Advertisement

Annals of Hematology

, 88:301 | Cite as

Deferasirox in MDS patients with transfusion-caused iron overload—a phase-II study

  • Georgia Metzgeroth
  • Dietmar Dinter
  • Beate Schultheis
  • Alexandra Dorn-Beineke
  • Kira Lutz
  • Oliver Leismann
  • Rüdiger Hehlmann
  • Jan HastkaEmail author
Original Article

Abstract

Blood transfusions represent a main component of supportive care in myelodysplastic syndromes (MDS). To avoid organ damage caused by transfusion-dependent iron overload, an adequate iron chelation therapy is required. Recently, a new oral iron chelator deferasirox (ICL670, Exjade®) has become available. A study was conducted to demonstrate the efficacy and tolerability of deferasirox in transfusion-dependent iron-overloaded patients with MDS. The efficacy of deferasirox was monitored by changes in serum ferritin, bone marrow iron, and liver iron concentration (LIC), as determined by T2*-weighted magnetic resonance imaging. Twelve patients with MDS of different subtypes (median age 76 years, range 53–91) were enrolled. Deferasirox administered in a once-daily dose of 20–30 mg/kg for 12 months was effective in reducing median ferritin concentration from 1,515 µg/L (range 665–6,900) to 413 µg/L (range 105–3,052). Within the first 4 weeks of treatment before the continuous decline of ferritin levels, the values markedly rose in eight of 12 patients. The median LIC declined from 315 to 230 µmol/g (p = 0.02) at the end of study, accompanied by a reduction of bone marrow siderosis. The most common adverse events were mild and transient gastrointestinal disturbances, skin rash, nonprogressive transient increases in serum creatinine and urine β2-microglobulin, and a temporary reduction of the creatinine clearance. The renal parameters normalized after end of treatment. No hematologic toxicities were observed. Deferasirox proved to be effective in transfusion-dependent iron overload in MDS by mobilizing iron deposits in liver and at least stabilizing iron stores in bone marrow.

Keywords

Myelodysplastic syndromes Transfusional iron overload Iron chelator Deferasirox LIC assessment by MRI 

Abbreviations

MDS

myelodysplastic syndromes

LIC

liver iron concentration

MRI

magnetic resonance imaging

RA

refractory anemia

RARS

refractory anemia with ringed sideroblasts

RCMD

refractory cytopenia with multilineage dysplasia

RAEB-I

refractory anemia with excess of blasts

RBC

red blood cells

AML

acute myeloid leukemia

ALAT

alanine aminotransferase

References

  1. 1.
    Porter JB (2001) Practical management of iron overload. Br J Haematol 115(2):239–252PubMedCrossRefGoogle Scholar
  2. 2.
    Britton RS, Leicester KL, Bacon BR (2002) Iron toxicity and chelation therapy. Int J Hematol 76(3):219–228PubMedCrossRefGoogle Scholar
  3. 3.
    Kushner JP, Porter JP, Olivieri NF (2001) Secondary iron overload. Hematology Am Soc Hematol Educ Program 2001:47–61Google Scholar
  4. 4.
    McLaren GD, Muir WA, Kellermeyer RW (1983) Iron overload disorders: natural history, pathogenesis, diagnosis, and therapy. Crit Rev Clin Lab Sci 19(3):205–266PubMedGoogle Scholar
  5. 5.
    Jensen PD, Heickendorff L, Pedersen B, Bendix-Hansen K, Jensen FT, Christensen T et al (1996) The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol 94(2):288–299PubMedCrossRefGoogle Scholar
  6. 6.
    Aessopos A, Farmakis D, Hatziliami A, Fragodimitri C, Karabatsos F, Joussef J et al (2004) Cardiac status in well-treated patients with thalassemia major. Eur J Haematol 73(5):359–366PubMedCrossRefGoogle Scholar
  7. 7.
    Wolfe L, Olivieri N, Sallan D, Colan S, Rose V, Propper R et al (1985) Prevention of cardiac disease by subcutaneous deferoxamine in patients with thalassemia major. N Engl J Med 312(25):1600–1603PubMedGoogle Scholar
  8. 8.
    Borgna-Pignatti C, Franchini M, Gandini G, Vassanelli A, De Gironcoli M, Aprili G (1998) Subcutaneous bolus injection of deferoxamine in adult patients affected by onco-hematologic diseases and iron overload. Haematologica 83(9):788–790PubMedGoogle Scholar
  9. 9.
    Ceci A, Baiardi P, Felisi M, Cappellini MD, Carnelli V, De S V, Galanello R, Maggio A, Masera G, Piga A, Schettini F, Stefano I, Tricta F (2002) The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol 118(1):330–336PubMedCrossRefGoogle Scholar
  10. 10.
    Cohen AR, Galanello R, Piga A, Dipalma A, Vullo C, Tricta F (2000) Safety profile of the oral iron chelator deferiprone: a multicentre study. Br J Haematol 08(2):305–312CrossRefGoogle Scholar
  11. 11.
    Hoffbrand AV, Cohen A, Hershko C (2003) Role of deferiprone in chelation therapy for transfusional iron overload. Blood 102(1):17–24PubMedCrossRefGoogle Scholar
  12. 12.
    Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L et al (2006) A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 107(9):3455–3462PubMedCrossRefGoogle Scholar
  13. 13.
    Cappellini MD (2005) Iron-chelating therapy with the new oral agent ICL670 (Exjade). Best Pract Res Clin Haematol 18(2):289–298PubMedCrossRefGoogle Scholar
  14. 14.
    Hershko C, Konijn AM, Nick HP, Breuer W, Cabantchik ZI, Link G (2001) ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture. Blood 97(4):1115–1122PubMedCrossRefGoogle Scholar
  15. 15.
    Nick H, Acklin P, Lattmann R, Buehlmayer P, Hauffe S, Schupp J et al (2003) Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem 10(12):1065–1076PubMedCrossRefGoogle Scholar
  16. 16.
    Galanello R, Piga A, Forni GL, Bertrand Y, Foschini ML, Bordone E et al (2006) Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with beta-thalassemia major. Haematologica 91(10):1343–1351PubMedGoogle Scholar
  17. 17.
    Galanello R, Piga A, Alberti D, Rouan MC, Bigler H, Sechaud R (2003) 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 43(6):565–572PubMedGoogle Scholar
  18. 18.
    Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Sechaud R et al (2003) Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 361(9369):1597–1602PubMedCrossRefGoogle Scholar
  19. 19.
    Piga A, Galanello R, Forni GL, Cappellini MD, Origa R, Zappu A et al (2006) Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 91(7):873–880PubMedGoogle Scholar
  20. 20.
    Porter J (2007) Clinical evaluation of deferasirox (Exjade((R)), ICL670). Semin Hematol 44(2):16–20CrossRefGoogle Scholar
  21. 21.
    Porter JB (2006) Deferasirox: an effective once-daily orally active iron chelator. Drugs Today (Barc) 42(10):623–637CrossRefGoogle Scholar
  22. 22.
    Goldberg SL (2007) Novel treatment options for transfusional iron overload in patients with myelodysplastic syndromes. Leuk Res 31(Suppl 3):16–22Google Scholar
  23. 23.
    Jaffe ES, Harris NL, Stein H, Vardiman JW (2001) Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC, LyonGoogle Scholar
  24. 24.
    Gandon Y, Olivie D, Guyader D, Aube C, Oberti F, Sebille V et al (2004) Non-invasive assessment of hepatic iron stores by MRI. Lancet 363(9406):357–362PubMedCrossRefGoogle Scholar
  25. 25.
    Wood JC, Enriquez C, Ghugre N, Tyzka JM, Carson S, Nelson MD et al (2005) MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood 106(4):1460–1465PubMedCrossRefGoogle Scholar
  26. 26.
    Alexopoulou E, Stripeli F, Baras P, Seimenis I, Kattamis A, Ladis V et al (2006) R2 relaxometry with MRI for the quantification of tissue iron overload in beta-thalassemic patients. J Magn Reson Imaging 23(2):163–170PubMedCrossRefGoogle Scholar
  27. 27.
    Pennell DJ, Berdoukas V, Karagiorga M, Ladis V, Piga A, Aessopos A et al (2006) Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood 107(9):3738–3744PubMedCrossRefGoogle Scholar
  28. 28.
    Wood JC, Otto-Duessel M, Aguilar M, Nick H, Nelson MD, Coates TD et al (2005) Cardiac iron determines cardiac T2*, T2, and T1 in the gerbil model of iron cardiomyopathy. Circulation 112(4):535–543PubMedCrossRefGoogle Scholar
  29. 29.
    Tanner MA, Galanello R, Dessi C, Smith GC, Westwood MA, Agus A et al (2007) A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation 115(4):1876–1884PubMedCrossRefGoogle Scholar
  30. 30.
    Westwood MA, Firmin DN, Gildo M, Renzo G, Stathis G, Markissia K et al (2005) Intercentre reproducibility of magnetic resonance T2* measurements of myocardial iron in thalassaemia. Int J Cardiovasc Imaging 21(5):531–538PubMedCrossRefGoogle Scholar
  31. 31.
    Rose C, Vandevenne P, Bourgeois E, Cambier N, Ernst O (2006) Liver iron content assessment by routine and simple magnetic resonance imaging procedure in highly transfused patients. Eur J Haematol 77(2):145–149PubMedCrossRefGoogle Scholar
  32. 32.
    Greenberg PL (2006) Myelodysplastic syndromes: iron overload consequences and current chelating therapies. J Natl Compr Canc Netw 4(1):91–96PubMedGoogle Scholar
  33. 33.
    Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P et al (2007) A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 136(3):501–508PubMedCrossRefGoogle Scholar
  34. 34.
    Mavrogeni SI, Markussis V, Kaklamanis L, Tsiapras D, Paraskevaidis I, Karavolias G et al (2005) A comparison of magnetic resonance imaging and cardiac biopsy in the evaluation of heart iron overload in patients with beta-thalassemia major. Eur J Haematol 75(3):241–247PubMedCrossRefGoogle Scholar
  35. 35.
    Pennell D (2006) MRI and iron-overload cardiomyopathy in thalassaemia. Circulation 113(11):43–44Google Scholar
  36. 36.
    Kontoghiorghes GJ (2007) Deferasirox: uncertain future following renal failure fatalities, agranulocytosis and other toxicities. Expert Opin Drug Saf 6(3):235–239PubMedCrossRefGoogle Scholar
  37. 37.
    Wood JC, Otto-Duessel M, Gonzalez I, Aguilar MI, Shimada H, Nick H et al (2006) Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil. Transl Res 148(5):272–280PubMedCrossRefGoogle Scholar
  38. 38.
    Kontoghiorghes GJ (2005) Effects of ICL670 (deferasirox) on cardiac iron concentrations. Lancet 366(9488):804PubMedCrossRefGoogle Scholar
  39. 39.
    Maggio A (2007) Light and shadows in the iron chelation treatment of haematological diseases. Br J Haematol 138(4):407–421PubMedCrossRefGoogle Scholar
  40. 40.
    Porter J, Galanello R, Saglio G, Neufeld EJ, Vichinsky E, Cappellini MD et al (2007) Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol 80:168–176, PMID 18028431PubMedGoogle Scholar
  41. 41.
    Weiss G (2002) Pathogenesis and treatment of anaemia of chronic disease. Blood Rev 16(2):87–96PubMedCrossRefGoogle Scholar
  42. 42.
    Aul C, Germing U, Gattermann N, Minning H (1998) Increasing incidence of myelodysplastic syndromes: real or fictitious? Leuk Res 22(1):93–100PubMedCrossRefGoogle Scholar
  43. 43.
    Burkhardt H, Bojarsky G, Gretz N, Gladisch R (2002) Creatinine clearance, Cockcroft-Gault formula and cystatin C: estimators of true glomerular filtration rate in the elderly? Gerontology 48(3):140–146PubMedCrossRefGoogle Scholar
  44. 44.
    Waller DG, Fleming JS, Ramsey B, Gray J (1991) The accuracy of creatinine clearance with and without urine collection as a measure of glomerular filtration rate. Postgrad Med J 67(783):42–46PubMedCrossRefGoogle Scholar
  45. 45.
    Walser M (1998) Assessing renal function from creatinine measurements in adults with chronic renal failure. Am J Kidney Dis 32(1):23–31PubMedCrossRefGoogle Scholar
  46. 46.
    Tefferi A (2006) Iron chelation therapy for myelodysplastic syndrome: if and when. Mayo Clin Proc 81(2):197–198PubMedCrossRefGoogle Scholar
  47. 47.
    Abstracts of the 8th International Symposium on Myelodysplastic Syndromes. Nagasaki, Japan (2005) Leuk Res 29(1):1–78Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Georgia Metzgeroth
    • 1
  • Dietmar Dinter
    • 2
  • Beate Schultheis
    • 1
  • Alexandra Dorn-Beineke
    • 3
  • Kira Lutz
    • 2
  • Oliver Leismann
    • 4
  • Rüdiger Hehlmann
    • 1
  • Jan Hastka
    • 1
    Email author
  1. 1.III. Medizinische UniversitätsklinikMedizinische Fakultät Mannheim der Universität HeidelbergMannheimGermany
  2. 2.Institut für Klinische Radiologie und Nuklearmedizin, Medizinische Fakultät MannheimUniversität HeidelbergMannheimGermany
  3. 3.Institut für Klinische Chemie, Medizinische Fakultät MannheimUniversität HeidelbergMannheimGermany
  4. 4.Novartis PharmaNürnbergGermany

Personalised recommendations