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Iron chelation therapy for myelodysplastic syndrome: a systematic review and meta-analysis

  • Hailing Liu
  • Nan Yang
  • Shan Meng
  • Yang Zhang
  • Hui Zhang
  • Wanggang ZhangEmail author
Review Article

Abstract

Iron overload remains a concern in myelodysplastic syndrome (MDS) patients especially those requiring recurrent blood transfusions. Whether iron chelating therapy (ICT) is beneficial to the long-term survival of myelodysplastic syndrome is still a controversial issue. Therefore, we conducted a systematic review and meta-analysis to clarify the relationship between ICT and long-term survival in patients with MDS. A total of 14 studies involving 7242 participants were identified; the outcomes revealed that for patients with MDS, ICT resulted in a lower risk of mortality compared to those with no ICT (HR 0.57; 95% CI 0.44–0.70; P < 0.001); what is more, ICT led to a lower risk of leukemia transformation (HR 0.70; 95% CI 0.52–0.93; P = 0.016). Results of subgroup analyses based on adequate ICT or any ICT, low/int-1 IPSS or unclassified IPSS and study types indicated that the ICT had a beneficial role in all these groups of patients.

Keywords

Iron overload Iron chelation therapy Myelodysplastic syndrome Overall survival Leukemia-free survival 

Notes

Funding

This manuscript was supported by Shaanxi International Scientific Research Cooperation and Exchange Program (Grant Number: 2016KW-020).

Compliance with ethical standards

Conflict of interest

We declare that we have no conflict of interest.

Ethical approval

The study was approved by the Second Affiliated Hospital of Xi’an Jiaotong University.

Informed consent

Informed consent was obtained from all individual participants included in this study in their original studies.

References

  1. 1.
    Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–65.  https://doi.org/10.1182/blood-2012-03-420489.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Jabbour E, Takahashi K, Wang X, Cornelison AM, Abruzzo L, Kadia T, et al. Acquisition of cytogenetic abnormalities in patients with IPSS defined lower-risk myelodysplastic syndrome is associated with poor prognosis and transformation to acute myelogenous leukemia. Am J Hematol. 2013;88(10):831–7.  https://doi.org/10.1002/ajh.23513.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Waszczuk-Gajda A, Madry K, Machowicz R, Drozd-Sokolowska J, Stella-Holowiecka B, Mital A, et al. Red blood cell transfusion dependency and hyperferritinemia are associated with impaired survival in patients diagnosed with myelodysplastic syndromes: results from the first polish MDS-PALG registry. Adv Clin Exp Med Off Org Wroc Med Univ. 2016;25(4):633–41.  https://doi.org/10.17219/acem/62397.CrossRefGoogle Scholar
  4. 4.
    Dreyfus F. The deleterious effects of iron overload in patients with myelodysplastic syndromes. Blood Rev. 2008;22(Suppl 2):S29–34.  https://doi.org/10.1016/S0268-960X(08)70006-7.CrossRefPubMedGoogle Scholar
  5. 5.
    Shammo JM, Komrokji RS. Clinical consequences of iron overload in patients with myelodysplastic syndromes: the case for iron chelation therapy. Expert Rev Hematol. 2018;11(7):577–86.  https://doi.org/10.1080/17474086.2018.1486188.CrossRefPubMedGoogle Scholar
  6. 6.
    Ghoti H, Amer J, Winder A, Rachmilewitz E, Fibach E. Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome. Eur J Haematol. 2007;79(6):463–7.  https://doi.org/10.1111/j.1600-0609.2007.00972.x.CrossRefPubMedGoogle Scholar
  7. 7.
    Lu WY, Zhao MF, Rajbhandary S, Xie F, Chai X, Mu J, et al. Free iron catalyzes oxidative damage to hematopoietic cells/mesenchymal stem cells in vitro and suppresses hematopoiesis in iron overload patients. Eur J Haematol. 2013;91(3):249–61.  https://doi.org/10.1111/ejh.12159.CrossRefPubMedGoogle Scholar
  8. 8.
    Chung YJ, Robert C, Gough SM, Rassool FV, Aplan PD. Oxidative stress leads to increased mutation frequency in a murine model of myelodysplastic syndrome. Leuk Res. 2014;38(1):95–102.  https://doi.org/10.1016/j.leukres.2013.07.008.CrossRefPubMedGoogle Scholar
  9. 9.
    Pileggi C, Di Sanzo M, Mascaro V, Marafioti MG, Costanzo FS, Pavia M. Role of serum ferritin level on overall survival in patients with myelodysplastic syndromes: results of a meta-analysis of observational studies. PLoS ONE. 2017;12(6):e0179016.  https://doi.org/10.1371/journal.pone.0179016.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Carreau N, Tremblay D, Savona M, Kremyanskaya M, Mascarenhas J. Ironing out the details of iron overload in myelofibrosis: lessons from myelodysplastic syndromes. Blood Rev. 2016;30(5):349–56.  https://doi.org/10.1016/j.blre.2016.04.003.CrossRefPubMedGoogle Scholar
  11. 11.
    Yassin MA, Soliman AT, De Sanctis V, Hussein RM, Al-Okka R, Kassem N, et al. Jadenu((R)) substituting exjade((R)) in iron overloaded beta-thalassemia major (BTM) patients: a preliminary report of the effects on the tolerability, serum ferritin level, liver iron concentration and biochemical profiles. Mediterr J Hematol Infect Dis. 2018;10(1):e2018064.  https://doi.org/10.4084/mjhid.2018.064.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bollig C, Schell LK, Rucker G, Allert R, Motschall E, Niemeyer CM, et al. Deferasirox for managing iron overload in people with thalassaemia. Cochrane Database Syst Rev. 2017;8:7476.  https://doi.org/10.1002/14651858.cd007476.pub3.CrossRefGoogle Scholar
  13. 13.
    Karami H, Kosaryan M, Amree AH, Darvishi-Khezri H, Mousavi M. Combination iron chelation therapy with deferiprone and deferasirox in iron-overloaded patients with transfusion-dependent beta-thalassemia major. Clin Pract. 2017;7(1):912.  https://doi.org/10.4081/cp.2017.912.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kattamis A, Aydinok Y, Taher A. Optimising management of deferasirox therapy for patients with transfusion-dependent thalassaemia and lower-risk myelodysplastic syndromes. Eur J Haematol. 2018;101(3):272–82.  https://doi.org/10.1111/ejh.13111.CrossRefPubMedGoogle Scholar
  15. 15.
    Leitch HA, Buckstein R, Zhu N, Nevill TJ, Yee KWL, Leber B, et al. Iron overload in myelodysplastic syndromes: evidence based guidelines from the Canadian consortium on MDS. Leuk Res. 2018;74:21–41.  https://doi.org/10.1016/j.leukres.2018.09.005.CrossRefPubMedGoogle Scholar
  16. 16.
    Zeidan AM, Griffiths EA. To chelate or not to chelate in MDS: that is the question! Blood Rev. 2018;32(5):368–77.  https://doi.org/10.1016/j.blre.2018.03.002.CrossRefPubMedGoogle Scholar
  17. 17.
    Gattermann N. Iron overload in myelodysplastic syndromes (MDS). Int J Hematol. 2018;107(1):55–63.  https://doi.org/10.1007/s12185-017-2367-1.CrossRefPubMedGoogle Scholar
  18. 18.
    Mitchell M, Gore SD, Zeidan AM. Iron chelation therapy in myelodysplastic syndromes: where do we stand? Expert Rev Hematol. 2013;6(4):397–410.  https://doi.org/10.1586/17474086.2013.814456.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Porter J, Galanello R, Saglio G, Neufeld EJ, Vichinsky E, Cappellini MD, et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol. 2008;80(2):168–76.  https://doi.org/10.1111/j.1600-0609.2007.00985.x.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    List AF, Baer MR, Steensma DP, Raza A, Esposito J, Martinez-Lopez N, et al. Deferasirox reduces serum ferritin and labile plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(17):2134–9.  https://doi.org/10.1200/jco.2010.34.1222.CrossRefGoogle Scholar
  21. 21.
    Gattermann N, Finelli C, Porta MD, Fenaux P, Ganser A, Guerci-Bresler A, et al. Deferasirox in iron-overloaded patients with transfusion-dependent myelodysplastic syndromes: results from the large 1-year EPIC study. Leuk Res. 2010;34(9):1143–50.  https://doi.org/10.1016/j.leukres.2010.03.009.CrossRefPubMedGoogle Scholar
  22. 22.
    Angelucci E, Santini V, Di Tucci AA, Quaresmini G, Finelli C, Volpe A, et al. Deferasirox for transfusion-dependent patients with myelodysplastic syndromes: safety, efficacy, and beyond (GIMEMA MDS0306 Trial). Eur J Haematol. 2014;92(6):527–36.  https://doi.org/10.1111/ejh.12300.CrossRefPubMedGoogle Scholar
  23. 23.
    Mainous AG 3rd, Tanner RJ, Hulihan MM, Amaya M, Coates TD. The impact of chelation therapy on survival in transfusional iron overload: a meta-analysis of myelodysplastic syndrome. Br J Haematol. 2014;167(5):720–3.  https://doi.org/10.1111/bjh.13053.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA J Am Med Assoc. 2000;283(15):2008–12.CrossRefGoogle Scholar
  25. 25.
    Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647.  https://doi.org/10.1136/bmj.g7647.CrossRefPubMedGoogle Scholar
  26. 26.
    Leitch HALC, Goodman TA, Wong KK, Wong DHC, Ramadan KM, Rollins MD, Barnett MJ, Galbraith PF, Vickars LM. Improved survival in patients with myelodysplastic syndrome receiving iron chelation therapy. Clin Leuk. 2008;2:205–11.CrossRefGoogle Scholar
  27. 27.
    Rose C, Brechignac S, Vassilief D, Pascal L, Stamatoullas A, Guerci A, et al. Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myelodysplasies). Leuk Res. 2010;34(7):864–70.  https://doi.org/10.1016/j.leukres.2009.12.004.CrossRefPubMedGoogle Scholar
  28. 28.
    Raptis A, Duh MS, Wang ST, Dial E, Fanourgiakis I, Fortner B, et al. Treatment of transfusional iron overload in patients with myelodysplastic syndrome or severe anemia: data from multicenter clinical practices. Transfusion. 2010;50(1):190–9.  https://doi.org/10.1111/j.1537-2995.2009.02361.x.CrossRefPubMedGoogle Scholar
  29. 29.
    Komrokji RS, Al Ali NH, Padron E, Lancet JE, List AF. Impact of iron chelation therapy on overall survival and AML transformation in lower risk MDS patients treated at the Moffitt cancer center. Blood. 2011;118(21):1196–7.CrossRefGoogle Scholar
  30. 30.
    Neukirchen J, Fox F, Kundgen A, Nachtkamp K, Strupp C, Haas R, et al. Improved survival in MDS patients receiving iron chelation therapy—a matched pair analysis of 188 patients from the Dusseldorf MDS registry. Leuk Res. 2012;36(8):1067–70.  https://doi.org/10.1016/j.leukres.2012.04.006.CrossRefPubMedGoogle Scholar
  31. 31.
    Lyons RM, Marek BJ, Paley C, Esposito J, Garbo L, DiBella N, et al. Comparison of 24-month outcomes in chelated and non-chelated lower-risk patients with myelodysplastic syndromes in a prospective registry. Leuk Res. 2014;38(2):149–54.  https://doi.org/10.1016/j.leukres.2013.11.004.CrossRefPubMedGoogle Scholar
  32. 32.
    Delforge M, Selleslag D, Beguin Y, Triffet A, Mineur P, Theunissen K, et al. Adequate iron chelation therapy for at least 6 months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes. Leuk Res. 2014;38(5):557–63.  https://doi.org/10.1016/j.leukres.2014.02.003.CrossRefPubMedGoogle Scholar
  33. 33.
    Remacha AF, Arrizabalaga B, Villegas A, Duran MS, Hermosin L, de Paz R, et al. Evolution of iron overload in patients with low-risk myelodysplastic syndrome: iron chelation therapy and organ complications. Ann Hematol. 2015;94(5):779–87.  https://doi.org/10.1007/s00277-014-2274-y.CrossRefPubMedGoogle Scholar
  34. 34.
    Langemeijer S, De Swart L, Yu G, Smith A, Crouch S, Johnston T, et al. Impact of treatment with iron chelators in lower-risk MDS patients participating in the European leukemianet MDS (EUMDS) registry. Blood. 2016;128(22):3186.CrossRefGoogle Scholar
  35. 35.
    Leitch HA, Parmar A, Wells RA, Chodirker L, Zhu N, Nevill TJ, et al. Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient-related factors and measuring from time of first red blood cell transfusion dependence: an MDS-CAN analysis. Br J Haematol. 2017;179(1):83–97.  https://doi.org/10.1111/bjh.14825.CrossRefPubMedGoogle Scholar
  36. 36.
    Wong SA, Leitch HA. Iron chelation therapy in lower IPSS risk myelodysplastic syndromes; which subtypes benefit? Leuk Res. 2018;64:24–9.  https://doi.org/10.1016/j.leukres.2017.11.005.CrossRefPubMedGoogle Scholar
  37. 37.
    Angelucci ELJ, Greenberg PL, Depei W, Hou M, Montaño Figueroa E, Rodriguez G, Dong X, Ghosh J, Bornstein O, Garcia-Manero G. Safety and efficacy, including event-free survival, of deferasirox versus placebo in iron-overloaded patients with low- and int-1-risk myelodysplastic syndromes (mds): outcomes from the randomized, double-blind telesto study. Blood. 2018;132(Suppl 1):234.CrossRefGoogle Scholar
  38. 38.
    Zeidan AM, Hendrick F, Friedmann E, Baer MR, Gore SD, Sasane M, et al. Deferasirox therapy is associated with reduced mortality risk in a medicare population with myelodysplastic syndromes. J Comp Eff Res. 2015;4(4):327–40.  https://doi.org/10.2217/cer.15.20.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zeidan AM, Giri S, DeVeaux M, Ballas SK, Duong VH. Systematic review and meta-analysis of the effect of iron chelation therapy on overall survival and disease progression in patients with lower-risk myelodysplastic syndromes. Ann Hematol. 2019;98(12):339–50.  https://doi.org/10.1007/s00277-018-3539-7.CrossRefPubMedGoogle Scholar
  40. 40.
    Abrahama I, Al Yami M, Yun S, Kim HJ, Vincelette ND, McBride A, et al. Survival outcomes in iron chelated and non-chelated patients with lower-risk myelodysplastic syndromes: review and pooled analysis of observational studies. Leuk Res. 2017;57:104–8.  https://doi.org/10.1016/j.leukres.2017.03.007.CrossRefGoogle Scholar
  41. 41.
    Maurillo L, Breccia M, Buccisano F, Voso MT, Niscola P, Trape G, et al. Deferasirox chelation therapy in patients with transfusion-dependent MDS: a “real-world’ report from two regional Italian registries: gruppo Romano Mielodisplasie and Registro Basilicata. Eur J Haematol. 2015;95(1):52–6.  https://doi.org/10.1111/ejh.12476.CrossRefPubMedGoogle Scholar
  42. 42.
    Gattermann N, Finelli C, Della Porta M, Fenaux P, Stadler M, Guerci-Bresler A, et al. Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica. 2012;97(9):1364–71.  https://doi.org/10.3324/haematol.2011.048546.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nolte F, Hochsmann B, Giagounidis A, Lubbert M, Platzbecker U, Haase D, et al. Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral Deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload. Ann Hematol. 2013;92(2):191–8.  https://doi.org/10.1007/s00277-012-1594-z.CrossRefPubMedGoogle Scholar
  44. 44.
    Goncalves AC, Cortesao E, Oliveiros B, Alves V, Espadana AI, Rito L, et al. Oxidative stress levels are correlated with P15 and P16 gene promoter methylation in myelodysplastic syndrome patients. Clin Exp Med. 2016;16(3):333–43.  https://doi.org/10.1007/s10238-015-0357-2.CrossRefPubMedGoogle Scholar
  45. 45.
    Di Renzo M, Pasqui AL, Voltolini L, Gotti G, Pompella G, Auteri A. Myelodysplasia and good syndrome A case report. Clin Exp Med. 2008;8(3):171–3.  https://doi.org/10.1007/s10238-008-0175-x.CrossRefPubMedGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Clinical HematologySecond Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina

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