Abstract number: 2184
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`http://ex2 excerptamedica.com/98ash/abstracts/abs2 184html
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`Abstract #2184 - Monday, December 7, 1998 - Hall C, 5:00-6:30 pm
`Posterboard 41-IV, THALASSEMIA AND GLOBIN GENE REGULATION I
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`CARDIAC FAILURE AND MYOCARDIAL FIBROSIS IN A PATIENT WITH
`THALASSEMIA MAJOR (TM) TREATED WITH LONG-TERM DEFERIPRONE
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`N.E. Olivieri, J. Butany*, D.M. Templeton*, G.M. Brittenham
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`University ofToronto, CanadaColumbia University, New York, USA
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`We report the development ofacute congestive cardiacfailure in a 23-year-old man with TM after
`prolonged treatment with deferiprone, an orally active iron chelator. This patient had complied with
`deferoxamine (DFO) for 15 years until 1993, when he was randomized to deferiprone treatment in a
`prospective trial comparing deferiprane and DFO. Deferiprone, 73 mg/kg/day, was givenfor 3.6 years;
`hepatic iron varied betweenQvand 13 milligrams per gram liver, dry weight (mg/g), and cardiac ejection
`fraction between 30 and 70% (normal >50%). Because ofconcerns about the safety ofdeferiprone, the
`patient was advised to discontinue deferiprone and resume DFO. Six months later, he presented with
`severe acute congestive cardiacfailure. Transthoracic echocardiogram and Doppler showed an ejection
`Jraction of<20% and markedly impaired diastolic relaxation.Myocardial and hepatic biopsies were
`performed: biochemical results are shown in the Table and compared with findings in the explanted
`heart and liver ofa 20-year-old TMpatient whe had been non-compliant with DFOfor several years,
`and had required combined heart and liver transplantationfor end-stage iron-induced disease (N Engl
`MMed 1994;330:1123-7}. Note that patients with TM in whom the body iron burden, as assessed by
`hepatic iron, is maintained below 15 mg/g have a low risk ofcardiac complications (N Engl J Med
`1994:331:567-73). Although the cardiac iron concentration in the patient treated with deferiprone was
`lower, both myocardial biopsies showed similar widespread endocardial and interstitialfibrosis with
`extensive musclefiber degeneration. No other riskfactorsfor cardiacfibrosis were present.
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`Patient
`
`Myocardial iron
`Hepatic iron
`(mg/g, dry weight) (mg/g, dry weight)
`13.2
`3.7
`Deferiprone therapy
`Noiron-chelating therapy 28.1
`3.8
`
`In cultured cardiomyocytes, deferipronefails to mobilize iron andpromotes iron-induced cardiotoxicity
`(Blood 1997;90 (Suppl. 1):1a}. Studies in an animal model ofhuman iron overload havefound that the
`combination ofiron overload and treatment with a hydroxypyridinone structurally similar te
`deferiprone was associated with redistribution ofiron, leading to increased cardiac ivon deposition and
`Fibrosis (BioMetals 1994;7:267-71). Long-term clinical studies suggest that deferiprone may accelerate
`hepaticfibrosis (N Engl J Med 1998;339:617-23). Deathsfrom cardiac causes have been reported in
`patients treated with deferiprone for up to 2 years (Blood 1998,91:295-300) but ascribed solely to the
`underlying iron overload; no autopsyresults have been reported. Overall, these observations raise
`concerns that deferiprone treatment in patients with TM may be associated with (i) redistribution of
`body iron, leading to increased cardiac iron deposition at lower bodyiron burdens, and (ii) an
`exacerbation or acceleration ofcardiac fibrosis. We conclude that the risk ofcardiac disease associated
`with deferiprone therapy needsfurther evaluation.
`
`Tron transport and kinetics
`Jron overload and hemochromatosis
`Thalassemias
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`Apotex Tech.
`Ex. 2012
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`Apotex Tech.
`Ex. 2012
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