長期輸血導致之慢性鐵質沈著
症的排鐵治療
兒科實證醫學課程
兒科林佩瑾主治醫師
2006年7月19日
Background
Hemochromatosis
鐵質沈著症（ Hemochromatosis）
Hereditary Hemochromatosis
Secondary Iron Overload
Iron-loading anemias +/- transfusion
– Thalassemia major
– Sideroblastic anemia
– Other chronic hemolytic anemias
Dietary iron overload
Chronic liver diseases
–
–
–
–
Hepatitis C and B
Alcohol-induced liver disease
Porphyria cutanea tarda
Fatty liver disease
Miscellaneous causes of iron overload
–
–
–
–
African iron overload
Neonatal iron overload
Aceruloplasminemia
Congenital atransferrinemia
Iron metabolism
Iron metabolism
Toxicity of Iron
Non-transferrin bound iron
Fe--(catalytic reaction)--> free hydroxyl
radical --> lipid peroxidation of cellular
organelle
catalytic reaction: inhibited by strong
binding between plasma iron & transport
protein
heavy iron-loaded state--> fully saturation
of transferrin --> nontransferrin-bound iron
Effect of iron chelating agent is induced by
power of binding with nontransferrin bound
iron
The impact of iron overload
Assessment of body iron
Hepatic iron
concentration(HIC)
most quantitative, specific &
sensitive method, but invasive
Serum ferritin
- the most commonly used indirect estimate of body
iron stores
- influenced by ascorbate deficiency, fever, acute
infection, inflammation etc.
- 95% prediction intervals for hepatic iron
concentration,given the plasma ferritin ,were so
broad to make determination of plasma ferritin a poor
predictor of body stores.
Iron chelating agents
Deferoxamine
Since 1960’s
The only iron-chelating agent presently
available for clinical use (before L1 approval)
Striking improvement of survival in thalassemia
Poorly absorbed orally and rapidly metabolized
in plasma : principal drawback.
 the requirement for prolonged parenteral infusions
during which plasma concentrations reach a plateau
at 12hrs
nightly 12hrs subcutaneous infusion, 5d/wk
Toxicity of deferoxamine
Local erythema ,painful subcutaneous
nodule at infusion site
Allergic reaction
Neurosensory toxicity
high frequency hearing loss
- night & color blindness
-
Cartilagenous dysplasia: interfere
linear growth
Cartilagenous dysplasia
initially
3 years later
6 years later
Orally active iron chelator :
deferiprone
First reviewed by representatives of the
FDA in 1991, at which time approval was
refused.
At the second review in 1993, the FDA
required
1) a prospective,randomized trial to compare
therapy with deferiprone with deferoxamin.
2) a prospective study to estimate the incidence
of serious adverse effects of deferiprone in a
large cohort of patients.
Toxicity of deferiprone
Combination Therapy
: deferiprone and deferoxamine
Can provide additive effect
Two drug access different pools of iron
Deferoxamine
Form stable complex with NTBI
Deferipron
Chelating iron from tissue parenchyma and
RE cells
Mobilized iron from transfferin, lactoferrin
and hemosiderin
Deferasirox (ICL670)
A member of a new class of tridentate iron chelators,
the N-substituted bis-hydroxyphenyl-triazoles.
Orally bioavailable
Terminal elimination half-life (t1/2) is between 8 and
16 hours, allowing for once-daily administration.
Metabolism and elimination of deferasirox and the
iron chelate (Fe-[deferasirox]2) is primarily by
glucuronidation followed by hepatobiliary excretion
into the feces.
No significant drug-drug interactions been identified
to date.
Enter and remove iron from cells.
臨床問題
對於重症海洋性貧血個案使用
何種排鐵治療最適當
EBM Step I
ask an answerable question
Patient : thalassemia major
Intervention: Deferoxamine (DFO)
Comparison: oral iron chelations (Deferiprone,L1
or Deferasirox, ICL670)
Outcome:
Mortality
Evidence of reduced end-organ damage
Measures of iron overload
Adverse events or toxicity
Compliance
EBM Step II
Search the database
EBM Step III
Critical appraisal
Guideline
NGC (National Guideline Clearinghouse)
Iron chelation : 5 results (1 selected)
Thalassemia : 0
Iron overload : 0
Diagnosis and Management of Hemochromatosis
ANTHONY S. TAVILL
HEPATOLOGY May 2001
In secondary iron overload associated with ineffective
erythropoiesis, iron chelation therapy with parenteral
deferoxamine is the treatment of choice.
Deferoxamine mesylate (Desferal) is the only approved
iron chelation agent that is widely available.
Administered subcutaneously, using an implanted
minipump, by continuous infusion over a 24-hour cycle at
a dose of 20 to 40 mg/kg/d. A total dose of about 2 g per
24 hours usually achieves maximum urinary iron
excretion.
Cochrane library
Key words : iron overload ,iron chelating therapy ,
thalassemia
Systemic review: 2 results (1 selected) ;1
protocal
Desferrioxamine mesylate for managing transfusional iron
overload in people with transfusion-dependent thalassaemia
(Review)
Roberts DJ, Rees D, Howard J, Hyde C, Brunskill S
19 October 2005 in Issue 4, 2005
Oral deferiprone for iron chelation in people with
thalassaemia (Protocol)
Roberts D, Rees D, Howard J, Williams S, Hyde C, Brunskill S
Desferrioxamine mesylate for managing transfusional iron
overload in people with transfusion-dependent thalassaemia
(Review)
Roberts DJ, Rees D, Howard J, Hyde C, Brunskill S
19 October 2005 in Issue 4, 2005
Objectives
To determine the effectiveness (dose and
method of administration) of
desferrioxamine in people with
transfusion-dependent thalassaemia.
Selection criteria
Randomised controlled trials
comparing desferrioxamine with
placebo; with another iron chelator; or
comparing two schedules of
desferrioxamine, in people with
transfusion-dependent thalassaemia.
Description of studies
Three hundred and eighty five citations were
identied from the searches, 31 from CENTRAL,
279 from MEDLINE, 55 from EMBASE and 20
from ZETOC
Initial screening of the citations and trials for
relevancy excluded 306 papers. The remaining
50 papers represented 44 trials.
Eight trials reported in 14 publications were
included in the review.
Types of intervention
DFO compared with placebo or no
placebo;
DFO compared with another iron
chelating treatment schedule;
DFO schedule A (either
subcutaneous method of
administration or dose A) compared
with DFO schedule B (either
intravenous method of administration
or dose B).
Types of outcome measures
Primary outcome
(1) Mortality
Secondary outcomes
(1) Evidence of reduced end-organ damage
(2)Measures of iron overload (hepatic or non-invasive) - including
serum ferritin, assessment of liver and other tissue iron levels by
biopsy with biochemical measurement by SQUID (superconducting
quantum interference device) or by MRI (magnetic resonance
imaging).
(3) Adverse events or toxicity due to treatment with DFO, including
ocular damage, ototoxicity and non-endocrine growth failure
which is felt to be due to direct toxicity of DFO on vertebral height
growth.
(4) Participant compliance with DFO treatment
(5) Cost of DFO
ResultsDFO COMPARED WITH ANOTHER IRON CHELATOR
Individual study data (mean +/- standard deviation): measures of iron overload
Results
DFO COMPARED WITH ANOTHER IRON CHELATOR
ResultsSerum ferritin concentration
No significant difference between DFO and
DFP
ResultsSerum ferritin concentration
ResultsUrinary iron excretion
No significant difference between DFO
and DFP
ResultsUrinary iron excretion
No siginificant difference between DFO and
combined Tx.
ResultsLiver iron concentration
13.7
Liver iron concentration: baseline and end of trial values
ResultsAdverse events
ResultsParticipant compliance
DFO versus deferiprone (Olivieri 1997)
Compliance was significantly better in the control
group (deferiprone) 94.9 +/- 6.69% than that in the
DFO treated group 71.6 +/- 22.51% (P . 0.005).
DFO versus DFO and deferiprone (Mourad
2003)
Participant compliance with DFO was measured in
this trial.
Compliance was rated as excellent in 11 participants
and good in three participants in the DFO group; and
as excellent in 10 participants and good in one
participant in the control (DFO with deferiprone) group.
Conclusion
The results from the included trials do not
suggest that a change in practice is required.
The one trial comparing DFO with placebo
demonstrated a benefit for those receiving DFO
without the definite optimal schedule for DFO.
Future trials comparing DFO with deferiprone
should
include outcomes for the long-term effectiveness and
safety of these agents.
need to record full details of participant's baseline iron
status and biochemical levels, previous iron chelation
therapy and methods used to measure iron overload.
ACP Journal Club
Key words
iron overload: 0
iron chelation: 0
hemosiderosis: 0
Deferiprone: 0
DFO :1 (none selected)
Thalassemia :1 (none selected)
PubMed
PubMed (iron overload, iron chelation,
thalassemia)
313 (review 74)
Limits: published in the last 10
years, Clinical Trial, Meta-Analysis,
Practice Guideline, Randomized
Controlled Trial
24 (15 selected)
Updated Literature
Iron chelation treatment with combined therapy
with deferiprone and deferioxamine: a 12-month
trial.
Blood Cells Mol Dis. 2006 Jan-Feb;36(1):21-5.
Epub 2006 Jan 4.
Evaluation of ICL670, a once-daily oral iron
chelator in a phase III clinical trial of betathalassemia patients with transfusional iron
overload.
Ann N Y Acad Sci. 2005;1054:183-5.
A phase 3 study of deferasirox (ICL670), a oncedaily oral iron chelator, in patients with thalassemia
Blood. 2006;107:3455-3462
Iron chelation treatment with combined therapy with
deferiprone and
deferioxamine: A 12-month trial
Patients:
Fifty patients (29 females) with transfusiondependent TM Their age ranged from 15 to36
(mean: 25.2 )years.
Either severe hemosiderosis defined by
ferritin>2000 Ag/L (32 patients) and/or cardiac
dysfunction defined by left ventricular
shortening fraction (SF) <29% (19 patients).
Iron chelation treatment with combined therapy with deferiprone
and
deferioxamine: A 12-month trial
Study design:
Fifty patients uniformly treated with DFP for 4
days per week and combined therapy with DFP
and DFO for 3 days of the week.
Efficacy was evaluated by ferritin and cardiac
shortening fraction (SF).
Hepatic hemosiderosis was also assessed by
estimation of the T2 relaxation time by
magnetic resonance in a subgroup of patients.
Forty-three patients completed 1 year of
therapy.
Iron chelation treatment with combined therapy with deferiprone
and
deferioxamine: A 12-month trial
Iron chelation treatment with combined therapy with deferiprone
and
deferioxamine: A 12-month trial
Iron chelation treatment with combined therapy with deferiprone
and
deferioxamine: A 12-month trial
Mean ferritin decreased from 3363.7 +/- 2144.5 Ag/L
to2323.2 +/- 1740.8 Ag/L ( P < 0.0001).
Significant improvement in T2 relaxation and SF was
observed.
The most common adverse events were gastrointestinal
symptoms (20%) and transaminasemia (18%). The rate
of agranulocytosis was 4.2 cases per 100 patient–years.
Combined therapy may be related with a higher
incidence of agranulocytosis, emphasizing the
importance of careful monitoring.
Randomized phase II trial of deferasirox (Exjade®,
ICL670), a once-daily, orally-administered iron chelator,
in comparison to deferoxamine in thalassemia patients
with transfusional iron overload
Background and Objectives
the tolerability and efficacy of deferasirox
were compared with those of DFO in 71
adults with transfusional hemosiderosis.
Design and Methods
Patients were randomized to receive oncedaily deferasirox (10 or 20 mg/kg; n=24 in
both groups) or DFO (40 mg/kg, 5 days/week;
n=23) for 48 weeks.
Randomized phase II trial of deferasirox (Exjade®,
ICL670), a once-daily, orally-administered iron chelator,
in comparison to deferoxamine in thalassemia patients
with transfusional iron overload
Results
Both treatments were well tolerated and no
patient discontinued deferasirox due to drugrelated adverse events.
Transient, mild to moderate gastrointestinal
disturbances was higher in the deferasirox
group than in the DFO group, settled
spontaneously without dose interruption.
Decreases in liver iron concentration (LIC) were
comparable in the deferasirox 20 mg/kg/day
and DFO groups.
Randomized phase II trial of deferasirox (Exjade®,
ICL670), a once-daily, orally-administered iron chelator,
in comparison to deferoxamine in thalassemia patients
with transfusional iron overload
Interpretation and Conclusions
Deferasirox at daily doses of 10 or 20 mg/kg
was well tolerated.
20 mg/kg, showed similar efficacy to DFO 40
mg/kg in terms of decreases in LIC.
A phase 3 study of deferasirox (ICL670), a once-daily oral iron
chelator, in
patients with -thalassemia
Paitents:
Between March and November 2003, 586
patients were randomized and started study
treatment at 65 centers in 12 countries (296 on
deferasirox; 290 on deferoxamine).
Most patients completed 1 year of therapy on
this study: 541 (92.3%) of 586 underwent both
baseline and 1-year LIC assessments.
Discontinuations were relatively similar in the
groups receiving deferasirox (n= 17) and
deferoxamine (n=12).
A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator,
in
patients with -thalassemia
The primary response criterion
maintenance or reduction of LIC below
7mg Fe/g dw.
Secondary criteria
evaluation of the change in serum ferritin
levels over time and evaluation of net
body iron balance.
A phase 3 study of deferasirox (ICL670), a once-daily oral iron
chelator, in
patients with -thalassemia
Results
In both arms, patients with LIC values > 7 mg Fe/g
dry weight (dw) had significant and similar dosedependent reductions in LIC and serum ferritin, and
effects on net body iron balance.
the primary endpoint was not met in the overall
population, possibly due proportionally lower doses
of deferasirox relative to deferoxamine for patients
with LIC values less than 7 mg Fe/g dw.
The most common adverse events:
rash, gastrointestinal disturbances, and mild
nonprogressive increases in serum creatinine.
No agranulocytosis, arthropathy, or growth failure
EBM Step IV
臨床應用
DFO 目前仍為 beta-thalassemia patients with
transfusional iron overload 排鐵治療的首選療法
單獨使用Deferiprone作為chelation therapy 的治療
似乎無法達到等同DFO的效果
合併使用DFO及Deferiprone 可達到優於單用DFO
的效果，但會有較高的副作用比例
最新的口服iron chelator , ICL670, 由其phase 2 及
phase 3 study 的結果， 似乎可達到等同DFO的效
果 ，且較無嚴重副作用。
Thanks for your attention