Thalassemia Workshop:Chelation Therapy

Chi-Kong Li, MBBS, MDDepartment of PaediatricsPrince of Wales Hospital

The Chinese University of Hong Kong

BTG 2013

Transfusion therapy and iron loading in thalassemia

1 blood unit contains 200 mg iron

A 60 kg thalassemia patient receiving 45 units of blood annually has transfusional iron intake of 9 g iron/year

0.4 mg iron/kg body wt/day

In addition, up to 4 mg/day may be absorbed from the gut

Up to 1.5 g iron/year

Porter JB. Br J Haematol 2001;115:239–252

200–250 mg iron:Whole blood: 0.47 mg iron/mL ‘Pure’ red cells: 1.16 mg iron/mL

Rate of iron loading influences the therapeutic goal

Hepatic Fibrosis --> Cirrhosis

Cardiac arrhythmia

Hypogonadism

Diabetes

Hypothyroidism

Hypoparathyroidism

Cardiac Failure

0

20

40

60

80

100

120

1 3 5 7 9 11 13 15 17 19

Age (years)

Iro

n (

g)

Transf

usional

Iron Death

Transfusional Iron Overload in Thalassemia

Currently Marketed Iron Chelators

Deferoxamine (Desferal )Deferiprone (Ferriprox)

N

OH

O

Me

Me

Desferasirox

(Exjade)

Comparison of chelators

Property DFO Deferiprone Deferasirox

Usual dose (mg/kg/day)

25–60 75 20–30

Routesc, iv

(8–12 hours, 5 days/week)

Oral

3 times daily

Oral

Once daily

Half-life 20–30 minutes 3–4 hours 12–16 hours

Excretion Urinary, fecal Urinary Fecal

Adverse effects

Local reactions, ophthalmologic, auditory, growth

retardation, allergic

Gastrointestinal disturbances,

agranulocytosis/ neutropenia,

arthralgia

Gastrointestinal disturbances, rash,

mild non-progressive creatinine increase,

ophthalmologic, auditory

Status Licensed Licensed Licensed

 

Side effects of desferral

local reactions, severe allergic reaction: rare yersinia enterocolitica infection Hearing: high tone deafness, Visual: night blindness, reduction of

visual field & visual acuity, reduced growth velocity, skeletal lesions.

Effect of DFO compliance on outcome

Gabutti V, Piga A. Acta Haematol. 1996;95:26-36.

Su

rviv

al

0

60

80

50

40

30

20

10

70

90

100

0 282624222018161412108642 30 32 34 36 38 40

Years

300–365225–300150–22575–1500–75

Infusions/year

DFO = desferrioxamine.

GI and Joint complications

Agranulocytosis and NeutropeniaNeutropenia 1-3%, agranulocytosis <1%

Need Weekly blood counts

Discontinue therapy if ANC <1500/mm3 and confirm neutrophil count

Re-challenge only with caution

Deferiprone: oral tablet and suspension

Simultaneous use - may get drug interaction -shuttle

Sequential (alternate) use - longer ‘protection time’

Combined therapy of Desferrioxamine & Deferiprone

Agranulocytosis and Milder Neutropenia

Advantages of Combined Chelation of desferral and

deferiprone Different iron pools of chelation

Increasing efficacy Dose decrease toxicity decrease Better tolerability better compliance Quality of life improvement Preventing NTBI accumulation Use of oral chelators as “shuttling” agents

Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: retrospective analysis

• treated for at least 4 years with deferiprone or deferoxamine January 1995 and March 2001

• None of the 54 patients treated with deferiprone died,

• 4 of the 75 patients treated with deferoxamine died during the study period.

 A. Piga et al; 2003, Thalassemia Centre, University of Torino  

265 patients with β-thalassaemia major Monotherapy DFO or DFP, or combined DFP–DFO

DFO alone (n = 124) DFP (n = 55) sequential DFP–DFO (n = 68),combined DFP–DFO

(n = 18)

8/124 DFO developed arrhythmia, and 3/141 other chelators had arrhythmia

12 deaths, 7 of which were related to cardiac disease6/7 had received DFO prior to death

Survival analysis of patients initially randomized to

DFO + DFP vs monotherapy with DFO or DFP

Maggio A, et al. Blood Cells Mol Dis. 2009 Feb 20].

Monitoring of Iron overload

Cardiac iron overload – cardiomyopathy - death

Liver biopsy

Quantitative assessment of liver iron content

Good correlation with total body iron Invasive, not without risk, poor

patient acceptance

R2 MRI: a new measure for Liver Iron Content

R2 MRI is a validated and standardized method for measuring LIC. This technique is now approved by TGA and FDA and in the EU

St Pierre TG et al. Blood 2005;105:855–861

30

20

40

50

0.5 1.0 1.5 2.0

Biopsy iron concentration (mg.g-1 dry tissue)

Mea

n t

ran

sver

se r

elax

atio

n r

ate

<R

2> (

s-1)

0

100

200

50

150

250

300

0 10 20 30 40 50

Hereditary hemochromatosis

Hepatitis

β-thalassemia

β-thalassemia / hemoglobin E

LiverLiver

Lack of Correlation: Liver and Cardiac Iron

T2* MRI: emerging new standard for cardiac iron

Anderson LJ et al. Eur Heart J 2001;22:2171–2179,

Left

ven

tric

ula

r eje

cti

on

fra

cti

on

(%

)

0

50

70

40

30

20

10

60

80

90

0 20 40 60 9080 10010 30 50 70

Heart T2* (ms)

Cardiac T2* value of 37 in a normal heart

Cardiac T2* value of 4 in a significantly iron overloadedheart

Relationship between myocardial T2* values and left ventricular ejection fraction. Below a myocardial T2* of 20 ms, there was a progressive and significant decline in left ventricular ejection fraction (R=0·61, P<0·0001)

Cardiac T2* and risk for cardiac dysfunction

0

50

70

40

30

20

10

60

80

1 3 5 7 101112131415161718199 202 4 6 8

T2* Heart (ms)

Per

cen

tag

e o

f as

ses

sme

nts

wit

h L

VE

F <

56%

Westwood MA et al. J Magn Reson Imaging 2005;7:46–47,

100

Improvement in liver fibrosis with at least 3 years of deferasirox treatment

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 those who did not

Fibrosis score

7.3 8.2 5.3

10.0 6.0 15.8

55.7 59.7 48.7

26.9 26.1 30.3

0

10

20

30

40

50

60

70

80

90

Overall LIC responders LIC non-responders

Pat

ient

s (%

)

Worsened by ≥2 Ishak stagesRemained stable (no change or ±1)Improved by ≥2 Ishak stages Missing

Deugnier Y et al. Presented at ASH 2010 [Blood 2010;116(21):abst 4274] Studies 107 and 107E

Monotherapy of Desferasirox: MRI cardiac T2*, 3 year study

68717171All patients

4447474710–<20 ms

24242424<10 ms

68717171All patients

4447474710–<20 ms

24242424<10 ms

Patients, n

>5–<10 ms>5–<10 ms 10–<20 ms All patientsA

0

5

10

15

20

25

30

Baseline 12 24 36

Time (months)

Ge

om

etr

ic m

ean

T2

* ±

95

% C

I(m

s)

7.78.6† 9.4‡

10.5‡12.0

13.9‡

15.6‡17.1‡

15.0

17.7‡

20.3‡22.3‡

Pennel DJ et al. Haematologica | 2012; 97(6)

Telfer et al, Haematologica 2006

Causes of death : UK, Italy, Cyprus

7

6

5

4

3

2

1

0

Annual Death rate

year

uncertain

Others

Cancer

Iron overload

Infection

anemia

1950-

1954

1955-

1959

1960-

1964

1965-

1969

1970-

1974

1975-

1979

1980-

1984

1985-

1989

1990-

1994

1995-

1999

2000-

2004

Summary

More accurate body iron assessment: MRI liver and heart Non-invasive, reproducible

Newer oral chelators improves compliance, reduce complications and mortality