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

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1 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 CHILDREN S HOSPITAL OF LOS ANGELES, CALIFORNIA

2 Data From Corinth Thalassaemia Unit, General Hospital of Corinth, Greece From the year 2000 patients were changed from desferrioxamine monotherapy to combination therapy with desferrioxamine plus deferiprone

3 The Effect of Combined Chelation on Total Body Iron Overload The results of 90% of compliant patients ( n=45) N=45 Reference Before After p Serum Ferritin g/l 3, < MRI T 2 Liver >33 ms 22.7 severe 37.2 Iron free LIC Ferriscan <0,8 mg/g dw Iron free MRI T 2 Heart >35 ms 28.2 moderate 38.1 Iron free < < < Farmaki et al. Br J Hematol, 2010;148(3):466-75

4 Baseline NYHA Cardiac Classification Farmaki et al, British Journal of Hematology, 2010;148(3): 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

5 After Combined Chelation Significant Improvement of Glucose Metabolism Abnormalities Glucose Metabolism N=50 Before After Insulin dependent Diabetes 6 6 Insulin requirements Type II Diabetes: Glucose 0 >126mg/dl & 120 >200mg/dl) IGΤ Impaired Glucose Tolerance: Glucose 120 >140<200mg/dl IFG Impaired Fasting Glucose: Glucose 0 >100<126mg/dl 14 Reversal in 9 (64%) 16 Reversal in 10 (63%) 3 Reversal in 3 (100%) NORMAL GLUCOSE METABOLISM Farmaki et al, BrJ Hematol, 2010;148(3):466-75

6 Hypogonadism (40-91%)

7 Farmaki et al, British J of Hematology, 2010;148(3): Reversal of Male Hypogonadism after Combined Chelation 24 males 14 on testosterone replacement therapy Abnormal Testosterone & GnRH test: LH, FSH 7 (50%) stopped testosterone after FSH improvement. Correlated with decrease Ferritin, MRI, LIC 10 without HRT Normal Testosterone: 5,7 & GnRH test: LH, FSH No new cases of hypogonadism Mean Testosterone increased significally: 7,8 (p<0.001) GnRH test: LH (p=0.05)

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

9 Farmaki et al, British J Hematology, 2010;148(3): Females Before 19 on Hormone replacement Θ 9 Primary amenorrhea 10 Secondary amenorrhea 8 without HRT Normal Estradiol, LH, FSH After 6 hypogonadal (2 with primary & 4 with secondary amenorrhea) gave birth to 6 children. 2 with normal conception and 4 with IVF. No new cases of hypogonadism 2 eugonadal gave birth to 2 children with normal conception

10 Hypothyroidism (5-30%)

11 Farmaki et al, British J of Hematology, 2010;148(3): Reversal of Hypothyroidism after Combined Chelation 51 patients mean age 30 years 18 Hypothyroid with HRT TSH > 5 μiu/ml, FT4 N or Abnormal TRH test 33 Euthyroid Normal TSH & FT4 Normal TRH test Thyroxin discontinued in 10 (56%) with normal TSH= 4.12 ± 0.63 μiu/ml & normal FT4 = 1.1 ± 0.02 ng/ml and Thyroxin reduced in 4 (22%) No new cases of hypothyroidism Normal TRH test FT4 increased p<0.05

12 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/mm 3 and the other 1000/mm 3 ; 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 ( /mm 3 ). 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.

13 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

14 Intensive Combined Chelation: SC Desferal: 40 mg/kg/day Ferriprox: 100 mg/kg/day Because of Cardiac dysfunction & Diabetes

15 Reversal of cardiac dysfunction and discontinuation of ACE Inhibitors 70 DFO+DFP LVEF % MRI T2*H (msec)

16 Patient s Iron load after combined chelation (DFO + DFP) DFO+DFP FERRITIN (μg/l) MRI T2*L (msec)

17 Recurrence of Glucose metabolism abnormalities with decreased compliance DFO+DFP 2274 Diabetes:2h glucose >200 IGT: 2h Glucose >140 <200 Compliance Normal 2h Glucose < T2*L:12,4 LIC:2, FERRITIN (μg/l) 2h Glucose OGTT (mg/dl)

18 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 Also in countries where the drug has been available for many years very low ferritins have been achieved Personal communications from colleagues in Turkey

19 Conclusion 1 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.

20 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.

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22 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

23 Intensive Combined Chelation: SC Desferal: 40 mg/kg/day Ferriprox: 100 mg/kg/day

24 Dramatic decrease in patient s iron load after combined chelation (DFO + DFP) DFO+DFP ,2 30,2 25,2 20, ,2 10,2 5,2 0,2 FERRITIN (μg/l) MRI T2*L (msec)

25 Reversal of cardiac dysfunction after combined chelation Cardiac Disease SPLENECTOMY LVEF % MRI T2*H (msec)

26 Glucose metabolism abnormalities fluctuated & he receives oral antidiabetic treatment Diabetes: 2h Glucose > IGT: 2h Glucose >140 <200 Normal Glucose Tolerance < FERRITIN (μg/l) 2h Glucose (mg/dl)

27 Combined chelation ameliorated his Hypogonadism Testo ng/ml LH 0 LH 30 LH 60 LH 90 FSH 0 FSH 30 FSH 60 FSH 90 Bf 0,6 1,2 0,5 0,8 0,9 0,9 0,9 1,2 1,1 After 5,4 3,7 5,3 5,8 5,3 5,3 5,2 5,6 5 From beardless, now he has a goatee and has progressed to Tanner stage 5