Background

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• 2006?7?19?

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Background
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Hemochromatosis

• ?????( 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

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Iron metabolism
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Iron metabolism
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Toxicity of Iron Non-transferrin bound iron

• Fe--(catalytic reaction)--gt free hydroxyl radical
  --gt lipid peroxidation of cellular organelle
• catalytic reaction inhibited by strong binding
  between plasma iron transport protein
• heavy iron-loaded state--gt fully saturation of
  transferrin --gt nontransferrin-bound iron
• Effect of iron chelating agent is induced by
  power of binding with nontransferrin bound iron

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The impact of iron overload
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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.

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Iron chelating agents
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Deferoxamine

• Since 1960s
• 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

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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

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Cartilagenous dysplasia
3 years later
6 years later
initially
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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.

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Toxicity of deferiprone
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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

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Deferasirox (ICL670)

• A member of a new class of tridentate iron
  chelators, the N-substituted bis-hydroxyphenyl-tri
  azoles.
• 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-deferasirox2) 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.

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EBM Step Iask 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

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EBM Step IISearch the database

• EBM Step IIICritical appraisal

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Guideline

• NGC (National Guideline Clearinghouse)
• Iron chelation 5 results (1 selected)
• Thalassemia 0
• Iron overload 0

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Diagnosis and Management of HemochromatosisANTHON
Y S. TAVILLHEPATOLOGY 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.

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Cochrane library

• Key words iron overload ,iron chelating therapy
  , thalassemia
• Systemic review 2 results (1 selected) 1
  protocal

Desferrioxamine mesylate for managing
transfusional ironoverload in people with
transfusion-dependent thalassaemia(Review)Robert
s DJ, Rees D, Howard J, Hyde C, Brunskill S19
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
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Desferrioxamine mesylate for managing
transfusional ironoverload in people with
transfusion-dependent thalassaemia(Review)Robert
s DJ, Rees D, Howard J, Hyde C, Brunskill S19
October 2005 in Issue 4, 2005
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Objectives

• To determine the effectiveness (dose and method
  of administration) of desferrioxamine in people
  with transfusion-dependent thalassaemia.

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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.

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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.

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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).

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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

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Results-DFO COMPARED WITH ANOTHER IRON CHELATOR
Individual study data (mean /- standard
deviation) measures of iron overload
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ResultsDFO COMPARED WITH ANOTHER IRON CHELATOR
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Results-Serum ferritin concentration
No significant difference between DFO and DFP
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Results-Serum ferritin concentration
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Results-Urinary iron excretion
No significant difference between DFO and DFP
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Results-Urinary iron excretion
No siginificant difference between DFO and
combined Tx.
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Results-Liver iron concentration
13.7
Liver iron concentration baseline and end of
trial values
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Results-Adverse events
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Results-Participant 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.

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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.

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ACP Journal Club

• Key words
• iron overload 0
• iron chelation 0
• hemosiderosis 0
• Deferiprone 0
• DFO 1 (none selected)
• Thalassemia 1 (none selected)

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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)

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Updated Literature

• Iron chelation treatment with combined therapy
  with deferiprone and deferioxamine a 12-month
  trial.Blood Cells Mol Dis. 2006
  Jan-Feb36(1)21-5. Epub 2006 Jan 4.
• Evaluation of ICL670, a once-daily oral iron
  chelator in a phase III clinical trial of
  beta-thalassemia patients with transfusional iron
  overload.Ann N Y Acad Sci. 20051054183-5.
• A phase 3 study of deferasirox (ICL670), a
  once-daily oral iron chelator, in patients with
  -thalassemia Blood. 20061073455-3462

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Iron chelation treatment with combined therapy
with deferiprone anddeferioxamine A 12-month
trial

• Patients
• Fifty patients (29 females) with
  transfusion-dependent TM Their age ranged from 15
  to36 (mean 25.2 )years.
• Either severe hemosiderosis defined by
  ferritingt2000 Ag/L (32 patients) and/or cardiac
  dysfunction defined by left ventricular
  shortening fraction (SF) lt29 (19 patients).

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Iron chelation treatment with combined therapy
with deferiprone anddeferioxamine 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.

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Iron chelation treatment with combined therapy
with deferiprone anddeferioxamine A 12-month
trial
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Iron chelation treatment with combined therapy
with deferiprone anddeferioxamine A 12-month
trial
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Iron chelation treatment with combined therapy
with deferiprone anddeferioxamine A 12-month
trial

• Mean ferritin decreased from 3363.7 /- 2144.5
  Ag/L to2323.2 /- 1740.8 Ag/L ( P lt 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
  patientyears.
• Combined therapy may be related with a higher
  incidence of agranulocytosis, emphasizing the
  importance of careful monitoring.

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Randomized phase II trial of deferasirox
(Exjade,ICL670), a once-daily,
orally-administered iron chelator,in comparison
to deferoxamine in thalassemia patientswith
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 once-daily
  deferasirox (10 or 20 mg/kg n24 in both groups)
  or DFO (40 mg/kg, 5 days/week n23) for 48
  weeks.

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Randomized phase II trial of deferasirox
(Exjade,ICL670), a once-daily,
orally-administered iron chelator,in comparison
to deferoxamine in thalassemia patientswith
transfusional iron overload

• Results
• Both treatments were well tolerated and no
  patient discontinued deferasirox due to
  drug-related 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.

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Randomized phase II trial of deferasirox
(Exjade,ICL670), a once-daily,
orally-administered iron chelator,in comparison
to deferoxamine in thalassemia patientswith
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.

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A phase 3 study of deferasirox (ICL670), a
once-daily oral iron chelator, inpatients 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 (n12).

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A phase 3 study of deferasirox (ICL670), a
once-daily oral iron chelator, inpatients 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.

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A phase 3 study of deferasirox (ICL670), a
once-daily oral iron chelator, inpatients with
-thalassemia

• Results
• In both arms, patients with LIC values gt 7 mg
  Fe/g dry weight (dw) had significant and similar
  dose-dependent 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

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EBM Step IV????

• DFO ???? beta-thalassemia patients with
  transfusional iron overload ?????????
• ????Deferiprone??chelation therapy
  ???????????DFO???
• ????DFO?Deferiprone ???????DFO???,???????????
• ?????iron chelator , ICL670, ??phase 2 ?phase 3
  study ???, ???????DFO??? ,?????????

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Thanks for your attention