How far one should go with iron chelation in thalassemia? Is iron - - PowerPoint PPT Presentation

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How far one should go with iron chelation in thalassemia? Is iron deficiency indicated? DR. KALLISTHENI FARMAKI THALASSAEMIA UNIT GENERAL HOSPITAL OF CORINTH, GREECE VASILI BERDOUKAS PEDIATRIC HEMATOLOGIST DIVISION OF HEMATOLOGY ONCOLOGY

SLIDE 1

DR. KALLISTHENI FARMAKI

THALASSAEMIA UNIT GENERAL HOSPITAL OF CORINTH, GREECE VASILI BERDOUKAS PEDIATRIC HEMATOLOGIST DIVISION OF HEMATOLOGY ONCOLOGY CHILDREN’S HOSPITAL OF LOS ANGELES, CALIFORNIA

How far one should go with iron chelation in thalassemia? Is iron deficiency indicated?

SLIDE 2

Data From Corinth

Thalassaemia Unit, General Hospital of Corinth, Greece (kallistheni.farmaki@gmail.com)

From the year 2000 patients  were changed from desferrioxamine monotherapy  to combination therapy with desferrioxamine plus deferiprone

SLIDE 3

N=45 Reference Before

After

p Serum Ferritin 80-120 g/L 3,421

87 <0.0001 MRI T2Liver >33 ms 22.7

severe

37.2

Iron free

<0.0001 LIC Ferriscan™ <0,8 mg/g dw 12.7

0.8

Iron free

<0.0001 MRI T2Heart >35 ms 28.2

moderate

38.1

Iron free

<0.0001 The results of 90% of compliant patients ( n=45)

The Effect of Combined Chelation on Total The Effect of Combined Chelation on Total Body Iron Overload Body Iron Overload

Farmaki et al. Br J Hematol, 2010;148(3):466-75

SLIDE 4

NYHA Cardiac Classification

Baseline After 7 years of combined treatment Normal LVEF 63% (n=34) LVEF 72% (p<0.001) Class I 6 All normal Class II 7 All normal Class III 3 2 Normal 1 Class I Class IV 2 Class II LVEF in Class I-IV 54% 67% (p<0.001 Farmaki et al, British Journal of Hematology, 2010;148(3):466-75

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Glucose Metabolism N=50 Before After Insulin dependent Diabetes 6 6  Insulin requirements Type II Diabetes: Glucose 0΄>126mg/dl & 120’>200mg/dl) 14 Reversal in 9 (64%) IGΤ Impaired Glucose Tolerance: Glucose 120’>140<200mg/dl 16 Reversal in 10 (63%) IFG Impaired Fasting Glucose: Glucose 0΄>100<126mg/dl 3 Reversal in 3 (100%) NORMAL GLUCOSE METABOLISM 11 33

After Combined Chelation After Combined Chelation   Significant Improvement of Glucose Significant Improvement of Glucose Metabolism Abnormalities Metabolism Abnormalities

Farmaki et al, BrJ Hematol, 2010;148(3):466-75

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Hypogonadism Hypogonadism

(40-91%) (40-91%)

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Reversal of Male Hypogonadism after Reversal of Male Hypogonadism after Combined Chelation Combined Chelation

14 on testosterone replacement therapy Abnormal Testosterone & GnRH test: LH, FSH 7 (50%) stopped testosterone after FSH improvement.

Correlated with decrease Ferritin, MRI, LIC

24 males 24 males

10 without HRT Normal Testosterone: 5,7 & GnRH test: LH, FSH No new cases of hypogonadism Mean Testosterone increased significally: 7,8 ( (p p<0.001) <0.001) GnRH test: LH (p=0.05)

Farmaki et al, British J of Hematology, 2010;148(3):466-75

SLIDE 8

One of the male patients became One of the male patients became the father of twins without IVF the father of twins without IVF

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19 on Hormone replacement Θ 9 Primary amenorrhea 10 Secondary amenorrhea 6 hypogonadal ♀ (2 with primary & 4 with secondary amenorrhea) gave birth to 6

children. 2 with normal

conception and 4 with IVF.

27 Females 27 Females

8 without HRT Normal Estradiol, LH, FSH No new cases of hypogonadism 2 eugonadal ♀ gave birth to 2 children with normal conception

Farmaki et al, British J Hematology, 2010;148(3):466-75

Before After

SLIDE 10

Hypothyroidism Hypothyroidism (5-30%) (5-30%)

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5 51 1 patients mean age 30 years patients mean age 30 years

18 Hypothyroid with HRT TSH > 5 TSH > 5 μIU/ml, FT4 N or FT4 N or ↘ ↘ Abnormal TRH test 33 Euthyroid Normal Normal TSH TSH & FT4 FT4 Normal TRH test

Thyroxin discontinued in 10 ( (56 56%) %) with normal TSH= TSH= 4.12 ± 0.63 4.12 ± 0.63 μIU/ml & normal FT4 = FT4 = 1.1 ± 0.02 1.1 ± 0.02 ng/ml and Thyroxin reduced in 4 (2 (22 2%) %) No new cases of hypothyroidism Normal TRH test FT4 increased FT4 increased p<0.05

Reversal of Hypothyroidism after Reversal of Hypothyroidism after Combined Chelation Combined Chelation

Farmaki et al, British J of Hematology, 2010;148(3):466-75

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Adverse events with low LIC and Ferritin



Two non splenectomised patients withdrew from the study because of repeated episodes of neutropenia.

 The episodes appeared at 14 and 18 months after the start of combined

chelation.

 One patient had an ANC of approximately 500/mm3 and the other 1000/mm3;  The former patient presented with tonsillitis, which was managed only with

antibiotics and continued CBC monitoring. DFP therapy was interrupted for one year after which re-challenge was attempted, leading to a mild neutropenia (800- 1.200/mm3).

 Both patients refused to continue the study protocol.



Patients were advised to reduce their DFP dose temporarily in the event of:

 Joint symptoms (reported in 5% of patients),  Gastrointestinal Symptoms (8%) or  Increase in liver enzymes (11%).



DFO was transiently interrupted for 1-2 months in the case of tinnitus (1 patient - 2%) and ocular problems (1 patient - 2%) which reversed, in both cases.

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Case report: Medical history



Female, thalassaemia major, 32 years



Started transfusions at the age of 1 yr and chelation with SC Desferal at 3 yr



Short stature:1.52m (-3SD growth chart percentile) but normal pubertal maturation (Tanner 5)



Cardiac dysfunction at the age of 18 yr



Diabetes at the age of 21 yr



Hypothyroidism treated with thyroxin



Hypogonadism treated with HRT

SLIDE 14



SC Desferal: 40 mg/Kg/day



Ferriprox: 100 mg/Kg/day Because of Cardiac dysfunction &

Diabetes

Intensive Combined Chelation:

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45 50 56 61 63 67 66 66 64 59 63

10 20 30 40 50 60 70 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 5 10 15 20 25 30 35 40

LVEF % MRI T2*H (msec)

Reversal of cardiac dysfunction and discontinuation of ACE Inhibitors

DFO+DFP

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2274 807 125 175 193 138 180 281 307 83 21

500 1000 1500 2000 2500 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 5 10 15 20 25 30 35 40

FERRITIN (μg/l) MRI T2*L (msec)

Patient’s Iron load after combined chelation (DFO + DFP)

DFO+DFP

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2274 807 125 175 193 138 180 281 307 83 21

500 1000 1500 2000 2500 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 50 100 150 200 250

FERRITIN (μg/l) 2h Glucose OGTT (mg/dL)

Recurrence of Glucose metabolism abnormalities with decreased compliance

Normal 2h Glucose <140

IGT: 2h Glucose >140 <200

Diabetes:2h glucose >200 DFO+DFP

↘ Compliance

T2*L:12,4 LIC:2,3

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Deferasirox

With appropriate dosage and adjustments

particularly according to the ongoing iron intake, Deferasirox can effect a significant reduction in serum ferritin from baseline (-264 ng/mL; P<0.0001).

Cappellini, et al., Haematologica 2010.
Also in countries where the drug has been available

for many years very low ferritins have been achieved

Personal communications from colleagues in Turkey

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 Prevention or/and reversal of Endocrinopathies in TMps is achieved by inducing NEGATIVE IRON BALANCE & decreasing total body iron to NORMAL LEVELS.  Intensive combined chelation by Desferal & Ferriprox improves multiple endocrine functions, particularly in the early stages of the disease. Peripheral glands as well as pituitary axis may be improved.  Both oral iron chelators can achieve very low LIC  without an increase in adverse events or new previously unreported adverse events.

Conclusion 1 Conclusion 1

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Conclusion 2 Conclusion 2

 The aim in haemochromatosis is to achieve marginal

iron deficiency.

 This results in improvement in morbidities  In thalassaemia, with the continual iron loading, it

seems we need to aim for very low body iron levels even to the level of marginal iron deficiency, to prevent new morbidities and reversal, if possible, of existing ones.

SLIDE 21

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Case report #2: Medical history



Male, thalassaemia major, 49 years



Started transfusions at the age of 4 yr and chelation with SC Desferal at 15 yr



Short stature (1.55m) -3SD growth chart percentile & abnormal pubertal maturation (Tanner stage 4)



Cardiac dysfunction (28 yr) & Pulmonary arterial hyprtension (46 yr)



Hypoparathyroidism at the age of 28 yr tt with Calcitriol



Bilateral cataract operated at the age of 30 yr



Increase of creatinine (34 yr) & Nephrolithiasis



Hypothyroidism treated with thyroxin at the age of 39 yr



Diabetes at the age of 39 yr, treated with oral antidiabetics



Hypogonadism treated with HRT (Testo IM+Restadol)



Splenectomy & cholecystectomy at the age of 45 yr

SLIDE 23

Intensive Combined Chelation:



SC Desferal: 40 mg/Kg/day



Ferriprox: 100 mg/Kg/day

SLIDE 24

2362 1408 270 72 79 73 111 60 63 62 51

500 1000 1500 2000 2500 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 0,2 5,2 10,2 15,2 20,2 25,2 30,2 35,2 FERRITIN (μg/l) MRI T2*L (msec)

Dramatic decrease in patient’s iron load after combined chelation (DFO + DFP)

DFO+DFP

SLIDE 25

45 55 57 59 63 63 54 57 55 58 61 63

10 20 30 40 50 60 70 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 5 10 15 20 25 30 35 40

LVEF % MRI T2*H (msec)

SPLENECTOMY

Reversal of cardiac dysfunction after combined chelation

Cardiac Disease

SLIDE 26

2362 1408 270 72 79 73 111 60 63 62 51

500 1000 1500 2000 2500 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 50 100 150 200 250 300

FERRITIN (μg/l) 2h Glucose (mg/dL)

Glucose metabolism abnormalities fluctuated & he receives oral antidiabetic treatment

Normal Glucose Tolerance <140 IGT: 2h Glucose >140 <200

Diabetes: 2h Glucose >200