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Chelation Therapy for Iron Overload Kathy Ponder February 2, 2007
Case Presentation  May 2006 <ul><li>TJ is a 42 y.o. white female with hemochromatosis for whom the hematology service was ...
Patient History <ul><li>As a child she was told she had anemia and was treated with iron therapy </li></ul><ul><li>At age ...
Patient History <ul><li>In 2002 (age 37) she developed symptoms of CHF </li></ul><ul><li>In 2004 she received cardiac cath...
Patient History <ul><li>After 6 months of chelation, her ferritin was not improved, and her physician switched her to phle...
Patient History <ul><li>In 12-05 she had a mildly dilated LV with global hypokinesis and overall severely decreased LV sys...
<ul><li>Other medical problems </li></ul><ul><ul><li>Diabetes; not clear when started </li></ul></ul><ul><ul><li>Hypothyro...
Exam after Transplant <ul><li>Skin looked bronze </li></ul>
Laboratory Values over 2 Years 95 44 35 46 AST 97 27 56 35 ALT 2.8 4.7 4.8 4.7 Alb 3656 1528 2208 2121 Ferritin 146 231/ 2...
Peripheral Smear <ul><li>Numerous nucleated RBC and anisocytosis; no spherocytes; nRBC were noted on numerous previous sme...
Iron Storage in Heart at Heart Transplant
Contibuting Factors to Early Onset Hemochromatosis: <ul><li>Hemolytic anemia, possibly hereditary spherocytosis </li></ul>...
Causes of Hemochromatosis Hoffman, 2005
Role of Proteins that can be Mutated in Hemochromatosis <ul><li>Ferroportin </li></ul><ul><ul><li>An iron transporter in t...
Andrews and Schmidt, Annual Rev Physiology 69:161 Andrews NEJM 353:2508
Pietrangelo  A BBA 1763:700 Normal  State Classical Hemochromatosis HFE or TfR2 Juvenile  Hemochromatosis Hepcidin or hemo...
Treatment of Hemochromatosis <ul><li>Avoid extra iron (vitamins without iron) </li></ul><ul><li>Phlebotomy </li></ul><ul><...
Chemical Structures of Iron Chelators Deferoxamine (Desferal ® )  Hexadentate (1:1); high MW Deferiprone (Ferriprox ® , Ke...
ICL670: a New, Oral Iron Chelator <ul><li>Selected from more than 700 compounds tested </li></ul><ul><li>Tridentate* iron ...
Two ICL670 Molecules Chelate  One Iron Atom From Blinder talk, 2004
Efficacy of Exjade for Iron Overload <ul><li>Most studies in patients with thalassemia or other diseases that lead to bloo...
Cappellini et al; Blood 107:3436, 2006
Cappellini et al; Blood 107:3436, 2006
Capellini
Side Effects of Exjade <ul><li>5% discontinue </li></ul><ul><li>GI in 15%:  Nausea, abdominal pain, vomiting, diarrhea, co...
EJ Neufeld Blood 107:3436, 2006
EJ Neufeld Blood 107:3436, 2006
Do different agents remove iron from the heart better?
Borgna Pignatti et al
Borgna-Pignatti et al DFO:  Cardiac events in 52 of 359 patients (15%); 15 died Deferiprone:  Cardiac events in 0 of 157
Conclusions of Borgna-Pignati : <ul><li>Patients on DFO still have significant cardiac events at 15% over 9 years </li></u...
Action of chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and functional consequences. ...
BJC Pharmacy Costs <ul><li>30 tablets of 125 mg each is $423 </li></ul><ul><li>30 tablets of 250 mg each is $843 </li></ul...
Conclusions <ul><li>Anemia workup should include evaluation of iron </li></ul><ul><li>Classical hemochromatosis can presen...
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  • Free iron has 6 coordination (chelatable interaction) sites Hexadentate chelators therefore bind more tightly Polydentate chelators are usually higher molecular weight Higher molecular weight pharmaceuticals are generally not orally bioavailable and have poorer pharmacokinetic parameters Deferoxamine Binds to all 6 sites of iron (1:1 ratio; high-affinity chelator) Poor oral bioavailability—must be infused Rapidly cleared from the body—slow infusion needed Bidentate chelators 3 molecules are required to chelate free iron Generally less stable binding Lower molecular weight compounds are available Deferiprone Binds iron in a 3:1 deferiprone to iron ratio; not as high affinity as deferoxamine Good oral bioavailability and pharmacokinetics Tridentate chelators 2 molecules bind and chelate free iron (2:1 binding ratio) ICL670 is a novel, high-affinity, low molecular weight compound Deferoxamine-like affinity but lower molecular weight Orally bioavailable; good pharmacokinetics and efficacy in preclinical testing Reference Nick H, Acklin P, Lattmann R, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem . 2003;10:1065-1076.
  • ICL670 is an orally active iron chelator Selected from &gt; 700 compounds High affinity and specificity for iron ICL670 tablets can be dispersed in noncarbonated water (which takes ~ 3 minutes of manual stirring with a nonmetallic rod) and ingested orally ICL670 is tridentate (“3-toothed”—meaning that it interacts with the ferric ion using 3 polar moieties within the interaction “mouth”) 2 molecules of ICL670 form a complete complex with iron 1 ICL670 belongs to a novel class of iron chelators Iron chelated by ICL670 is processed through the hepatic/biliary route and is excreted mainly in the feces The efficacy and safety of ICL670 have been demonstrated in animal models Doses up to 80 mg/kg were well tolerated in phase I 2 and doses up to 40 mg/kg were well tolerated in phase II 3 The most common transient adverse events were rashes, nausea, and diarrhea ICL670 therapy can generate a dose-dependent net negative iron balance in thalassemic patients Reference Nick H, Acklin P, Lattmann R, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem . 2003;10:1065-1076. Galanello R, Piga A, Alberti D, Rouan MC, Bigler H, Sechaud R. Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia. J Clin Pharmacol. 2003;43:565-572. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2003;361:1597-1602.
  • 2 molecules of ICL670 bind iron with high affinity, interacting with all 6 coordination sites
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    1. 1. Chelation Therapy for Iron Overload Kathy Ponder February 2, 2007
    2. 2. Case Presentation May 2006 <ul><li>TJ is a 42 y.o. white female with hemochromatosis for whom the hematology service was consulted for consideration of chelation therapy after surgery for heart transplant </li></ul>
    3. 3. Patient History <ul><li>As a child she was told she had anemia and was treated with iron therapy </li></ul><ul><li>At age 15 she received splenectomy and CCK for hemolytic anemia and gallstones, respectively, and was told she had small RBC </li></ul><ul><li>She was told that the surgeon noted cirrhosis on her liver at the time of surgery </li></ul><ul><li>In her mid 20’s, she became amenorheic and was infertile </li></ul>
    4. 4. Patient History <ul><li>In 2002 (age 37) she developed symptoms of CHF </li></ul><ul><li>In 2004 she received cardiac cath that showed severe global hypokinesis with LVEF 15% and moderate dilation of the LV. Endomyocardial heart biopsy showed iron in the interstitium and the cardiocytes, and interstitial fibrosis </li></ul><ul><li>In 2004 she was found to be homozygous for the C282Y HFE gene mutation </li></ul><ul><li>In 2004 she initiated chelation therapy with desferroxamine 7 nights a week </li></ul><ul><li>In 2004 she received a defibrillator for arrhytmias </li></ul>
    5. 5. Patient History <ul><li>After 6 months of chelation, her ferritin was not improved, and her physician switched her to phlebotomy, which she tolerated poorly due to hypotension (SBP 80 to 100 at baseline) </li></ul><ul><li>In 2005, she saw Dr. Blinder for consideration of oral iron therapy with Exjade (still experimental) </li></ul><ul><li>He suggested that aggressive chelation be resumed in combination with gentle phlebotomy </li></ul>
    6. 6. Patient History <ul><li>In 12-05 she had a mildly dilated LV with global hypokinesis and overall severely decreased LV systolic function with LVEF ~15-20%. A restrictive LV filling pattern was seen with LV diastolic dysfunction </li></ul><ul><li>Symptoms of CHF worsened in 3-06 </li></ul><ul><li>Patient received biventricular assist device on 3-19-06 for cardiogenic shock </li></ul><ul><li>She received heart transplant on 3-19-06 </li></ul><ul><li>Post-op she did developed kidney failure and remained bedridden, and died on 5-20-06 </li></ul>
    7. 7. <ul><li>Other medical problems </li></ul><ul><ul><li>Diabetes; not clear when started </li></ul></ul><ul><ul><li>Hypothyroidism </li></ul></ul><ul><ul><li>Infertility </li></ul></ul><ul><li>Family history: </li></ul><ul><ul><li>No history of hemochromatosis </li></ul></ul><ul><ul><li>Mom had anemia that resolved with pregnancy </li></ul></ul><ul><ul><li>Dad had liver problems in his 50’s </li></ul></ul>
    8. 8. Exam after Transplant <ul><li>Skin looked bronze </li></ul>
    9. 9. Laboratory Values over 2 Years 95 44 35 46 AST 97 27 56 35 ALT 2.8 4.7 4.8 4.7 Alb 3656 1528 2208 2121 Ferritin 146 231/ 261 >/99% TIBC 137 216 246 236 Fe 9.1 3.0 3.3 2.9 Bili 101 100.3 100.9 98.6 MCV 8.8 13.1 13.7 14.3 Hb 5-06 11-05 3-05 9-04 Test
    10. 10. Peripheral Smear <ul><li>Numerous nucleated RBC and anisocytosis; no spherocytes; nRBC were noted on numerous previous smears </li></ul><ul><li>No reticulocyte count </li></ul><ul><li>No LDH </li></ul>
    11. 11. Iron Storage in Heart at Heart Transplant
    12. 12. Contibuting Factors to Early Onset Hemochromatosis: <ul><li>Hemolytic anemia, possibly hereditary spherocytosis </li></ul><ul><li>Iron therapy </li></ul><ul><li>HFE C282Y hemochromatosis </li></ul>
    13. 13. Causes of Hemochromatosis Hoffman, 2005
    14. 14. Role of Proteins that can be Mutated in Hemochromatosis <ul><li>Ferroportin </li></ul><ul><ul><li>An iron transporter in the lumenal side of the intestinal epithelial cells </li></ul></ul><ul><ul><li>Dominant mutation that loses regulation by hepcidin </li></ul></ul><ul><li>Hepcidin </li></ul><ul><ul><li>A 25 aa peptide produced by liver that leads to degradation of ferroportin </li></ul></ul><ul><li>Proteins necessary for transcription of hepcidin </li></ul><ul><ul><li>HFE </li></ul></ul><ul><ul><li>Transferrin receptor 2 </li></ul></ul><ul><ul><li>Hemojuvulin (associates with BMP receptor), and results in activation of SMAD4 </li></ul></ul>
    15. 15. Andrews and Schmidt, Annual Rev Physiology 69:161 Andrews NEJM 353:2508
    16. 16. Pietrangelo A BBA 1763:700 Normal State Classical Hemochromatosis HFE or TfR2 Juvenile Hemochromatosis Hepcidin or hemojuvulen
    17. 17. Treatment of Hemochromatosis <ul><li>Avoid extra iron (vitamins without iron) </li></ul><ul><li>Phlebotomy </li></ul><ul><li>Chelation </li></ul>
    18. 18. Chemical Structures of Iron Chelators Deferoxamine (Desferal ® ) Hexadentate (1:1); high MW Deferiprone (Ferriprox ® , Kelfer ® ) Bidentate (3:1); low MW Deferasirox (ICL670) Exjade Tridentate (2:1); low MW From Blinder talk 2004; Nick H. Curr Med Chem. 2003;10:1065-1076. O OH HO OH N N N H 2 N O O O O O N N OH OH OH N N H H 2 N O O O O O N N N OH OH N N H H CH 3 CH 3 CH 3 OH N O
    19. 19. ICL670: a New, Oral Iron Chelator <ul><li>Selected from more than 700 compounds tested </li></ul><ul><li>Tridentate* iron chelator </li></ul><ul><ul><li>An oral, dispersible tablet </li></ul></ul><ul><ul><li>Administered once daily </li></ul></ul><ul><ul><li>Highly specific for iron </li></ul></ul><ul><li>Chelated iron excreted mainly in feces (< 10% in urine) </li></ul>*3 polar interaction sites in the binding pocket. Nick H, Current Medicinal Chemistry. 2003;10:1065-1076. Clinical trial formulation or preparation From Blinder talk, 2004 O OH HO OH N N N Fe * * *
    20. 20. Two ICL670 Molecules Chelate One Iron Atom From Blinder talk, 2004
    21. 21. Efficacy of Exjade for Iron Overload <ul><li>Most studies in patients with thalassemia or other diseases that lead to blood transfusions </li></ul><ul><li>Normal iron uptake is 1 to 2 mg/day </li></ul><ul><li>Patients with 3 to 4 transfusions per month accumulate ~0.5 mg/kg/day or 30 mg for a 60 kg person (20 times normal) </li></ul><ul><li>Hemochromatosis: if 0.5 units every month maintains steady state, 125 ml of PRBC per month, or 125 mg/month or 4 mg per day </li></ul>
    22. 22. Cappellini et al; Blood 107:3436, 2006
    23. 23. Cappellini et al; Blood 107:3436, 2006
    24. 24. Capellini
    25. 25. Side Effects of Exjade <ul><li>5% discontinue </li></ul><ul><li>GI in 15%: Nausea, abdominal pain, vomiting, diarrhea, constipation; usually last 8 days or less </li></ul><ul><li>Rash in 11% </li></ul><ul><li>Mild increase in creatinine in 38% </li></ul>
    26. 26. EJ Neufeld Blood 107:3436, 2006
    27. 27. EJ Neufeld Blood 107:3436, 2006
    28. 28. Do different agents remove iron from the heart better?
    29. 29. Borgna Pignatti et al
    30. 30. Borgna-Pignatti et al DFO: Cardiac events in 52 of 359 patients (15%); 15 died Deferiprone: Cardiac events in 0 of 157
    31. 31. Conclusions of Borgna-Pignati : <ul><li>Patients on DFO still have significant cardiac events at 15% over 9 years </li></ul><ul><li>Patients on deferiprone had no cardiac events </li></ul><ul><li>Deferiprone may be more effective at clearing iron from the heart </li></ul><ul><li>This was a retrospective study without randomization </li></ul>
    32. 32. Action of chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and functional consequences. Glickstein H Blood 108:3195, 2006
    33. 33. BJC Pharmacy Costs <ul><li>30 tablets of 125 mg each is $423 </li></ul><ul><li>30 tablets of 250 mg each is $843 </li></ul><ul><li>30 tablets of 500 mg each is $1682 </li></ul><ul><ul><li>10 mg/kg costs $20,184 per year if 50 kg </li></ul></ul><ul><ul><li>20 mg/kg costs $40,368 per year if 50 kg </li></ul></ul><ul><ul><li>30 mg/kg costs $60,552 per year if 50 kg </li></ul></ul>
    34. 34. Conclusions <ul><li>Anemia workup should include evaluation of iron </li></ul><ul><li>Classical hemochromatosis can present early in patients with hemolytic anemia </li></ul><ul><li>The new chelator Exjade is effective but very expensive; it may be better than desferroxamine at clearing iron from the heart </li></ul><ul><li>Screening of populations with iron studies is being considered </li></ul>
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