iron chelation in beta thalassemia

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

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Page 1: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

Iron Chelation in Beta Thalassemia

Dr. Hasmukh R. BalarDepartment of HaematologySahyadri Specialty Hospital Pune

Page 2: Iron chelation in Beta thalassemia

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

Page 3: Iron chelation in Beta thalassemia

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 are1.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.

Page 4: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

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Dr Hasmukh R Balar

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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

Page 7: Iron chelation in Beta thalassemia

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.

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Dr Hasmukh R Balar

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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

Page 10: Iron chelation in Beta thalassemia

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)

NT

BI

or

DF

O (

µM

)

DFO–Control of Plasma NTBI Levels

DFO (µM)

NTBI (µM)

Intravenous continuous infusion

DFO = desferrioxamine, NTBI = non–transferrin-bound iron.

Page 11: Iron chelation in Beta thalassemia

Dr Hasmukh R BalarReprinted from Borgna-Pignatti C, et al. Haematologica. 2004;891:187, with permission from theFerrata Storti Foundation, Pavia, Italy.

Su

rviv

al P

rob

ab

ility

P < .00005

0

1.00

0.75

0.50

0.25

0 5 10 15 20 25 30

Age (years)

Birth cohort

1960–19641965–19691970–19741975–19791980–19841985–1997

DFO = desferrioxamine; TM = thalassaemia major.

DFO–Improved Survival in TM

Page 12: Iron chelation in Beta thalassemia

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†

Page 13: Iron chelation in Beta thalassemia

Dr Hasmukh R BalarDesferal [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)

Page 14: Iron chelation in Beta thalassemia

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

Page 15: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

DesferrioxamineSummary 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

Page 16: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

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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.

1999.2. Anderson LJ, et al. Lancet. 2002;360:516.

17

Page 18: Iron chelation in Beta thalassemia

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

Page 19: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

Cardioprotective Effect of Deferiprone Monotherapy?

Author n Data

Piga, 2003 1 54 DFP more effective than DFO inpreventing 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.

Page 20: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

Prospective Comparison of DFO vs DFP

Effect on Myocardial T2*M

yoca

rdia

l T2*

(g

eom

etric

mea

n ±

SE

M)

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 theAmerican 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.

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Dr Hasmukh R Balar

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Dr Hasmukh R Balar

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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.

Page 24: Iron chelation in Beta thalassemia

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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Dr Hasmukh R Balar

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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.

Page 28: Iron chelation in Beta thalassemia

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

Page 29: Iron chelation in Beta thalassemia

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.

Page 30: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

India5

2004

Lebanon4

2003

Malaysia3

2000

Turkey2

1999

London1

1998

CenterYear

Not doneMax decreaseNS from DFOLess decrease

52-

-7575

1230Rand

Not doneFall in both6/11 ≥ 2500 final

52

-75

121411

Rand

No significant fall7/9 ≥ 15 mg/g

7/9 ≥ 2500275–85129Obs

LIC 19% decrease6/7 ≥ 15 mg/g

30% decrease4/7 ≥ 2500 final

275 (4/7)

67Obs

Not done1/5 ≥ 2500 final2–688–1106–155Obs

LIC(Total Excretion)

Ferritin(μg/L)

Days DFO

DFP dose(mg/kg/d)

MonthsNDesign

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.

Page 31: Iron chelation in Beta thalassemia

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

Ch

ang

e in

Hea

rt T

2* (

ms)

Between groups:P = .02

CombinedDesferrioxamine

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Dr Hasmukh R Balar

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Page 35: Iron chelation in Beta thalassemia

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

Page 36: Iron chelation in Beta thalassemia

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.

Page 37: Iron chelation in Beta thalassemia

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

OHO

Page 38: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

0

20

40

60

80

100

0 4 8 12 16 20 24Time Postdose with Deferasirox 20 mg/kg/day (hours)

Pla

sma

Co

nce

ntr

atio

n I

ron

-Fre

e D

efer

asir

ox

(µm

ol/

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

Page 39: Iron chelation in Beta thalassemia

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 theFerrata 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

Mea

n L

PI

(µm

ol/

L)

Predose (n = 13) 2 hours postdose (n = 13)

P < .0001* P = .0119*

*Vs predose

P = .0187P = .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

Page 40: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

5 10 20 30

n = 325; R = 0.63

Ch

ang

e in

LIC

(m

g F

e/g

dw

)

-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 EffectsDose-dependent change in ferritin predicts change in LIC,

with zero change at dose of 10 mg/kg/dayDeferasirox, mg/kg/day

Page 41: Iron chelation in Beta thalassemia

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 theAmerican Society of Hematology.

Page 42: Iron chelation in Beta thalassemia

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

Ca

rdia

c T

2* m

s

9 thalassaemia major patients randomized to DFO arm; T2* pre = 18.1, post = 21.1 (not shown)

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Dr Hasmukh R Balar

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• 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)

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Page 48: Iron chelation in Beta thalassemia

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DeferasiroxSummary 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

Page 49: Iron chelation in Beta thalassemia

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.

Page 50: Iron chelation in Beta thalassemia

Dr Hasmukh R Balar

Combined therapy: DFP and DFXThree 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.

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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 DFOWere 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.

Page 53: Iron chelation in Beta thalassemia

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.

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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.

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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.

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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).

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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 at10–30 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 patientsChelation 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.

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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.

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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.

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• 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

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“The most important key of chelation success factor is;Compliance, Compliance & Compliance”

Thank you