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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]

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 Presentation

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Page 1: Monitoring and treatment iron overload in  thalassaemia

Monitoring and treatment iron overload in thalassaemia

Professor John PorterRed Cell Disorders Unit

University College London Hospitals and UCL [email protected]

Page 2: Monitoring and treatment iron overload in  thalassaemia

Professor John PorterRed Cell Disorders Unit

University College London Hospitals and UCL [email protected]

Monitoring and treatment iron overload in thalassaemia

Page 3: Monitoring and treatment iron overload in  thalassaemia

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

Page 4: Monitoring and treatment iron overload in  thalassaemia

Monitoring options

• Iron loading rate• Serum ferritin• Liver Iron concentration• Cardiac evaluation – function & T2* • Endocrine evaluation – growth, function & MRI• Adherence and quality of life

Page 5: Monitoring and treatment iron overload in  thalassaemia

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

Page 6: Monitoring and treatment iron overload in  thalassaemia

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.

Page 7: Monitoring and treatment iron overload in  thalassaemia

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

Page 8: Monitoring and treatment iron overload in  thalassaemia

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

Page 9: Monitoring and treatment iron overload in  thalassaemia

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.

Page 10: Monitoring and treatment iron overload in  thalassaemia

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.

Page 11: Monitoring and treatment iron overload in  thalassaemia

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

Page 12: Monitoring and treatment iron overload in  thalassaemia

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

Page 13: Monitoring and treatment iron overload in  thalassaemia

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

Page 14: Monitoring and treatment iron overload in  thalassaemia

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

Page 15: Monitoring and treatment iron overload in  thalassaemia

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

Page 16: Monitoring and treatment iron overload in  thalassaemia

• 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

Page 17: Monitoring and treatment iron overload in  thalassaemia

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

Page 18: Monitoring and treatment iron overload in  thalassaemia

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

Page 19: Monitoring and treatment iron overload in  thalassaemia

‘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

Page 20: Monitoring and treatment iron overload in  thalassaemia

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

Page 21: Monitoring and treatment iron overload in  thalassaemia

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.

Page 22: Monitoring and treatment iron overload in  thalassaemia

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

Page 23: Monitoring and treatment iron overload in  thalassaemia

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.

Page 24: Monitoring and treatment iron overload in  thalassaemia

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

Page 25: Monitoring and treatment iron overload in  thalassaemia

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.

Page 26: Monitoring and treatment iron overload in  thalassaemia

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)

Page 27: Monitoring and treatment iron overload in  thalassaemia

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

Page 28: Monitoring and treatment iron overload in  thalassaemia

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.

Page 29: Monitoring and treatment iron overload in  thalassaemia

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

Page 30: Monitoring and treatment iron overload in  thalassaemia

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.

Page 31: Monitoring and treatment iron overload in  thalassaemia

DFX + DFO:improvements in iron overload

Lal , Porter et al Blood.Cells Mol Dis. 2012 in press.

Page 32: Monitoring and treatment iron overload in  thalassaemia

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

Page 33: Monitoring and treatment iron overload in  thalassaemia

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

Page 34: Monitoring and treatment iron overload in  thalassaemia

How has chelation therapy and monitoring impacted on outcome

in transfusion dependent thalassaemia

- a local perspective in UK

Page 35: Monitoring and treatment iron overload in  thalassaemia

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

Page 36: Monitoring and treatment iron overload in  thalassaemia

70%

21%

9%

1999-2000

DFO

DFP

DFP + DFO

DFO

DFPDFP + DFO

DFX

2010

Chelation regimes

DFP + DFODFP

DFX

Page 37: Monitoring and treatment iron overload in  thalassaemia

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

Page 38: Monitoring and treatment iron overload in  thalassaemia

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

Page 39: Monitoring and treatment iron overload in  thalassaemia

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

Page 40: Monitoring and treatment iron overload in  thalassaemia

Chelator regime at death

• DFO (n= 4)

• DFP (n= 2)

• Combination DFP + DFO ( n= 1)

• DFX ( n= 1)

Page 41: Monitoring and treatment iron overload in  thalassaemia

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

Page 42: Monitoring and treatment iron overload in  thalassaemia

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

Page 43: Monitoring and treatment iron overload in  thalassaemia

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’

Page 44: Monitoring and treatment iron overload in  thalassaemia

Then and Now

What can be achieved with transfusion, chelation and optimal monitoring

Page 45: Monitoring and treatment iron overload in  thalassaemia

Thankyou

Page 46: Monitoring and treatment iron overload in  thalassaemia

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

Page 47: Monitoring and treatment iron overload in  thalassaemia

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

Page 48: Monitoring and treatment iron overload in  thalassaemia

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

Page 49: Monitoring and treatment iron overload in  thalassaemia

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

Page 50: Monitoring and treatment iron overload in  thalassaemia

Impact of monitoring and comprehensive support

on outcome

Page 51: Monitoring and treatment iron overload in  thalassaemia

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

Page 52: Monitoring and treatment iron overload in  thalassaemia

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

Page 53: Monitoring and treatment iron overload in  thalassaemia

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%

Page 54: Monitoring and treatment iron overload in  thalassaemia

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 ?

Page 55: Monitoring and treatment iron overload in  thalassaemia

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

Page 56: Monitoring and treatment iron overload in  thalassaemia

UK National Guidelines for Thalassaemia

• Transfusion and other care locally but

• At least yearly review in specialist centre

UK Thalassaaemia Society

Page 57: Monitoring and treatment iron overload in  thalassaemia

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

Page 58: Monitoring and treatment iron overload in  thalassaemia

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

Page 59: Monitoring and treatment iron overload in  thalassaemia

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

Page 60: Monitoring and treatment iron overload in  thalassaemia

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

Page 61: Monitoring and treatment iron overload in  thalassaemia

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

Page 62: Monitoring and treatment iron overload in  thalassaemia

Chelator regime at death

• DFO (n= 4)

• DFP (n= 2)

• Combination DFP + DFO ( n= 1)

• DFX ( n= 1)

Page 63: Monitoring and treatment iron overload in  thalassaemia

Changing Causes of death in TM

Page 64: Monitoring and treatment iron overload in  thalassaemia

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

Page 65: Monitoring and treatment iron overload in  thalassaemia

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

Page 66: Monitoring and treatment iron overload in  thalassaemia

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……..

Page 67: Monitoring and treatment iron overload in  thalassaemia

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

Page 68: Monitoring and treatment iron overload in  thalassaemia

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

Page 69: Monitoring and treatment iron overload in  thalassaemia

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

Page 70: Monitoring and treatment iron overload in  thalassaemia

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

Page 71: Monitoring and treatment iron overload in  thalassaemia

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)

Page 72: Monitoring and treatment iron overload in  thalassaemia

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

Page 73: Monitoring and treatment iron overload in  thalassaemia

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.

Page 74: Monitoring and treatment iron overload in  thalassaemia

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.

Page 75: Monitoring and treatment iron overload in  thalassaemia

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

Page 76: Monitoring and treatment iron overload in  thalassaemia

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.

Page 77: Monitoring and treatment iron overload in  thalassaemia

• 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

Page 78: Monitoring and treatment iron overload in  thalassaemia

Combination Tharapies

• Desferrioxamine + Deferiprone

• Desferrioxamine + Deferasirox

• Deferiprone + Deferasirox

Page 79: Monitoring and treatment iron overload in  thalassaemia

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

Page 80: Monitoring and treatment iron overload in  thalassaemia

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

Page 81: Monitoring and treatment iron overload in  thalassaemia

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.

Page 82: Monitoring and treatment iron overload in  thalassaemia

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

Page 83: Monitoring and treatment iron overload in  thalassaemia

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

Page 84: Monitoring and treatment iron overload in  thalassaemia

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

Page 85: Monitoring and treatment iron overload in  thalassaemia

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

Page 86: Monitoring and treatment iron overload in  thalassaemia

• 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.

Page 87: Monitoring and treatment iron overload in  thalassaemia

• 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].

Page 88: Monitoring and treatment iron overload in  thalassaemia

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

Page 89: Monitoring and treatment iron overload in  thalassaemia

Treatment of Iron overload

• Which conditions ?– Transfusion dependent Thalassaemia Major– Multi transfused SCD– DBA– Sideroblastic– Aplastic Anaemia– Iron loaded NTDT– MDS

Page 90: Monitoring and treatment iron overload in  thalassaemia

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.

Page 91: Monitoring and treatment iron overload in  thalassaemia

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

Page 92: Monitoring and treatment iron overload in  thalassaemia

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.

Page 93: Monitoring and treatment iron overload in  thalassaemia

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

Page 94: Monitoring and treatment iron overload in  thalassaemia

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

Page 95: Monitoring and treatment iron overload in  thalassaemia

Organs susceptible to iron overload

DiabetesPancreasHypogonadotrophic HypogonadismGonads

Cirrhosis, carcinomaLiverCardiomyopathyHeartHypoparathyoidismParathyroidHypothyroidismThyroid

Hypogonadotrophic HypogonadismPituitary

ConsequencesOrgan