iron chelation in beta thalassemia

1. Dr Hasmukh R Balar
Iron Chelation in Beta
Thalassemia
Dr. Hasmukh R. Balar
Department of Haematology
Sahyadri Specialty Hospital
Pune

2. Dr Hasmukh R Balar
What is Chelation Therapy?
• Chelation (KEE-LAY-SHUN) comes from
the Greek word – “chele”- which means
claw.
• “The use of a chelating agent to bind with a
metal in the body to form a chelate so that
the metal loses its toxic effect or
physiological activity”
~Merriam-Webster's Medical Dictionary

3. Dr Hasmukh R Balar
Introduction
• Iron overload is a leading cause of morbidity, mortality and organ
injury. Even nontransfused patients develop iron overload secondary
to increased intestinal absorption of dietary iron.
• The only treatment options for removing excess iron are
1.Phlebotomy and 2. Chelation.
-Phlebotomy is a very effective way of removing iron, it is not
appropriate for patients with Thalassemia except after bone marrow
transplantation.
Thalassemia patients who are not transfusion dependent cannot
maintain an adequate hemoglobin level and become symptomatic
after phlebotomy.
Outpatient exchange transfusion can be used in selected cases
to decrease iron intake, but it is not effective in rapidly reducing heavy
iron loads and would not be appropriate in the face of cardiac iron
loading.
-The primary treatment for iron overload in thalassemia is chelation.

4. Dr Hasmukh R Balar

5. Dr Hasmukh R Balar

6. Dr Hasmukh R Balar
The Challenge of Iron Chelation—
A Question of Balance
Too much iron Too much chelator
• Uncoordinated iron
• Free-radical generation
• Organ damage
• Growth failure
• Organ failure
• Cardiac death
• Uncoordinated chelator
• Inhibition of
metalloenzymes
• Neurotoxicity
• Growth failure
• Bone marrow toxicity

7. Dr Hasmukh R Balar
Goals of Chelation Treatment
• Iron balance with “safe” tissue iron levels by removal of iron from the body.
– 0.4–0.5 mg/kg day excretion1
– Slow process2
• Detoxification of iron
– Extracellular (NTBI)
– Intracellular (LIP)
– Iron-chelate complex
-Detoxification of excess iron is the most important function of chelation therapy.
It is clear that symptoms of iron overload, such as cardiac arrhythmia and heart
failure, can be improved well before local tissue levels of iron have decreased by
the continual presence of a chelator in the plasma.
NTBI = non–trasnsferrin-bound iron; LIP = labile iron pools.
1. Porter J. Hematol/Oncol Clinics. 2005;19:7.
2. Porter JB. Am J Hematol. 2007;82:1136.

8. Dr Hasmukh R Balar

9. Dr Hasmukh R Balar
Desferrioxamine Therapy for
Iron Overload
• Available for > 3 decades with improving survival
• Hexadentate molecule not absorbed from gut
• Short half-life (20 min), so must be given by
continuous infusion
– 8 –12 h/d, 5 – 7 d/w (40–50 mg/kg SC)
• Commenced after 15–20 transfusions or when
ferritin >1000 µg/L
• Audiometric, retinopathic, and growth effects at
high doses and low iron loading
• Compliance often is poor, leading to variable
outcome
Porter JB, Huehns CR. Baillieres Clin Haematol. 1989;2:459. Courtesy of Dr. J. Porter

10. Dr Hasmukh R BalarReprinted from Porter JB, et al. Blood. 1996;88:705, with permission from the American Society of
Hematology.
544842363024181260-6
-1
0
1
2
3
4
5
6
7
Time (hours)
NTBIorDFO(µM)
DFO–Control of Plasma NTBI
Levels
DFO (µM)
NTBI (µM)
Intravenous continuous infusion
DFO = desferrioxamine, NTBI = non–transferrin-bound iron.

11. Dr Hasmukh R BalarReprinted from Borgna-Pignatti C, et al. Haematologica. 2004;891:187, with permission from the
Ferrata Storti Foundation, Pavia, Italy.
SurvivalProbability
P < .00005
0
1.00
0.75
0.50
0.25
0 5 10 15 20 25 30
Age (years)
Birth cohort
1960–1964
1965–1969
1970–1974
1975–1979
1980–1984
1985–1997
DFO = desferrioxamine; TM = thalassaemia major.
DFO–Improved Survival in TM

12. Dr Hasmukh R Balar
DFO–Decline in
Complications
Patients with thalassaemia major born after 1960 (n = 977)
With permission from Porter JB. Am J Hematol. 2007;82:1136.
*DFO IM, 1975; †
DFO SC, 1980.
In 1995, 121 patients switched to deferiprone (censored at this time).
DFO = desferrioxamine.
Death at age 20 years 5% 1%
Hypogonadism 64.5% 14.3%
Diabetes 15.5% 0.8%
Hypothyroidism 16.7% 4.9%
Birth 1970-1974* Birth 1980-1984†

13. Dr Hasmukh R Balar
Desferal [package insert]. East Hanover, NJ: Novartis Pharmaceuticals, 2006.
Porter JB, Huehns ER. Bailliere’s Clin Haematol.1989;2:459.
Unwanted Effects of
Desferrioxamine
• Effect
– Retinopathy
– Ototoxicity
– CNS, coma
– Growth retardation
– Bony changes
– Yersinia infection
– Sensitivity
– Misc (pulmonary fibrosis)
• Contributing factor
– Dose
– Dose, ferritin, therapeutic index
– Iron status, other drugs
– Dose, age <3 y, ferritin <1000
ug≠L
– Age, dose, ferritin
– Natural siderophore
– Intermittent use
– Very high dose (short term)

14. Dr Hasmukh R Balar1. Desferal [Package insert]. East Hanover, NJ: Novartis Pharmaceuticals, 2006.
How to Minimize Desferrioxamine’s
Unwanted Effects?
• Avoid >40 mg/kg mean daily dose when growing1
• Avoid >50 mg/kg mean daily dose in routine use
• Avoid starting too early
• Dose adjustment as ferritin falls
– Adjust mean daily dose downwards
– Try NOT to reduce frequency of treatment
– Keep therapeutic index <.025 (dose mg/kg / ferritin µg/L)
• Monitor regularly for toxic effects

15. Dr Hasmukh R Balar
Desferrioxamine
Summary of Advantages and
Disadvantages• Advantages
– Recognized first-line treatment in iron overload
– Long-term experience and data—reduced morbidity and mortality
– Effective in maintaining near-normal iron stores
• Specific affinity for iron with high chelating efficiency
• Achieves negative iron balance
– Reversal of cardiac disease with intensive therapy
• Disadvantages
– Requires maximum exposure for optimal outcome
– Not absorbed from GI tract
– Rapidly eliminated—30-minute half-life requires prolonged infusions
– Requires parenteral infusion
– Challenges—compliance
– Dose-dependent adverse events limit achievable goals
• Ear, eye, bone toxicity

16. Dr Hasmukh R Balar

17. Dr Hasmukh R Balar
Deferiprone
• History
– Patented 1982; licensed in EU 1999
• Pharmacology
– Bidentate, short plasma half-life — given TID
– Rapidly glucuronidated, low efficiency (7%)
– Urine excretion
• Efficacy
– Indicated when desferrioxamine therapy is contraindicated or inadequate1
– May be less effective than desferrioxamine in reducing LIC
– Possible cardioprotective effect 2
• Side effects
– Neutropaenia/agranulocytosis (weekly neutrophil count recommended1
)
– Nausea, vomiting, abdominal pain
– Arthralgia and arthritis (variable 6%–39%)
CH3
CH3
OH
N
O
EU = European Union; LIC = liver iron concentration.
1. Ferriprox®
[Summary of Product Characteristics]. Apotex Europe Ltd.
1999. 17

18. Dr Hasmukh R Balar
DW = dry weight; FU = follow-up; LIC = liver iron concentration.
1. Olivieri N, et al. N Engl J Med. 1995;332:918.
2. Olivieri N, et al. N Engl J Med. 1998;339:417.
3. Töndury P, et al. Br J Haematology. 1998;101:413.
4. Del Vecchio GC, et al. Acta Haematologica. 2000;104:99.
5. Mazza P, et al. Haematologica. 1998;83:496.
6. Hoffbrand AV, et al. Blood. 1998;91:295.
Percentage Deferiprone Patients with Liver Iron
>7 or >15 mg/g DW After 1-4 Years of Treatment
FU LIC LIC
Publication n Years % >7 % >15
Olivieri, 19951
21 3 52 10
Olivieri, 19982
19 4.6 65 39
Tondury, 19983
7 8 53 18
Del Vecchio, 20004
13 1 64 11
Mazza,19985
20 1–3 85 65
Hoffbrand,19986
51(17) 2–4 88 53

19. Dr Hasmukh R Balar
Cardioprotective Effect of
Deferiprone Monotherapy?
Author n Data
Piga, 2003 1
54 DFP more effective than DFO in
preventing cardiac disease (retrospective)
Anderson, 2002 2
15 DFP more effective than DFO in reducing
cardiac T2* (retrospective control)
Maggio, 2002 3
71 Similar decrease in cardiac MRI by both
drugs
Hoffbrand, 1998 4
51 4 died of cardiac causes
Ceci, 2002 5
532 9 died of heart failure
1. Piga A, et al. Haematologica. 2003;88:489.
2. Anderson LJ, et al. Lancet. 2002;360:516.
3. Maggio A, et al. Blood Cell Mol Dis. 2002;28:196.
4. Hoffbrand AV, et al. Blood. 1998;91:295.
5. Ceci A, et al. Br J Haematol. 2002;118:330.

20. Dr Hasmukh R Balar
Prospective Comparison of DFO vs
DFP
Effect on Myocardial T2*MyocardialT2*
(geometricmean±SEM)
DFP (delta 3.5 ms; n = 29)
DFO (delta 1.7 ms; n = 32)
Reprinted from Pennell DJ, et al. Blood. 2006;107:3738, with permission from the
American Society of Hematology
• DFP 92 mg/kg orally
• DFO 43 mg/kg x 5.7 SC
12
13
14
15
16
17
18
Baseline 6 Months 12 Months
DFO = desferrioxamine; DFP = deferiprone; SEM = standard error of the mean.

21. Dr Hasmukh R Balar

22. Dr Hasmukh R Balar

23. Dr Hasmukh R Balar
How to Minimize Deferiprone’s
Unwanted Effects
• Frequent monitoring of white count (1–2 weeks)
– Avoid exposure if stem cell disorder or neutropenia
• Monitor liver function, liver iron, and histology
• Monitor serum zinc
• Avoid exposure at young age.
• Use of other chelators concomitantly.

24. Dr Hasmukh R Balar
Deferiprone:Summary of Advantages and
Disadvantages
• Advantages
– Orally active
– Enhanced removal of cardiac iron
– Increased effectiveness when combined with desferrioxamine
• Disadvantages
– Short plasma half-life and rapid inactivation by metabolism
– Administered 3 times daily—may negatively impact patient compliance
and outcome
– May not achieve negative iron balance at 75 mg/kg/day
– Risk of agranulocytosis and need for weekly blood counts
– Limited data
• Relationship of dose to tolerability and efficacy
• Effects of combined therapy on tolerability
– Second-line therapy in thalassaemia major

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27. Dr Hasmukh R Balar
Combined therapy: DFO and DFP
• DFP given on each day of the week, and subcutaneous DFO infusions given on
some or all of these days was introduced in 1998 for patients inadequately
chelated by maximum tolerated doses of DFP
• The effect of the combined drugs on iron excretion has been found on the basis
of urine iron excretion and iron balance studies : additive or even synergistic.
• This has been explained as a shuttle mechanism with DFP entering cells and
removing iron, which is then passed on to DFO for excretion in urine or feces.
The DFP may reenter cells and extract more iron.
• In addition, recent studies show that DFP is capable of rapidly accessing NTBI
fractions in plasma and transferring this iron to DFO. Shuttling of iron from DFP to
DFO also applies to iron removed from transferrin.

28. Dr Hasmukh R Balar
The “shuttle” mechanism by which DFP given orally binds iron from transferrin (TF), NTBI, and
intracellular compartments and transfers some of this iron to DFO. The free DFP is then
available to bind more iron. Some DFO also enters cells to bind iron directly

29. Dr Hasmukh R Balar
Best way to give combined therapy
• DFO 40 mg/kg/d given at night
– Effectively removes LPI at night
– No protection during the day
• DFP 75 mg/kg/d given during the day
– Intermittent decrease in LPI during the day
– Rebound effect at night
• DFO 40mg/kg/d given at night + DFP 75
mg/kg/d given during the day
– Provides 24 hour protection against LPI
Cabantchik ZI, et al. Best Pract Res Clin Hematol. 2005;18:277.

30. Dr Hasmukh R Balar
India5
2004
Lebanon4
2003
Malaysia3
2000
Turkey2
1999
London1
1998
Center
Year
Not doneMax decrease
NS from DFO
Less decrease
5
2
-
-
75
75
1230
Rand
Not doneFall in both
6/11 ≥ 2500 final
5
2
-
75
1214
11
Rand
No significant fall
7/9 ≥ 15 mg/g
7/9 ≥ 2500275–85129
Obs
LIC 19% decrease
6/7 ≥ 15 mg/g
30% decrease
4/7 ≥ 2500 final
275
(4/7)
67
Obs
Not done1/5 ≥ 2500 final2–688–1106–155
Obs
LIC
(Total Excretion)
Ferritin
(μg/L)
Days
DFO
DFP dose
(mg/kg/d)
MonthsN
Design
Combinations of DFO and DFP
1. Wonke B, et al. Br J Haematol. 1998;103:361. 2. Aydinok Y, et al. Acta Haematol. 1999;102:17.
3. Balveer K, et al. Med J Malaysia. 2000;55:493. 4. Mourad FH, et al. Br J Haematol. 2003;121:187.
5. Gomber S, et al. Indian Pediatrics. 2004;41:21.
Obs = observational; Rand = randomised.

31. Dr Hasmukh R Balar
Prospective Randomized Comparison of
DFO Monotherapy vs Combination Therapy with DFP
Design
65 adult patients with TM
Mild to moderate T2* shortening (8–20 ms)
Normal heart function (LVEF >56%)
Pretreatment with SC DFO 30–40 mg/kg/night x5
Randomised to
• SC DFO monotherapy 43 mg/kg x5/week
• Placebo or deferiprone 75 mg/kg/day
Outcome
Improvement better in combined arm for
T2* (see graph)
Ferritin (-233 vs -976 µg/L)
LV function (0.6% vs 2.6%)
DFO = desferrioxamine; DFP = deferiprone; TM = thalassaemia major; LVEF = left ventricular ejection fraction.
With permission from Tanner M, et al. Circulation. 2007;115:1876.
0 6 12
Months
0
1
2
3
4
5
6
7
8
ChangeinHeartT2*(ms)
Between groups:
P = .02
Combined
Desferrioxamine

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35. Dr Hasmukh R Balar
Potential Value of 24-Hour
Chelation
• Minimizes exposure to labile iron
– In tissues
– In plasma
• Continuous capture of iron released from
– Red cell catabolism in macrophages
– Ferritin catabolism (mainly in liver)
• Minimizes new cellular uptake of NTBI

36. Dr Hasmukh R Balar
Alternating therapy: DFP and DFO
• The regimen of giving the 2 drugs on different days each
week has been termed alternating or sequential therapy.
• It is aimed at improving compliance with both drugs and
at giving some form of chelation every day.
• In the largest prospective study in the sequential arm,
the patients received DFP 75 mg/kg on 4 days a week
and DFO 50 mg/kg on 3 days.
– Follow-up was a minimum of 5 years.
– One death from cardiac arrhythmia occurred.
– In view of the efficacy of and usual compliance with combined
DFO and DFP therapy, they have not found it necessary to
resort to alternating therapy.

37. Dr Hasmukh R Balar
Deferasirox (ICL670)
• Tridentate iron chelator (high specificity)1
• High therapeutic safety in animal data
• Lipophilic but protein bound1
• Long plasma half-life in humans1
• Primarily excreted in faeces1
• Given as once-daily1
• Prospective 1-y phase II/III studies in wide range of
anaemias, including (TM2,4,5
, SCD3
, MDS4
, DBA4
)
• Randomised 1-y comparison with DFO in adult TM2
(n
= 586), children with TM2,3
, and adults and children with
SCD3
(n = 195)
1. EXJADE [Package Insert]. East Hanover, NJ:Novartis Pharmaceuticals 2007
2. Cappellini MD, Blood. 2006;107:3455.
3. Vichinsky E, Br J Haematol. 2007;136:501.
4. Porter J. Eur J Haematol. 2008; 80: 168.
5. Piga A. Haematologica. 2006; 91:873.
N N
N
OH HO
OH
O

38. Dr Hasmukh R Balar
0
20
40
60
80
100
0 4 8 12 16 20 24
Time Postdose with Deferasirox 20 mg/kg/day (hours)
PlasmaConcentrationIron-Free
Deferasirox(µmol/L)
Degree of constant chelation coverage with 20 mg/kg dose
24-Hour Chelation Coverage
After Repeated Daily Dosing
Mean values of measurements taken on weeks 2, 4, 8, and 12 are presented
With permission from Piga A, et al. Haematologica. 2006;91:873.
Steady-state levels with daily deferasirox

39. Dr Hasmukh R Balar
LPI After Single and Multiple Deferasirox Dosing in β-
thalassaemia
Adapted from Daar S, et al. Haematologica. 2006;91:13, with permission from the
Ferrata Storti Foundation, Pavia, Italy.
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Baseline Week 4 Week 16
MeanLPI(µmol/L)
Predose (n = 13) 2 hours postdose (n = 13)
P < .0001* P = .0119*
*Vs predose
P = .0187
P = .0007Washout
P = .1948*
Once-daily administration of deferasirox provides 24-hour chelation
coverage and cumulative reduction in peak LPI with multiple dosing
20 mg/kg/day

40. Dr Hasmukh R Balar
5 10 20 30
n = 325; R = 0.63
ChangeinLIC(mgFe/gdw)
-30
-25
-20
-15
-10
-5
0
5
10
15
20
Change in Ferritin (µg/mL)
-7500 -6250 -5000 -3750 -2500 -1250 0 1250 2500 3750 5000
Novartis data on file.
Deferasirox Dosing Effects
Dose-dependent change in ferritin predicts change in LIC,
with zero change at dose of 10 mg/kg/day
Deferasirox, mg/kg/day

41. Dr Hasmukh R Balar
Iron Intake, Dose, and Outcome
with Deferasirox
n = 11 44 42 63
Increase
Decrease
Proportion of patients with increase or decrease of LIC
Deferasirox dose (mg/kg/d) 5 10 20 30
Iron Intake (mg/kg/d)
1 10 19 17
>0.5
(>4 units/mo)
0.3–0.5
(2–4 units/mo)
3 14 16
28
<0.3
(<2 units/mo)
100%
100%
0%
Reprinted from Cohen AR, et al. Blood. 2008;111;583, with permission from the
American Society of Hematology.

42. Dr Hasmukh R Balar
Change in Cardiac T2* in Studies 0107 and 0108 in
UCLH Patients at Doses
10, 20, 30 mg/kg/day (n = 22)
With permission from Porter JB, et al. Blood. 2005;106: abstr 3600.
0
10
20
30
40
50
60
1
Pre Post 1 y
20.0
±2.0
gm =
18.0
26.4
±2.8
(gm = 23.1)
P = .0026
16 thalassaemias
6 other anaemias
CardiacT2*ms
9 thalassaemia major patients randomized to DFO arm; T2* pre = 18.1, post = 21.1 (not shown)

43. Dr Hasmukh R Balar

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45. Dr Hasmukh R Balar
• Most common treatment-related adverse events were mild to moderate, transient
gastrointestinal disturbances and skin rash1,2,3
• No drug-induced agranulocytosis, neutropaenia, or arthralgia
• Mild, nonprogressive, dose-dependent elevations in serum creatinine (>33% above
baseline in 36% of patients, in 10% managed by dose adjustment)1,2,3
– No increase of incidence or progression in extension studies
• 2 cases of suspected drug-related hepatitis1
• Cataract/lens opacities: 2 patients discontinued — 2 with DFO also1
• 30 mg/kg/day generally well tolerated in children as young as 2 years4
• Sexual and physical development proceeded within normal parameters4
Tolerability and Unwanted Effects of Deferasirox in
Adults and Children During Prospective Studies
1. Cappellini MD, Blood. 2006;107:3455. (Study 107, randomised vs DFO in TM, n= 586).
2. Vichinsky E, Br J Haematol. 2007;136:501. (Study, 108…randomised vs DFO in sickle, n= 195)
3. Porter J. Eur J Haematol, 2008;80:168. (Study 109… n TM n= 85, MDS n=47, DBA n=30, other=22)
4. Piga A. Haematologica, 2006;91:873. (Study 106…randomised vs DFO in TM paediatric, n=71)

46. Dr Hasmukh R Balar

47. Dr Hasmukh R Balar

48. Dr Hasmukh R Balar
Deferasirox
Summary of Advantages and
Disadvantages• Advantages
– Orally active with long plasma half-life
– Generally well tolerated over a range of transfusion-dependent anaemias
– Once-daily administration
• Ease of administration, 24-h chelation, increased chelation efficiency
– Clear dose response effect on iron balance
– Demonstrated equivalency to desferrioxamine at higher doses
– Prospective studies in MDS, thalassaemia, SCD, other anaemias
– Ferritin trend follows trend in LIC and hence iron balance
– Licensed as first-line treatment in iron overload
• Disadvantages
– Long-term data less than 5 years follow-up
– Need to monitor renal function
– Limited data on cardiac effects
– Not all patients achieve negative iron balance at highest recommended dose

49. Dr Hasmukh R Balar
Combined or alternating therapy: DFX and DFO
As yet, there are no reports of large studies,
• In one study published by abstract only, 15 TM patients with LIC 15 mg/kg or
with lower LIC concentration, but evidence of iron-related organ damage was
treated with DFX 20-30 mg/kg daily combined with DFO 35-50 mg/kg
subcutaneously on 3-7 days each week.
• Liver iron improved significantly after a mean of 29 weeks. No excessive toxicity
was seen. As both DFO and DFX primarily remove liver iron, their combined
effects may not be additive as they may compete for the same iron pool.
Sequential therapy of these chelators has been suggested as an attractive option.
• In a small study of 7 iron-overloaded TM patients, patients received 20-30 mg/kg
per day of oral DFX for 4 consecutive days, then a subcutaneous infusion of 20-
40 mg/kg per day of DFO for 8-12 hours on the next 3 consecutive days.
• All of the patients showed a decrease in serum ferritin without any side effects.
This protocol warrants further evaluation in larger patient numbers.

50. Dr Hasmukh R Balar
Combined therapy: DFP and DFX
Three studies of combined chelation with the 2 oral chelators DFP and DFX
have been reported.
• In the largest, 16 patients were treated with DFP 75-100 mg/kg per day
in 3 divided doses together with DFX 20-25 mg/kg each day.
– There was a fall in total body iron measured by serum ferritin, liver iron and
cardiac iron measured by T2* MRI. Improvements occurred in LVEF, gonadal
function, and glucose metabolism.
– Compliance was excellent and quality of life improved for the patients who
stopped using DFO infusions.
– Side effects were no different from those when the drugs are used as
monotherapy.
• In 2 other reports, a total of 4 patients also showed improvement in
cardiac iron, cardiac function with excellent compliance, and no
unexpected side effects.
• Further long term studies in a larger number of patients are needed
before this combined, attractive (to patients), oral chelation strategy can
be recommended.

51. Dr Hasmukh R Balar

52. Dr Hasmukh R Balar
Comparison Of Two Combination Iron Chelation Regimens,
Deferiprone and Deferasirox Versus Deferiprone and
Deferoxamine, In Pediatric Patients With β-Thalassemia
Major
Data from this randomized prospective study showed that
both forms of combination therapy
• DFP with DFX and DFP with DFO
Were effective in reducing iron overload in multi-transfused β-
thalassemia major, patients
• Who received DFP and DFX showed
- A higher decline in serum ferritin,
- Greater improvement in cardiac T2*,
- Higher treatment satisfaction,
- Better compliance
- More improvement in QoL than did patients who received
DFP and DFO, with no increased toxicity.

53. Dr Hasmukh R Balar
NEW CHELATORS IN DEVELOPMENT
SSP-004184-Previously termed FBS0701, this is a desferrithiocin derivative, a
tridentate chelator, currently in phase 2/3 trials in several centers around the
world.
-In the phase 1b study, it was found to be safe,
– Mean half-life of 16.2–21.3h.
– Administered once-daily for 7 days.
– Toxicity including headache, gastro- intestinal symptoms and a mild prolongation of
the QTc in one individual with sickle cell disease.
-Current phase 2/3 studies in individuals with thalassemia and sickle cell anemia
with transfusional siderosis are underway, But results : Awaited.
Deferitrin
• Tridentate chelator stalled initially when the animal models (rodent and primate)
developed severe nephrotoxicity.
• Several modifications in the chemical structure with numerically designated
derivatives 2, 3, 6, 7, 8, 9 and 10 have been studied in animals.
• Each ligand’s iron-clearing efficacy (ICE), tissue distribution, biliary ferrokinetics
and tissue iron reduction profile are being analyzed in both models.
• Once the appropriate molecule has been synthesized, there is hope that it will
move into human clinical trials.

54. Dr Hasmukh R Balar

55. Dr Hasmukh R Balar
Starting and adjusting chelation therapy:
what do the guidelines say?
• In thalassemia major, chelation therapy is usually initiated in children 2 years of age or older
who have received 10 units of RBCs and/or have a serum ferritin level above 1000 ng/mL on
at least 2 measurements (not obtained when ill). This level of iron overload typically occurs
after 1-2 years of transfusions.
TIF guidelines: Published by TIF in 2014 recommend
• DFO at a dose of 20–40 mg/kg/day five to seven times per week as a first line in
children of age 2–6 years.
• DFX (20–40 mg/kg/day) may be used as first line in US and as second line in
Europe when therapy with DFO is inadequate or contraindicated.
• The same recommendations apply for children older than 6 years and adults,
except that the dose of DFO may reach 60 mg/kg/day. Moreover, in patients older
than 6 years, DFP may be used at 75–100 mg/kg/day if other agents are not
tolerated or effective.
• Also recommends intensive 24-hour therapy with DFO (50–60 mg/kg/day) in case
of a persistently high SF or LIC .15 mg/g dw.
• Significant heart disease may be treated by intensive DFO therapy or combination
therapy with DFP + DFO.

56. Dr Hasmukh R Balar
Multiple methods of assessing the
degree of iron overload
• Serum ferritin levels,
• Liver iron concentration by biopsy,
superconducting quantum interference device
(SQUID), and magnetic resonance imaging
(MRI), and
• Cardiac iron loading assessed by MRI
Each method has benefits and limitations, and
often combinations of these tests are used to
monitor iron burden.

57. Dr Hasmukh R Balar
Maintenance therapy
• Maintenance therapy is adjusted to prevent tissue damage because of
iron overload.
• ALIC 15 mg/g dry weight, serum ferritin 2500 g/L or cardiac T2* MRI
20 ms indicate inadequate chelation.
• If cardiac iron overload is present (T2* 20 ms), cardiac iron removal
becomes the primary goal of therapy.
• All patients may not be satisfactorily chelated on DFO, DFP, or DFX
alone. In many, the dose or frequency of DFO infusions must be
revised or the patient switched to another chelator or switched to
combined therapy (eg, of DFO with DFP).
• The iron intake from blood can also be reduced in TM patients by
splenectomy if blood requirements are unusually high ( 200- 220 mL
packed red cells/kg/year).

58. Dr Hasmukh R Balar
 Desferrioxamine: 13% (10%–17%) efficient when given at 25–50 mg/kg over
8–10 hours, 5 times per week1
 Deferiprone: 4% of administered dose eliminated in urine bound to iron
at 25 mg/kg/day, 3 times daily2
 Deferasirox: 27% of drug eliminated in iron-bound form when given at
10–30 mg/kg/day, once daily1
1. Porter J, et al. Blood. 2005;106:abstr 2690.
2. Hoffbrand V, et al. Blood. 2003;102:17.
Efficiency of Chelation Therapy
• Definition
– Proportion of administered drug that is eliminated in iron-bound forms
• How calculated
– Formal iron balance studies
– Iron excretion or change in body iron (LIC) relative to dose and
transfusion rate

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Pediatric patients
Chelation strategies in the adult TM population can be applied in children with
special considerations as follows.
• Initially in children a dose of DFO 20-30 mg/kg per day is used to avoid toxicity
with a maximum dose of 40 mg/kg in children whose growth has ceased.
• Close monitoring of growth and bone development is needed if DFO is started at
age 3 years.
• In the United States (FDA), DFX can also be used to initiate treatment in children
as young as 2 years, commencing at a dose of 20 mg/kg.
• In Europe (European Medicines Evaluation Agency), DFX is only approved as a
second-line drug for children younger than 6 years.
• DFX has also had no reported adverse effect on children’s growth or on
adolescent sexual development in both patients with TM and SCD. However,
monitoring for renal toxicity in children is particularly important.
• A recent study of DFP therapy found that, with the newly introduced liquid
formulation, the efficacy and safety profile in 100 children 1-10 years of age was
similar to that in older children or adults.
• In developing countries, cost and compliance considerations may make DFP a
first choice for children.

64. Dr Hasmukh R Balar
Pregnancy
• DFO is the only chelating drug that can be used in pregnancy.
• It should be interrupted during the first trimester and can be used in the
second and third trimesters.
• A continuous intravenous infusion of DFO (50 mg/kg over 24 hours)
can be given before a planned pregnancy.
• DFP and DFX should be stopped in pregnancy and during breast
feeding.
• Sexually active patients receiving DFX or DFP should use
contraception.

65. Dr Hasmukh R Balar
Non transfusion-dependent thalassemia
(NTDT)
• NTDT describes patients with genetic disorders of hemoglobin synthesis who are not sufficiently
severe to warrant regular blood transfusions but are more severely anemic than patients with
thalassemia trait.
• Many different genotypes underlie NTDT, thalassemia intermedia, hemoglobin E/ thalassemia,
hemoglobin H, and hemoglobin E/ thalassemia being the most common.
• The patients become progressively iron loaded with increasing age mainly through increased iron
absorption. In some patients, transfusions often given at times of infections, during pregnancy or
to avoid bone complications, contribute to iron loading.
• Direct assessment of LIC by biopsy or by MRI is recommended because serum ferritin
underestimates iron load in this patient population.
• Chelation is usually started with DFO but switched to one or other oral chelator in those unable or
unwilling to comply with DFO.
• In some studies on E/-thalassemia, iron chelation with DFP has resulted in an improvement in
erythropoiesis and hemoglobin levels.
• Clear guidelines are not available, but we can use an LIC 7 mg/g dry weight as an indicator to
start iron removal.
• Preliminary data show that DFX is safe and removes iron in TI patients.99, A large 1-year
randomized, double blind, placebo controlled phase 2 prospective study on 166 NTDT patients
reported DFX to be both safe and efficacious.
• Venesections not recommend to reduce iron burden because these may aggravate bone
abnormalities by increasing anemia.

66. Dr Hasmukh R Balar
• DFX 10 mg/kg/day (escalated to max: 30 mg/kg/day) resulted in significant and
clinically relevant reductions in iron overload, with a similar safety profile as reported
in THALASSA study; Taher et al Blood 2012;120:970–977 (in both DFX- and
placebo-treated patients). With early dose escalation at week 4 with further
adjustment at week 24, patients with a higher iron burden received higher DFX doses.
These results support early dose escalation of DFX to optimize chelation in more
heavily iron-overloaded patients with non-transfusion-dependent anemias.

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Conclusions
• Ease of administration, ensuring compliance, is an important property in
choosing an iron chelator.
• DFX at dose of 30 mg is efficacious and safe with newer dosing being
studied (up to 40 mg).
• Treatment of iron overload may initially require higher doses to achieve
iron balance.
• Maintaining iron balance with “safe” tissue iron levels may require lower
dose levels.
• Dosage for an individual patient is determined by number of blood
transfusions received and patient’s iron burden.
• Randomized, controlled trials comparing deferiprone and deferasirox
monotherapy are needed.
• Similarly, carefully controlled comparison of combination therapies
(DFP-DFO, DFX-DFO, DFX-DFP) must also be evaluated

68. Dr Hasmukh R Balar
“The most important key of chelation success factor is;
Compliance, Compliance & Compliance”
Thank you