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
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
The Effect of Combined Chelation on Total The Effect of Combined Chelation on Total Body Iron Overload Body Iron Overload The results of 90% of compliant patients ( n=45 ) After N=45 Reference Before p 80-120 g/L 3,421 Serum Ferritin 87 <0.0001 >33 ms 22.7 MRI T 2 Liver 37.2 <0.0001 severe Iron free <0,8 mg/g dw 12.7 0.8 LIC Ferriscan™ <0.0001 Iron free >35 ms 28.2 38.1 MRI T 2 Heart <0.0001 moderate Iron free Farmaki et al. Br J Hematol, 2010;148(3):466-75
NYHA Cardiac Classification Farmaki et al, British Journal of Hematology, 2010;148(3):466-75 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
After Combined Chelation After Combined Chelation Significant Improvement of Glucose Significant Improvement of Glucose Metabolism Abnormalities Metabolism Abnormalities Glucose Metabolism N=50 Before After Insulin dependent Diabetes 6 6 Insulin requirements Type II Diabetes: Glucose 14 Reversal 0΄>126mg/dl & 120’>200mg/dl) in 9 (64%) IGΤ Impaired Glucose Tolerance: 16 Reversal Glucose 120’>140<200mg/dl in 10 (63%) IFG Impaired Fasting Glucose: 3 Reversal Glucose 0΄>100<126mg/dl in 3 (100%) NORMAL GLUCOSE METABOLISM 11 33 Farmaki et al, BrJ Hematol, 2010;148(3):466-75
Hypogonadism Hypogonadism (40-91%) (40-91%)
Reversal of Male Hypogonadism after Reversal of Male Hypogonadism after Combined Chelation Combined Chelation 24 males 24 males 10 without HRT Normal Testosterone: 5,7 14 on testosterone & GnRH test: LH, replacement therapy FSH Abnormal Testosterone & GnRH test: LH, FSH No new cases of hypogonadism 7 (50%) stopped testosterone after FSH improvement . Mean Testosterone increased Correlated with decrease significally: 7,8 ( (p p<0.001) <0.001) Ferritin, MRI, LIC GnRH test: LH (p=0.05) Farmaki et al, British J of Hematology, 2010;148(3):466-75
One of the male patients became One of the male patients became the father of twins without IVF the father of twins without IVF
27 Females 27 Females 19 on Hormone replacement Θ 8 without HRT Before 9 Primary amenorrhea Normal Estradiol, 10 Secondary amenorrhea LH, FSH 6 hypogonadal ♀ (2 with No new cases of hypogonadism primary & 4 with secondary 2 eugonadal ♀ gave birth to 2 amenorrhea) gave birth to 6 After children with normal conception children. 2 with normal conception and 4 with IVF. Farmaki et al, British J Hematology, 2010;148(3):466-75
Hypothyroidism Hypothyroidism (5-30%) (5-30%)
Reversal of Hypothyroidism after Reversal of Hypothyroidism after Combined Chelation Combined Chelation 5 51 1 patients mean age 30 years patients mean age 30 years 18 Hypothyroid with HRT 33 Euthyroid ↘ FT4 N or ↘ TSH > 5 μIU/ml, FT4 N or Normal TSH TSH & FT4 FT4 TSH > 5 Normal Abnormal TRH test Normal TRH test Thyroxin discontinued in 10 ( (56 56%) %) with No new cases of normal TSH= TSH= 4.12 ± 0.63 4.12 ± 0.63 μIU/ml hypothyroidism & normal FT4 = FT4 = 1.1 ± 0.02 1.1 ± 0.02 ng/ml Normal TRH test and Thyroxin reduced in FT4 increased p<0.05 FT4 increased 4 (2 (22 2%) %) Farmaki et al, British J of Hematology, 2010;148(3):466-75
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 (800- 1.200/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.
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
Intensive Combined Chelation: SC Desferal: 40 mg/Kg/day Ferriprox: 100 mg/Kg/day Because of Cardiac dysfunction & Diabetes
Reversal of cardiac dysfunction and discontinuation of ACE Inhibitors 67 DFO+DFP 66 66 70 40 64 63 63 61 59 35 56 60 50 30 50 45 25 40 20 30 15 20 10 10 5 0 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 LVEF % MRI T2*H (msec)
Patient’s Iron load after combined chelation (DFO + DFP) 2500 40 2274 DFO+DFP 35 2000 30 25 1500 20 1000 807 15 10 500 307 281 193 180 175 5 138 125 83 21 0 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 FERRITIN (μg/l) MRI T2*L (msec)
Recurrence of Glucose metabolism abnormalities with decreased compliance DFO+DFP 2500 250 2274 ↘ Compliance Diabetes:2h glucose 2000 200 >200 IGT: 2h Glucose >140 <200 1500 150 T2*L:12,4 1000 100 807 Normal 2h LIC:2,3 Glucose <140 500 50 307 281 193 180 175 138 125 83 21 0 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 FERRITIN (μg/l) 2h Glucose OGTT (mg/dL)
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
Conclusion 1 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.
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.
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 o perated 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
Intensive Combined Chelation: SC Desferal: 40 mg/Kg/day Ferriprox: 100 mg/Kg/day
Dramatic decrease in patient’s iron load after combined chelation (DFO + DFP) 2362 2500 35,2 DFO+DFP 30,2 2000 25,2 1408 1500 20,2 15,2 1000 10,2 500 270 5,2 111 79 72 73 60 63 62 51 0 0,2 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 FERRITIN (μg/l) MRI T2*L (msec)
Reversal of cardiac dysfunction after combined chelation Cardiac SPLENECTOMY Disease 70 40 63 63 63 61 59 58 57 57 35 60 55 55 54 30 50 45 25 40 20 30 15 20 10 10 5 0 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 LVEF % MRI T2*H (msec)
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