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Thalassemia Workshop: Chelation Therapy Chi-Kong Li, MBBS, MD Department of Paediatrics Prince of Wales Hospital The Chinese University of Hong Kong BTG

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  • Thalassemia Workshop:Chelation TherapyChi-Kong Li, MBBS, MDDepartment of PaediatricsPrince of Wales HospitalThe Chinese University of Hong KongBTG 2013

  • Transfusion therapy and iron loading in thalassemia1 blood unit contains 200 mg iron A 60 kg thalassemia patient receiving 45 units of blood annually has transfusional iron intake of 9 g iron/year0.4 mg iron/kg body wt/dayIn addition, up to 4 mg/day may be absorbed from the gutUp to 1.5 g iron/yearPorter JB. Br J Haematol 2001;115:239252200250 mg iron:Whole blood: 0.47 mg iron/mL Pure red cells: 1.16 mg iron/mLRate of iron loading influences the therapeutic goal

  • Hepatic Fibrosis --> Cirrhosis Cardiac arrhythmiaHypogonadismDiabetesHypothyroidismHypoparathyroidismCardiac FailureDeathTransfusional Iron Overload in Thalassemia

  • Currently Marketed Iron ChelatorsDeferoxamine (Desferal )Deferiprone (Ferriprox)

    Desferasirox(Exjade)

  • Comparison of chelators

    PropertyDFODeferiproneDeferasiroxUsual dose (mg/kg/day)2560752030Routesc, iv(812 hours, 5 days/week)Oral3 times dailyOralOnce dailyHalf-life2030 minutes34 hours1216 hoursExcretionUrinary, fecalUrinaryFecalAdverse effectsLocal reactions, ophthalmologic, auditory, growth retardation, allergicGastrointestinal disturbances, agranulocytosis/ neutropenia, arthralgiaGastrointestinal disturbances, rash, mild non-progressive creatinine increase, ophthalmologic, auditoryStatusLicensedLicensedLicensed

  • Side effects of desferrallocal reactions,severe allergic reaction: rareyersinia enterocolitica infectionHearing: high tone deafness,Visual: night blindness, reduction of visual field & visual acuity, reduced growth velocity,skeletal lesions.

  • Effect of DFO compliance on outcomeGabutti V, Piga A. Acta Haematol. 1996;95:26-36. DFO = desferrioxamine.

  • GI and Joint complicationsAgranulocytosis and NeutropeniaNeutropenia 1-3%, agranulocytosis
  • Combined therapy of Desferrioxamine & DeferiproneAgranulocytosis and Milder Neutropenia

  • Advantages of Combined Chelation of desferral and deferiprone Different iron pools of chelation Increasing efficacy Dose decrease toxicity decrease Better tolerability better compliance Quality of life improvement Preventing NTBI accumulation Use of oral chelators as shuttling agents

  • Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: retrospective analysis treated for at least 4 years with deferiprone or deferoxamine January 1995 and March 2001 None of the 54 patients treated with deferiprone died, 4 of the 75 patients treated with deferoxamine died during the study period.

    A. Piga et al; 2003, Thalassemia Centre, University of Torino

  • 265 patients with -thalassaemia majorMonotherapy DFO or DFP, or combined DFPDFODFO alone (n = 124)DFP (n=55)sequential DFPDFO (n=68),combined DFPDFO (n=18)

    8/124 DFO developed arrhythmia, and 3/141 other chelators had arrhythmia

    12 deaths, 7 of which were related to cardiac disease6/7 had received DFO prior to death

    Survival analysis of patients initially randomized to DFO + DFP vs monotherapy with DFO or DFPMaggio A, et al. Blood Cells Mol Dis. 2009 Feb 20].

  • Monitoring of Iron overloadCardiac iron overload cardiomyopathy - death

  • Liver biopsy Quantitative assessment of liver iron contentGood correlation with total body ironInvasive, not without risk, poor patient acceptance

  • R2 MRI: a new measure for Liver Iron ContentR2 MRI is a validated and standardized method for measuring LIC. This technique is now approved by TGA and FDA and in the EUSt Pierre TG et al. Blood 2005;105:855861302040500.51.01.52.0Biopsy iron concentration (mg.g-1 dry tissue)Mean transverse relaxation rate (s-1)01002005015025030001020304050Hereditary hemochromatosisHepatitis-thalassemia-thalassemia / hemoglobin E

  • LiverLiverLack of Correlation: Liver and Cardiac Iron

  • T2* MRI: emerging new standard for cardiac ironAnderson LJ et al. Eur Heart J 2001;22:21712179, Left ventricular ejection fraction (%)05070403020106080900204060908010010305070Heart T2* (ms)Cardiac T2* value of 37 in a normal heart Cardiac T2* value of 4 in a significantly iron overloadedheartRelationship between myocardial T2* values and left ventricular ejection fraction. Below a myocardial T2* of 20 ms, there was a progressive and significant decline in left ventricular ejection fraction (R=061, P
  • Cardiac T2* and risk for cardiac dysfunction Westwood MA et al. J Magn Reson Imaging 2005;7:4647,

  • 100Improvement in liver fibrosis with at least 3 years of deferasirox treatment

    82.6% of patients experienced either stabilization or improvement in fibrosis stagingImprovements in fibrosis staging were observed in patients who met the LIC response criteria and those who did not

    Fibrosis score7.38.25.310.06.015.855.759.748.726.926.130.30102030405060708090OverallLIC respondersLIC non-respondersPatients (%)Worsened by 2 Ishak stagesRemained stable (no change or 1)Improved by 2 Ishak stages MissingDeugnier Y et al. Presented at ASH 2010 [Blood 2010;116(21):abst 4274] Studies 107 and 107E

  • Monotherapy of Desferasirox: MRI cardiac T2*, 3 year studyPennel DJ et al. Haematologica | 2012; 97(6)

  • Telfer et al, Haematologica 2006Causes of death : UK, Italy, Cyprus

  • SummaryMore accurate body iron assessment: MRIliver and heartNon-invasive, reproducible

    Newer oral chelators improves compliance, reduce complications and mortality

    *Red blood cell transfusion is the mainstay of therapy for thalassemia. Transfusions are initiated when hemoglobin falls below 7 g/dL, or at higher levels to help resolve specific problems such as growth impairment, bone changes, or progressive splenomegalyTransfusions are administered in sufficient quantity and frequency to achieve a hemoglobin level of at least 9.3 g/dL; this level partly suppresses the erythropoietic drive that is producing ineffective RBCs. A regimen that maintains the mean hemoglobin level above 10.5 to 11 g/dL reduces marrow expansion, arrests bone changes and minimizes splenomegaly. This leads to a reduction in plasma fluid volume, allowing an increase in relative concentration of hemoglobin. In children, growth may improve and more normal physical activity can be expected1,2

    ReferencesThalassemia management. Parts I and II. Semin Hematol 1995;32:1996:33(1)Olivieri NF & Brittenham GM. Iron-chelation therapy and the treatment of thalassemia. Blood 1997;89:739761*Thalassemia patients are the real iron man in our world**Thalassemia major is a rare, genetic disease that causes severe anemia due to the inadequate production of hemoglobin. In the absence of medical intervention, thalassemia results in death during childhood. Children who are afflicted with thalassemia major require lifelong blood transfusions if they are to grow and develop to adulthood. The unfortunate consequence of the transfusions is an inevitable progressive increase in body iron load. As there is no natural means for the body to eliminate the excessive iron, these patients inexorably develop a clinically worsening hemosiderosis. The excessive iron is deposited mainly in the liver and spleen, leading to liver fibrosis and cirrhosis. The excessive iron is also deposited in the endocrine glands and the heart, resulting in diabetes, heart failure and premature death. Death ultimately occurs, mainly due to cardiac hemosiderosis.

    *This slide covers some of the important characteristics of DFO, deferiprone (an oral chelator with a restricted license in a number of countries outside of North America) and deferasirox, a once-daily oral chelator which received FDA and Swiss approval in November 2005Deferiprone is licensed outside North America. The approved indication in Europe is for iron overload in patients with thalassemia major when DFO therapy is contraindicated or inadequateDeferiprone and deferasirox are administered orally, which eliminates a major hindrance to chelation therapy with deferoxamine the necessity for delivering the agent subcutaneously or intravenously over an extended period of time using specialized pumps. To date the indication of deferiprone is restricted to second line in Europe due to concerns about its efficacy and safetyDeferasirox also has a long half-life which allows for once-daily dosing versus deferiprones 23 times a day. Deferasirox has also been shown to be generally well tolerated*6*9**Kaplan-Meier analysis of survival in 257 consecutive thalassemic patients according to the mean compliance with subcutaneous DFO therapy

    **The goal of the second phase of the protocol was to evaluate the long-term efficacy and safety of combined therapyThe therapetic protocol that we applied consisted of Combined therapy consisted of DFO along with 2 doses of DFP, administered at the beginning and at least 2 hours before the end of the infusion, for 3 days of the week. and DFP at 75 mg/kg/day:3 for the next 4 days of the weekThe reason for selection of this therapeutic plan was to achieve better compliance, avoid significant toxicity that could be induced if both drugs were used at full dosage and to have an affordable cost increase of chelation therapy*NTBIPotential advantages of using two chelators.

    ***The R2 MRI technique, which measures mean liver proton transverse relaxation rates, is a recently validated and standardized method for easily and non-invasively measuring LIC

    *Although the T2* MRI is not yet fully validated, it is becoming the new standard for measuring cardiac iron levels. LIC and serum ferritin levels may correlate with cardiac iron levels, but more research is required to confirm thisIf there is no iron present in the heart, the incidence of cardiomyopathy is comparable to the normal population. In general, the lower the T2*, the higher the risk of cardiac dysfunction. However, some patients with iron overload also have high T2* and therefore apparently no cardiac problems

    *To address the question of whether iron chelation can stabilize or improve liver fibrosis in patients with -thalassemia, a subanalysis of two large studies (studies 107 and 108) was performed.219 patients who had liver biopsy assessment at baseline and at the end of at least 3 years of treatment with deferasirox were included. 210 patients had baseline and EOS LIC assessments were classified as having an LIC response success or LIC response failure according to the criteria on slide 98.The effect of deferasirox on liver fibrosis was based on Ishak fibrosis staging scores.For all patients, 82.6% (n=181; 85.8% [n=115] in Group A LIC response success, 78.9% [n=60] in Group B LIC response failure) experienced either stabilization or improvement (change of 2, 1, 0, or +1) in their Ishak fibrosis staging. Changes in Ishak staging did not correlate with changes in LIC (n=195; R=0.18), suggesting the observed effects may be independent of the drugs chelation effects.This is the first report from a large cohort of iron-overloaded patients with -thalassemia to show improvement in liver fibrosis with iron chelation therapy.

    ReferenceDeugnier Y et al. Presented at ASH 2010 [Blood 2010;116(21):abst 4274].

    **