Thalassemia Workshop: Chelation Therapy
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Transcript of Thalassemia Workshop: Chelation Therapy
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
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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
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60
80
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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
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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)
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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
(%
)
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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
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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
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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
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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
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6
5
4
3
2
1
0
Annual Death rate
year
uncertain
Others
Cancer
Iron overload
Infection
anemia
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Summary
More accurate body iron assessment: MRI liver and heart Non-invasive, reproducible
Newer oral chelators improves compliance, reduce complications and mortality