2)

Vomiting 60 (6.2) 46 (4.8) 13 (1.3) 1 (0.1)

Abdominal pain 50 (5.2) 36 (3.7) 10 (1.0) 4 (0.4)

Rash 50 (5.2) 28 (2.9) 19 (2.0) 3 (0.3)

Upper abdominal pain 48 (5.0) 37 (3.8) 10 (1.0) 1 (0.1)

aTotal number of patients: 964.With permission from Cappellini MD, et al. ASH 2007. December 8-10, 2007. Poster 967.

Drug-related adverse events during deferasirox treatment were generally transient and of mild-to-moderate severity

Studies 106–109

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Serum Creatinine Increase During 3.5 Years of Treatment

2 Consecutive Serum Creatinine Values >33%

Above Baseline

2 Consecutive Serum Creatinine Values >33% Above Baseline

and Beyond the ULN

β-thalassaemia (n = 680)

284 (41.8%) 39 (5.7%)

Other anaemias (n = 284)

92 (32.4%) 36 (12.7%)

• No patient has developed progressive increases in serum creatinine values >2 x ULN

• 2 patients discontinued due to stable creatinine increases of 1.5 x ULN and confounding circumstances (concomitant cyclosporin and multiple infections, respectively)

With permission from Cappellini MD, et al. ASH 2007. December 8-10, 2007. Poster 967.

Studies 106–109 Abbreviation: ULN, upper limit of normal.

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Hepatic Safety During 3.5 Years of Treatment

• 8 patients (0.8%) experienced an ALT value at 2 consecutive visits that exceeded 10 x ULN; ALT already exceeded ULN at baseline in 6 of these patients

• Discontinuation– 1 patient due to recurrent episodes of proteinuria

– 12 patients due to increases in transaminases

• Drug-induced liver toxicity was suspected in 2 patients with early onset and positive re-challenge

• In patients who showed increased LIC, underchelation was the likely explanation in at least some of the cases

Studies 106–109 Abbreviations: ALT, alanine transaminase; LIC, liver iron concentration; ULN, upper limit of normal.Cappellini MD, et al. ASH 2007. December 8-10, 2007. Poster 967.

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Deferasirox >30 mg/kg/dEfficacy

Population n Relative Change vs Levels Before Dose

Escalation (%)

Absolute Change vs Levels Before Dose

Escalation (µg/L)

P value

All patients 223 – 9.4 – 407 <.001

β-thalassaemia 195 – 12.0 – 437 <.001

Sickle cell disease 23 – 0.6 – 26 NS

Other anaemias 5 – 11.0 – 703 –

Adults 117 – 6.8 – 304 0.009

Paediatrics 103 – 15.2 – 572 <.001

P values based on paired Wilcoxon test; absolute serum ferritin changes vs pre-escalation.Abbreviation: NS, nonsignificant.

Median of relative and absolute change in serum ferritin levels at last observed assessment after dose escalation to >30 mg/kg/day, by subgroup (efficacy population)

With permission from Taher A, et al. Thalassemia International Federation 2008. October 8-11, 2008. Abstract CHE40.

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Deferasirox >30 mg/kg/daySafety

Adverse event Frequency, n (%)

Before Dose Escalation After Dose Escalation

Median exposure (wk) 115.4 36.1

ALT increase 12 (5.4) 7 (3.1)

Vomiting 17 (7.6) 6 (2.7)

Abdominal pain 15 (6.7) 3 (1.3)

Abdominal pain upper 3 (1.3) 3 (1.3)

Nausea 24 (10.7) 3 (1.3)

Serum creatinine increase 13 (5.8) 3 (1.3)

Rash 19 (8.5) 2 (0.9)

Diarrhoea 12 (5.4) 2 (0.9)

Most common drug-related adverse events, as assessed by investigators (observed in >1 patient after dose escalation to >30 mg/kg/day)

Abbreviation: ALT, alanine transaminase.With permission from Taher A, et al. Thalassemia International Federation 2008. October 8-11, 2008. Abstract CHE40.

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Deferasirox >30 mg/kg/daySerum Creatinine

Serum creatinine levels remained unchanged after dose escalation

>30 mg/kg/day (overall population)

0

20

40

60

80

100

120

− 9 − 6 − 3 Baseline 3 6 9 12 15 18

Dose escalation to>30 mg/kg/day

Time (months)

Ser

um

Cre

atin

ine

Leve

ls (

µm

ol/L

)

With permission from Taher A, et al. Thalassemia International Federation 2008. October 8-11, 2008. Abstract CHE40.

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Deferasirox >30 mg/kg/day—ALTAdverse Events

• 12 patients (5.4%) had ALT levels 5 x ULN at 2 consecutive assessments at least 7 days apart, 10 of whom had ALT >ULN prior to receiving deferasirox

• 1 patient, who had ALT >ULN prior to deferasirox treatment, had ALT values 10 x ULN at 2 consecutive visits after dose escalation

Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal.

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Long-Term Efficacy—DFP vs DFO vs DFP + DFO

(N = 64 patients with β-thalassaemia)

Mean T2* Myocardial Iron (msec)

DFO

DFPa DFP + DFOb

23.77 35.77 38.05

(+/- 13) (+/- 18.3) (+/- 15.3)

aDFO vs DFP: P = .02bDFO vs DFO + DFO: P = .001Dosages: DFO (30–50 mg/kg/d, >5 d/wk); DFP (75 mg/kg/d); DFO (30–50 mg/kg/d, >5 d/wk) + DFP (75 mg/kg/d)Abbreviations: DFO, desferrioxamine; DFP, deferiprone.

Perifanis V, et al. Int J Hematol. 2007;86:385-389.

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Long-Term Efficacy—DFP vs DFO vs DFP + DFO

(N = 64 patients with β-thalassaemia)

Mean T2* Hepatic Iron (msec)

DFOa DFP DFP + DFOb

8.16 3.29 11.3

(+/- 8.4) (+/- 2.5) (+/- 10.9)

aDFP vs DFO: P = .014bDFP vs DFO + DFP: P = .003Dosages: DFO (30–50 mg/kg/d, >5 d/wk); DFP (75 mg/kg/d); DFO (30–50 mg/kg/d, >5 d/wk) + DFP (75 mg/kg/d)Abbreviations: DFO, desferrioxamine; DFP, deferiprone.

Perifanis V, et al. Int J Hematol. 2007;86:385-389.

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Long-Term Efficacy— DFP vs DFO vs DFP + DFO

Conclusions

• DFO had significantly higher myocardial iron than DFP and DFP + DFO

• DFP had significantly higher hepatic iron than DFO and DFP + DFO

• DFO + DFP appears to combine the different benefits of DFO and DFP with respect to cardiac and hepatic iron

Abbreviations: DFO, desferrioxamine; DFP, deferiprone.Perifanis V, et al. Int J Hematol. 2007;86:385-389.

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Conclusions

• Ease of administration, ensuring compliance, is an important property in choosing an iron chelator

• DFS at dose of 30 mg is efficacious and safe with newer dosing being studied (up to 40 mg)

• Treatment of iron overload may initially require higher doses to achieve iron balance

• Maintaining iron balance with “safe” tissue iron levels may require lower dose levels

• Dosage for an individual patient is determined by number of blood transfusions received and patient’s iron burden

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