Nuovi Approcci alla Ferrochelazione

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1 Il Deficit di PKD 1 patient day Nuovi Approcci alla rrochelazione M. Domenica Cappellini Fondazione Ca Granda Policlinico Università di Milano Milano May

2 Genetic and acquired iron overload Genetic iron overload Not associated with anaemia haemochromatosis type1 (HFE) haemochromatosis type 2 or juvenile (HAMP, HJV) haemochromatosis type 3 (TFR2) haemochromatosis type 4 (FPN) Associated with anaemia atransferrinaemia DMT1 deficiency aceruloplasminaemia Acquired iron overload Chronic blood transfusions Iron-loading anaemias (congenital) β-thalassaemia intermedia CDA, sideroblastic anaemia haemolytic anaemias (SCD, PKU, spherocytosis) Iron-loading anaemias (acquired) MDS (RARS) Inappropriate parenteral iron therapy CDA = congenital dyserythropoietic anaemia; PKU = phenylketonuria; RARS = refractory anaemia with ringed sideroblasts; SCD = sickle cell disease. Pietrangelo A. Hepatology. 2007;46:

3 Normal iron distribution and storage Utilization Duodenum (average, 1 2 mg per day) Dietary iron Utilization Muscle (myoglobin) (300 mg) Transferrin Storage iron Functional iron pool Transferrin Circulating erythrocytes (hemoglobin) (1800 mg) Bone marrow (300 mg) Liver (1000 mg) Sloughed mucosal cells Desquamation/menstruation Other blood loss (average, 1 2 mg per day) Iron loss Andrews NC. N Engl J Med 1999;341: , Massachusetts Medical Society, with permission Reticuloendothelial macrophages (600 mg)

4 Iron overload in different anemias Mechanisms: Transfusion Increased absorption Inappropriate parenteral therapy There is no physiologic process for excreting excess iron Increased iron intake = iron overload

5 Transfusion therapy results in iron overload Transfusions 2 units/month 24 units/year ~ 100 units/4 years: 20 g iron mg iron Body iron storage normal: 3 4 g hereditary haemochromatosis: g ~ 90% of all MDS patients become transfusiondependent

6 Iron disequilibrium in trasfused patients Transfusions GI system Liver Blood (RBC + transferrin + NTBI) RE system Heart Endocrine organs NTBI, non-transferrin-bound iron; RE, reticuloendothelial Taher A, et al. Br J Haematol 2009;147:

7 Iron disequilibrium in Iron Loading Anemias GI system Liver Blood (RBC + transferrin + NTBI) RE system Heart Endocrine organs RE, reticuloendothelial Taher A, et al. Br J Haematol 2009;147:

8 Transferrin saturation % Iron overload and organ loading Transferrin saturation due to Frequent blood transfusions, or Ineffective erythropoiesis leading to increased iron absorption Subsequent formation of NTBI in plasma Uncontrolled iron loading of organs Pituitary 100% Normal: no NTBI produced Iron overload Parathyroid Thyroid Heart Liver Pancreas Gonads 30% NTBI = non-transferrin-bound iron.

9 Organ systems affected by iron overload Organ 1,2 Pituitary Thyroid Parathyroid Heart Liver Pancreas Gonads Bones Consequences Hypogonadotropic Hypogonadism Hypothyroidism Hypoparathyroidism Cardiomyopathy Cirrhosis, carcinoma Diabetes Hypogonadotropic Hypogonadism Osteomalacia Osteoporosis These tissues share L-type calcium-dependent channels for NTBI uptake 3 1. Taher A et al. Semin Hematol 2007;44:S2 S6. Review. 2. Ebrahimpour L et al. Hematology 2012;17: Prospective cross-sectional study; n= Oudit GY et al. Nat Med 2003;9: Animal study.

10 What is chelation therapy? Iron chelators reduce body iron by complexing and enabling excretion of free iron Chelator Metal Metal Excretion Cabantchik ZI et al. Best Pract Res Clin Haematol 2005;18: Review.

11 Evolution of iron chelators 1960s DFO came into clinical use 2006 DFX approved by EMEA 2012 FBS0701 Phase II results s to 1980s s 2000s 2010s Subcutaneous DFO 1999 DFP approved by EMEA 2005 DFX approved by FDA 2011 DFP approved by FDA DFO, deferoxamine; DFP, deferiprone; DFX, deferasirox; EMEA, European Medicines Agency; FDA, US Food and Drug Administration 1. Neufeld EJ et al. Blood 2012;119: Multicenter, openlabel, randomized, Phase II study; n=73.

12 Chelators and coordination with iron DFO Hexadentate (1:1) High MW DFX Tridentate (2:1) Low MW DFP Bidentate (3:1) Low MW OH 2 N COO - N H 2 N-(H 2 C) 5 N O H 2 O H 2 O NH F e O OH 2 OH 2 HN OH 2 N O H 2 O H 2 O N N OH 2 F e OHO 2 OH 2 OH 2 N H 2 O H 2 O OH 2 F e OH 2 OH 2 OHO 2 N N N - OOC MW, molecular weight Nick H et al. Curr Med Chem 2003;102: Review.

13 Overview of iron chelators: licensed indications and contraindications Property DFO 1 DFP 2 DFX 3 Therapeutic indications Chronic iron overload due to transfusional hemosiderosis (eg in patients with TM) or primary or secondary hemochromatosis in patients who can not undergo phlebotomy (eg because of severe anemia, hypoproteinemia, or renal or cardiac failure) Iron overload in patients with TM when DFO therapy is contraindicated or inadequate Chronic iron overload due to blood transfusions in patients aged 2 years; chronic iron overload in patients aged 10 years with NTDT and with a LIC of 5 mg /g dw and a serum ferritin >300 ng/ml Contraindications Hypersensitivity to DFO; patients with severe renal disease or anuria Hypersensitivity to DFP or excipients; Henoch Schonlein purpura, urticaria and periorbital edema with skin rash have been reported Hypersensitivity to DFX or excipients; serum creatinine >2 ULN or creatinine clearance <40 ml/min; poor performance status; high-risk MDS, advanced malignancies; platelet counts < /L Please refer to prescribing information in your country of practice. liver iron concentration; MDS, myelodysplastic syndromes; NTDT, non-transfusion-dependent thalassemia; TM, thalassemia major; ULN, upper limit of normal 1. Desferal (deferoxamine) US Prescribing Information. 2011; 2. rriprox (deferiprone) US Prescribing Information. 2012; 3. EXJADE (deferasirox) US Prescribing Information

14 Overview of iron chelators: pharmacokinetic profiles Property DFO 1 DFP 2 DFX 3 Daily dose mg/kg mg/kg mg/kg Administration Half-life SC (also IV, IM); 8 12 hours, 5 7 days/week First phase: 1 hour Second phase: 6 hours Oral; TID Oral; QD 2 3 hours 8 16 hours Lipid solubility 4 Low Intermediate High Excretion Urinary, fecal Urinary cal Efficiency 10 17% efficient when given at mg/kg over 8 10 hours, 5 7 days/week 4 4% of administered dose eliminated in urine bound to iron at 25 mg/kg/day, TID 5 27% of drug eliminated in iron-bound form when given at mg/kg/day, QD 4 Please refer to prescribing information in your country of practice. IM, intramuscular; IV, intravenous; QD, once daily; SC, subcutaneous; TID, three times daily 1. Desferal (deferoxamine) US Prescribing Information. 2011; 2. rriprox (deferiprone ) US Prescribing Information. 2012; 3. EXJADE (deferasirox) US Prescribing Information. 2013; 4. Porter J et al. Blood 2005;106(11):abst 2690; 5. Hoffbrand AV et al. Blood 2003;102:17 24.

15 Iron-bound DFO is excreted in urine and feces Bile Plasma Storage Macrophage Hepatocyte Kidney ces Urine Cohen AR and Porter JB. In: Steinberg MH, et al. editors. Disorders of hemoglobin: genetics, pathophysiology, and clinical management. Cambridge: Cambridge University Press; 2001.

16 Iron-bound DFP is excreted exclusively in urine Bile Plasma Storage Macrophage Hepatocyte Kidney ces Urine Cohen AR and Porter JB. In: Steinberg MH, et al. editors. Disorders of hemoglobin: genetics, pathophysiology, and clinical management. Cambridge: Cambridge University Press; 2001.

17 Iron-bound DFX is excreted primarily in feces Bile Plasma Storage Macrophage Hepatocyte ces Kidney Urine Cohen AR and Porter JB. In: Steinberg MH, et al. editors. Disorders of hemoglobin: genetics, pathophysiology, and clinical management. Cambridge: Cambridge University Press; 2001.

18 Rare transfusion-dependent anemias Not hemoglobinopathies or MDS Production anemias Pure red cell aplasia Fanconi anemia Diamond-Blackfan anemia (DBA) Acquired aplastic anemia Myelofibrosis Hemolytic anemias Pyruvate kinase deficiency (PKD) Erythropoietic protoporphyria Chronic autoimmune hemolytic anemia Dyserythropoietic anemias Congenital dyserythropoietic anemia (CDA) types I and II

19 Cardiac iron load in different transfusion-dependent anaemias UCLH patients with cardiac MRI SCD MDS DBA PK deficiency Congenital sideroblastic TI TM Patients (%) with T2* < 20 ms MRI = magnetic resonance imaging; PK = pyruvate kinase; UCLH = University College London Hospital. Porter JB. Am J Hematol. 2007;82:

20 Pyruvate kinase deficiency (PKD) and iron overload Serum ferritin > ULN in 60% non-transfused patients Liver fibrosis and siderosis in 8/9 Cirrhosis in 2 who died age 39 and 42 years Serum ferritin is independent of age, gender, haemolysis Splenectomy is a risk factor for iron overload HLA-A3-positive patients had higher iron overload than non-hla-a3 patients ULN = Upper limit of normal. Zanella A, et al. Br J Haematol. 1993;83:

21 Iron overload in DBA Retrospective study of 31 transfusion-dependent DBA patients 54% had severe liver iron overload (LIC >15 mg /g dw) Mean LIC: 13.4 ± 6.8 mg /g dw (range ) 23% had 1 iron-related complications Hypothyroidism (4) Hypogonadism (4) Hypoparathyroidism (1) Diabetes mellitus (2) Heart disease (2) Roggero S, et al. Am J Hematol 2009;84:

22 Iron overload in CDA types I and II CDA type I CDA type II (HEMPAS) Transfusion dependent Serum ferritin Complications Usually not after age 4 months 500 1,500 ng/ml by adult age (increased absorption) Hyperbilirubinemia and gallstones Splenomegaly (80 90%) 10% 40% >1,000 ng/ml by age 50 Hyperbilirubinemia and gallstones especially with Gilberts co-inheritance Paravertebral tumours rarely Liver cirrhosis (20%) 22

23 Iron status in adults with CDA type I Case Age (years) Group A (Hb < 10 g/dl) Serum (mmol/l) TIBC (mmol/l) Transferrin saturation (%) rritin (mg/l) NTBI (mmol/l) H63D mutation Neg 2* , Neg 3* , Neg Group B (Hb > 10 g/dl) Neg 5* Neg 6* Neg Homozygous *Cases 2, 3, 5, and 6 were previously treated with deferoxamine or deferoxamine plus venesections for 1, 0.7, 3, and 9 years, respectively. All cases were C282Y mutation negative. Wickramasinghe SN, et al. Br J Haematol 1999;107:

24 Iron overload in aplastic anemia Blood transfusions are the main supportive therapy in patients with AA 1 Iron overload secondary to blood transfusion therapy in 292 patients with various types of anemia, including 90 patients with AA, has been shown to correlate with 2 increased cardiac dysfunction increased hepatic dysfunction increased death To prevent these sequelae, regularly transfused patients require iron chelation therapy 3 iron chelation therapy should be considered when serum ferritin is >1,000 ng/ml 4 AA, aplastic anemia 1. Marsh JC, et al. Br J Haematol. 2003;123: Takatoku M, et al. Eur J Haematol. 2007;78: Kushner JP, et al. Hematology ASH Educ Program. 2001: Marsh JC, et al. Br J Haematol. 2009;147:43 70.

25 EPIC: response to chelation in patients with rare transfusion-dependent anaemias 57 patients with RTDAs 34 production anaemias pure red cell aplasia (n = 20) DBA (n = 14) 23 haemolytic anaemias haemolytic anaemia of uncharacterized cause (n = 11) pyruvate kinase deficiency anaemia (n = 5) autoimmune haemolytic anaemia (n = 4) congenital erythropoietic protoporphyria (n = 2) hereditary haemolytic anaemia (n = 1) RTDA = rare transfusion-dependent anaemia. Porter JB, et al. Eur J Haematol. 2011;87:

26 Iron measures in production and haemolytic anaemias Production anaemias (n = 34) Haemolytic anaemias (n = 23) All patients (N = 57) Mean ± SD iron intake rate, mg/kg/day 0.34 ± 0.14 (n = 30) 0.33 ± 0.24 (n = 20) 0.33 ± 0.18 (n = 50) Median baseline serum ferritin (range), µg/l 2,926 (908 10,861) (n = 33) 2,682 (568 13,078) (n = 22) 2,916 (568 13,078) (n = 56) Porter JB, et al. Eur J Haematol. 2011;87:

27 Median serum ferritin (µg/l) SF levels after deferasirox therapy in production and haemolytic anaemias 6,500 5,500 4,500 3,500 2,500 1, Haemolytic anaemias Production anaemias Mean deferasirox dose Mean deferasirox dose (mg/kg/day) 500 Baseline Time (months) PDA, n: HA, n: All patients, n: Porter JB, et al. Eur J Haematol. 2011;87:

28 Summary Acquired iron overload can occur through transfusions, increased absorption or inappropriate parenteral iron Iron overload leads to development of toxic iron species, which cause tissue damage Iron overload is associated with complications such as cardiac failure, endocrinopathies and liver dysfunction Different anemias have different tissue iron distribution 29