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Indications for Successful Iron Overload Treatment and Monitoring: Thalassaemia

Indications for Successful Iron Overload Treatment and Monitoring: Thalassaemia. M. Domenica Cappellini, MD Professor of Internal Medicine University of Milan Maggiore Hospital Milan, Italy. 250. 200. 150. 100. 50. Iron Loading Rates in Thalassaemia Major and Hereditary Haemochromatosis.

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Indications for Successful Iron Overload Treatment and Monitoring: Thalassaemia

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  1. Indications for Successful Iron Overload Treatment and Monitoring: Thalassaemia M. Domenica Cappellini, MD Professor of Internal MedicineUniversity of MilanMaggiore HospitalMilan, Italy

  2. 250 200 150 100 50 Iron Loading Rates in Thalassaemia Major and Hereditary Haemochromatosis Thalassaemia major: transfusion without chelation 50 Hereditary haemochromatosis (homozygous) 40 Hereditary haemochromatosis (heterozygous) 30 Hepatic Iron (µmol/g Wet Weight) Hepatic Iron (mg/g of Liver, Dry Weight) Threshold for cardiacdisease and early death 20 Increased risk of complications 10 Optimal level in chelated patients Normal 0 0 0 10 20 30 50 40 Age (years) Olivieri N, et al. Blood. 1997;89:739.

  3. Transfusion Therapy Results in Iron Overload • 1 blood unit contains 200 mg iron1 • A 60-kg thalassaemia patient receiving 45 units of blood annually has transfusional iron intake of 9 g iron/year • 0.4 mg iron/kg body weight/day • In addition, up to 4 mg/day may be absorbed from the gut1 • up to 1.5 g iron/year • Overload can occur after 10–20 transfusions1 • Transfusional iron intake = volume of packed RBCs (mL) x 1.082 • Volume of packed RBCs (mL)= volume of blood (mL) x haematocrit (%)2 • Example: • 285 mL blood transfused x 65% haematocrit = • 185 mL RBCs x 1.08 mg iron/mL RBCs = 200 mg iron 1. Porter JB. Br J Haematol. 2001;115:239. 2. Cappellini MD, et al. Blood. 2006;107:3455.

  4. Iron Intake Rates in Thalassaemia Major1,2 Iron Intake (mg/kg/day) 0.2 0.6 0.3 0.4 0.5 Deferasirox (n = 296) Desferrioxamine (n = 290) Range between 25th and 75th percentile of daily iron intake Mean daily iron intake Iron loading Subjects Mean Rate Annual Transfusion <0.3 mg/kg/day 24% 0.25 mg/kg/day 129 mL/kg 0.3–0.5 mg/kg/day 59% 0.39 mg/kg/day 203 mL/kg >0.5 mg/kg/day 17% 0.55 mg/kg/day 286 mL/kg Novartis. Data on file. 1. Cohen A, et al. Blood. 2005;106:Abstr 822. 2. Cappellini MD, et al. Blood. 2006;107:3455.

  5. Threshold Levels of Liver Iron • Liver iron concentration (LIC) predicts total body storage iron in thalassaemia major1 • Liver pathology • Abnormal alanine aminotransferase (ALT) level if LIC >7 mg/g dry weight2 • Liver fibrosis progression if LIC >16 mg/g dry weight3 • Cardiac pathology at high levels • LIC >15 mg/g dry weight associated with cardiac death • All of 9/53 thalassaemia major patients who died4 • Improvement of subclinical cardiac dysfunction with venesection post–bone-marrow transplant5 1. Angelucci E, et al. N Engl J Med. 2000;343:327. 2. Jensen PD, et al. Blood. 2003;101:91. 3. Angelucci E, et al. Blood. 2002;100:17. 4. Brittenham GM, et al. N Engl J Med. 1994;331:567. 5. Mariotti E, et al. Br J Haematol. 1998;103:916.

  6. 1.00 0.75 0.50 0.25 0.00 Benefits of Ferritin Control <33% ferritin measures>2500 ng/mL • Change in serum ferritin over time reflects change in LIC • Proportion of ferritin measurements >2500 ng/mL affects cardiac disease-free survival1 (see graph) • Maintenance of serum ferritin <2500 ng/mL • Significantly correlates with cardiac disease-free survival2–5 1.00 33%–67% ferritin measures >2500 ng/mL 0.75 Ferritin >2500 ng/mL on >1/3 of occasions Survival probability Proportion Without Cardiac Disease 0.50 0.25 >67% ferritin measures>2500 ng/mL Maintenance of Lower Ferritin Levelsa Positive Indicator for Survival at UCLH (unpublished data) 0 . 0 5 10 15 0 2 4 6 8 10 12 14 16 Years of Follow-Up Chelation Therapy (years) 1. Olivieri NF, et al. N Engl J Med. 1994;331:574. 2.Gabutti V, Piga A. Acta Haematol. 1996;95:26. 3.Telfer PT, et al. Br J Haematol. 2000;110:971. 4. Davis BA, et al. Blood. 2004;104:263. 5. Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.

  7. T2* MRI—Emerging New Standard for Cardiac Iron 90 80 70 60 50 LVEF (%) Cardiac T2* value of 37 in a normal heart 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Heart T2* (ms) Cardiac T2* value of 4 in a significantly iron overloaded heart Relationship between myocardial T2* values and left ventricular ejection fraction (LVEF). Below a myocardial T2* of 20 ms, there was a progressive and significant decline in LVEF (R = 0.61, P < .0001). Photos courtesy of Dr. M. D. Cappellini.Anderson LJ, et al. Eur Heart J. 2001;22:2171.

  8. Recommendations for Managing Iron Overload in Thalassaemia • Thalassaemia major vs intermedia • Who is a candidate for iron chelation? • How should iron chelation treatment be initiated? • What parameters should be monitored in patients receiving iron chelation?

  9. Current Status of Guidelines for Managing Iron Overload • Various recommendations, standards, and guidelines are currently in existence • Most based on experience in managing transfusion-dependent thalassaemia • No single comprehensive guideline exists for managing iron overload in thalassaemia, sickle cell disease, or myelodysplastic syndromes • A growing number of health authorities are using guidelines and evidence-based data to determine reimbursement of drug costs • Thus, there is a need to produce guidelines, which include oral chelation therapy

  10. New Thalassaemia Guidelines • Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia, 2nd edition. 2007. • Angelucci E, et al. Italian Society of Hematology Practice Guidelines for the Management of Iron Overload in Thalassemia Major and Related Disorders.Haematologica. 2008, In press.

  11. Thalassaemia major Iron overload primarily a function of chronic transfusion1 Iron loading in a regularly transfused patient with thalassaemia major is approximately 7–9 g/year Thalassaemia intermedia Iron overload primarily a function of increased GI iron absorption1 Sporadic transfusion Although rate of iron accumulation is slow, complications do occur late in life Iron loading may be on the order of 2–5 g/year Iron Overload in Thalassaemia 1. Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia, 2nd ed. 2007.

  12. Goals of Chelation Therapy in Thalassaemia • Prevent accumulation of harmful levels of body iron • Start treatment before iron accumulation is excessive • Maintain iron balance • Match iron excretion with transfusional loading • Prevent tissue damage from labile iron pools • Provide 24-hour chelation to • Minimize non–transferrin-bound iron uptake into tissues • Minimize exposure to labile iron in tissues and plasma • Minimize toxicity from excessive chelation • Rescue • Necessary if iron has already accumulated in tissues

  13. Uncoordinated iron Free-radical generation Organ damage Growth failure Organ failure Cardiac death Uncoordinated chelator Inhibition of metalloenzymes Neurotoxicity Growth failure Bone marrow toxicity The Challenge of Iron ChelationA Question of Balance Too much iron Too much chelator Graphic courtesy of Dr. J. Porter.

  14. Thalassaemia major1 >10 transfusions Serum ferritin levels >1000 ng/mL LIC >normal range of method used Thalassaemia intermedia* Assess iron overload in patients receiving 0–≤4 units =year through testing of serum ferritin, transferrin saturation, and LIC (or UIE if LIC is not available) Patients with transferrin saturation constantly >60% and LIC >4 mg/g dry weight (or UIE >3 mg/24 h, if LIC not available), should start iron chelation therapy Candidates for Iron Chelation LIC = liver iron concentration; UIE = urinary iron excretion. * M. Domenica Cappellini, MD (oral communications, 2008) 1. Angelucci E, et al. Haematologica. 2008; In press.

  15. Treatment Options for Iron Chelation TM = Thalassaemia major; TI = Thalassaemia intermedia Desferal (desferrioxamine). International Package Leaflet. Basel, Switzerland; Novartis, 1998. Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006. Ferriprox (deferiprone). Summary of Product Characteristics. EMEA, 2007.

  16. Administration of Chelating Agents 1. Desferal (desferrioxamine). International Package Leaflet. Basel, Switzerland; Novartis, 1998. 2. Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia, 2nd ed; 2007. 3. Exjade (deferasirox). Summary of Product Characteristics. EMEA, 2006. 4. Ferriprox (deferiprone). Summary of Product Characteristics. EMEA, 2007.

  17. 1960–1964 1965–1969 1970–1974 1975–1979 1980–1984 1985–1997 Increasing Efficacy of Chelation Therapy Has Significantly Improved Patient Survival 1.00 0.75 Birth cohort Survival Probability 0.50 0.25 (P < .00005) 0 0 5 10 15 20 25 30 Age (years) Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.

  18. Thalassaemia major1 Periodic monitoring of serum ferritin level Assess LIC if increasing or decreasing (<1000 ng/mL) serum ferritin trend to avoid under- or overtreatment In patients with LIC prior to start, LIC (liver biopsy, SQUID, or MRI) should be repeated every year Thalassaemia intermedia* Periodic monitoring of serum ferritin, transferrin saturation and LIC (or UIE, if LIC not available) Decrease iron load to safe limit, ie, LIC <4 mg/g dry weight (or UIE <3 mg/24 h, if LIC not available) Monitoring Iron Load in Patients on Iron Chelation Therapy LIC = liver iron concentration; SQUID = superconducting quantum interference; MRI = magnetic resonance imaging; UIE = urinary iron excretion. * M. Domenica Cappellini, MD (oral communications, 2008) 1. Angelucci E, et al. Haematologica. 2008; In press.

  19. Candidates for Aggressive Iron Chelation • Serum ferritin values persistently >2500 ng/mL • Liver iron >15 mg/g dry weight • Significant cardiac disease • Cardiac dysrhythmias • Evidence of failing ventricular function • Evidence of severe cardiac iron loading • Other indications • Female patient considering pregnancy • Patients planning bone marrow transplant • Patient with active hepatitis C Thalassaemia International Federation. Guidelines for the Clinical Management of Thalassaemia, 2nd ed. 2007.

  20. Switching Chelating Agents • Patients receiving desferrioxamine standard-dose therapy who develop severe iron overload (LIC >15 mg/g dry weight or serum ferritin >3000 ng/mL) • First, advise to strictly adhere to the chelation protocol • In absence of a reversal of iron overload, shift to an intensive or combined chelation therapy (grade B) • Available evidence favours use of deferiprone as chelator to be associated with desferrioxamine (grade B) • Switch to alternative iron chelator is mandatory in cases of nonadherence to desferrioxamine, or the occurrence of severe adverse effects that preclude its continuation (grade D) Angelucci E, et al. Haematologica. 2008, In press.

  21. Conclusions • Many tools are available for assessing iron overload • Combining these tools allows more accurate assessment of iron load • Serial ferritin evaluation (every 3–4 months) is the most practical tool for following iron load and iron chelation efficacy • Measure LIC (biopsy/MRI/SQUID) at least once • Assess cardiac iron load by MRI at least once • Closer monitoring is indicated in certain cases • Changes in transfusional iron load • Changes in chelation therapy • New signs of iron load toxicity

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