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Myelodysplasias

Is there a role for all-trans retinoic acid in combination with recombinant erythropoetin in myelodysplastic syndromes? A report on 59 cases

Leukemia volume 23, pages 673–678 (2009)Cite this article

Abstract

Erythropoiesis-stimulating agents (ESAs) remain the first-line treatment of anemia in lower risk myelodysplastic syndromes (MDS) without 5q deletion. A preliminary report suggested that adding all-trans retinoic acid (ATRA) to ESAs may improve their erythroid response, particularly in patients with high endogenous erythropoietin (EPO) level, and may improve other cytopenias. We conducted a prospective multicenter study of EPO-β and ATRA in anemic MDS patients with marrow blasts <10% and either previous ESA failure or relapse, endogenous EPO >500 U/l or other cytopenia(s) (absolute neutrophilic count <1.0 G/l or platelets <50 G/l). A total of 59 patients were evaluable after 12 weeks of treatment. The erythroid response rates according to IWG 2000 and 2006 criteria, respectively, were as follows: overall: 49 and 36%; patients with previous ESA failure (n=28): 43 and 32%; patients with endogenous EPO >500 U/l (n=18): 11 and 19%; patients transfused >2 red blood cells units/month (n=28) 43 and 39%. Only one neutrophil, but no platelet response, and no major side effect were observed. EPO-β–ATRA combination appears a possible therapeutic option in anemia of MDS having failed an ESA alone, but not in patients with high endogenous EPO level, and does not improve neutropenia and thrombocytopenia.

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References

  1. Hellstrom-Lindberg E, Malcovati L . Supportive care, growth factors, and new therapies in myelodysplastic syndromes. Blood Rev 2008; 22: 75–91.

    Article  Google Scholar 

  2. Steensma DP, Tefferi A . Anemia in the elderly: how should we define it, when does it matter, and what can be done? Mayo Clin Proc 2007; 82: 958–966.

    Article  CAS  Google Scholar 

  3. Malcovati L . Impact of transfusion dependency and secondary iron overload on the survival of patients with myelodysplastic syndromes. Leuk Res 2007; 31 (Suppl 3): S2–S6.

    Article  CAS  Google Scholar 

  4. Casadevall N, Durieux P, Dubois S, Hemery F, Lepage E, Quarre MC et al. Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial. Blood 2004; 104: 321–327.

    Article  CAS  Google Scholar 

  5. Jadersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellstrom-Lindberg E . Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood 2005; 106: 803–811.

    Article  Google Scholar 

  6. Negrin RS, Stein R, Vardiman J, Doherty K, Cornwell J, Krantz S et al. Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin. Blood 1993; 82: 737–743.

    CAS  PubMed  Google Scholar 

  7. Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl IM, Dybedal I et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol 2003; 120: 1037–1046.

    Article  CAS  Google Scholar 

  8. Park S, Grabar S, Kelaidi C, Beyne-Rauzy O, Picard F, Bardet V et al. Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood 2008; 111: 574–582.

    Article  CAS  Google Scholar 

  9. Kelaidi C, Eclache V, Fenaux P . The role of lenalidomide in the management of myelodysplasia with del 5q. Br J Haematol 2008; 140: 267–278.

    Article  CAS  Google Scholar 

  10. Evans T . Regulation of hematopoiesis by retinoid signaling. Exp Hematol 2005; 33: 1055–1061.

    Article  CAS  Google Scholar 

  11. Aul C, Runde V, Gattermann N . All-trans retinoic acid in patients with myelodysplastic syndromes: results of a pilot study. Blood 1993; 82: 2967–2974.

    CAS  PubMed  Google Scholar 

  12. Koeffler HP, Heitjan D, Mertelsmann R, Kolitz JE, Schulman P, Itri L et al. Randomized study of 13-cis retinoic acid v placebo in the myelodysplastic disorders. Blood 1988; 71: 703–708.

    CAS  PubMed  Google Scholar 

  13. Kurzrock R, Estey E, Talpaz M . All-trans retinoic acid: tolerance and biologic effects in myelodysplastic syndrome. J Clin Oncol 1993; 11: 1489–1495.

    Article  CAS  Google Scholar 

  14. Ohno R, Naoe T, Hirano M, Kobayashi M, Hirai H, Tubaki K et al. Treatment of myelodysplastic syndromes with all-trans retinoic acid. Leukemia Study Group of the Ministry of Health and Welfare. Blood 1993; 81: 1152–1154.

    CAS  PubMed  Google Scholar 

  15. Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R et al. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood 2004; 104: 1266–1269.

    Article  CAS  Google Scholar 

  16. Pilatrino C, Cilloni D, Messa E, Morotti A, Giugliano E, Pautasso M et al. Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid. Cancer 2005; 104: 101–109.

    Article  CAS  Google Scholar 

  17. Hofmann WK, Ganser A, Seipelt G, Ottmann OG, Zander C, Geissler G et al. Treatment of patients with low-risk myelodysplastic syndromes using a combination of all-trans retinoic acid, interferon alpha, and granulocyte colony-stimulating factor. Ann Hematol 1999; 78: 125–130.

    Article  CAS  Google Scholar 

  18. Giagounidis AA, Haase S, Germing U, Schlegelberger B, Wilkens L, Busche G et al. Treatment of myelodysplastic syndrome with isolated del(5q) including bands q31-q33 with a combination of all-trans-retinoic acid and tocopherol-alpha: a phase II study. Ann Hematol 2005; 84: 389–394.

    Article  CAS  Google Scholar 

  19. Zhang W, Zhou F, Cao X, Cheng Y, He A, Liu J et al. Successful treatment of primary refractory anemia with a combination regimen of all-trans retinoic acid, calcitriol, and androgen. Leuk Res 2006; 30: 935–942.

    Article  CAS  Google Scholar 

  20. Smith MA, Parkinson DR, Cheson BD, Friedman MA . Retinoids in cancer therapy. J Clin Oncol 1992; 10: 839–864.

    Article  CAS  Google Scholar 

  21. Stasi R, Brunetti M, Terzoli E, Amadori S . Sustained response to recombinant human erythropoietin and intermittent all-trans retinoic acid in patients with myelodysplastic syndromes. Blood 2002; 99: 1578–1584.

    Article  CAS  Google Scholar 

  22. Ganser A, Maurer A, Contzen C, Seipelt G, Ottmann OG, Schadeck-Gressel C et al. Improved multilineage response of hematopoiesis in patients with myelodysplastic syndromes to a combination therapy with all-trans-retinoic acid, granulocyte colony-stimulating factor, erythropoietin and alpha-tocopherol. Ann Hematol 1996; 72: 237–244.

    Article  CAS  Google Scholar 

  23. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000; 96: 3671–3674.

    CAS  PubMed  Google Scholar 

  24. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108: 419–425.

    Article  CAS  Google Scholar 

  25. Tamburini J, Elie C, Park S, Beyne-Rauzy O, Gardembas M, Berthou C et al. Effectiveness and tolerance of low to very low dose thalidomide in low-risk myelodysplastic syndromes. Leuk Res 2008, [e-pub ahead of print].

  26. Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008; 111: 86–93.

    Article  CAS  Google Scholar 

  27. Lyons RM, Cosgriff T, Modi S, McIntyre H, Fernando I, Backstrom J et al. Results of the Initial Treatment Phase of a Study of Three Alternative Dosing Schedules of Azacitidine (Vidaza(R)) in Patients with Myelodysplastic Syndromes (MDS). Blood 2007; 111: 819.

    Google Scholar 

  28. Sloand EM, Wu CO, Greenberg P, Young N, Barrett J . Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 2008; 26: 2505–2511.

    Article  PubMed Central  Google Scholar 

  29. Balleari E, Rossi E, Clavio M, Congiu A, Gobbi M, Grosso M et al. Erythropoietin plus granulocyte colony-stimulating factor is better than erythropoietin alone to treat anemia in low-risk myelodysplastic syndromes: results from a randomized single-centre study. Ann Hematol 2006; 85: 174–180.

    Article  CAS  Google Scholar 

  30. Hellstrom-Lindberg E, Ahlgren T, Beguin Y, Carlsson M, Carneskog J, Dahl IM et al. Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Blood 1998; 92: 68–75.

    CAS  PubMed  Google Scholar 

  31. Musto P, Falcone A, Carotenuto M, Catalano L, Cennamo A, Rotoli B . Granulocyte colony-stimulating factor and erythropoietin for the anemia of myelodysplastic syndromes: a real improvement with respect to erythropoietin alone? Blood 1994; 84: 1687–1688.

    CAS  PubMed  Google Scholar 

  32. Remacha AF, Arrizabalaga B, Villegas A, Manteiga R, Calvo T, Julia A et al. Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification of a subgroup of responders. The Spanish Erythropathology Group. Haematologica 1999; 84: 1058–1064.

    CAS  PubMed  Google Scholar 

  33. Stasi R, Pagano A, Terzoli E, Amadori S . Recombinant human granulocyte-macrophage colony-stimulating factor plus erythropoietin for the treatment of cytopenias in patients with myelodysplastic syndromes. Br J Haematol 1999; 105: 141–148.

    Article  CAS  Google Scholar 

  34. Maurer AB, Ganser A, Seipelt G, Ottmann OG, Mentzel U, Geissler GR et al. Changes in erythroid progenitor cell and accessory cell compartments in patients with myelodysplastic syndromes during treatment with all-trans retinoic acid and haemopoietic growth factors. Br J Haematol 1995; 89: 449–456.

    Article  CAS  Google Scholar 

  35. Tehranchi R, Fadeel B, Schmidt-Mende J, Forsblom AM, Emanuelsson E, Jadersten M et al. Antiapoptotic role of growth factors in the myelodysplastic syndromes: concordance between in vitro and in vivo observations. Clin Cancer Res 2005; 11: 6291–6299.

    Article  CAS  Google Scholar 

  36. Schmidt-Mende J, Gogvadze V, Hellstrom-Lindberg E, Zhivotovsky B . Early mitochondrial alterations in ATRA-induced cell death. Cell death and differentiation 2006; 13: 119–128.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

LA, PF and FD designed the study. RI, LA, HM, FC and PF collected and analyzed the data. RI drafted the paper. LA, HM, DV, EB, BS, NV, FS, OBR, AG, SC, XT, AS, MG, FB, AK, MCC, LL, GD enrolled patients.

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Authors and Affiliations

  1. Service d'hématologie clinique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Avicenne—Paris 13 University, Bobigny, France

    R Itzykson, P Fenaux & L Ades

  2. Groupe Francophone des Myelodysplasies (GFM), Bobigny, France

    R Itzykson, S Ayari, D Vassilief, E Berger, B Slama, N Vey, O Beyne-Rauzy, A Guerci, S Cheze, X Thomas, A Stamatoullas, M Gardembas, F Bauduer, A Kolb, M C Chaury, L Legros, G Damaj, F Chermat, F Dreyfus, P Fenaux & L Ades

  3. Service d′Hématologie Clinique, CHU de Nantes, Nantes, France

    S Ayari

  4. Service d'Hématologie, Hôpital Cochin, AP-HP, Paris, France

    D Vassilief & F Dreyfus

  5. Service d'Hématologie, CHU de Dijon, Dijon, France

    E Berger

  6. Service d'Hématologie, Hôpital d'Avignon, Avignon, France

    B Slama

  7. Département d'Hématologie, Institut Paoli-Calmette, Marseille, France

    N Vey

  8. Service d'Hématologie adulte, Hôpital Necker–Enfants-Malades, Paris, France

    F Suarez

  9. Service d'Hématologie, Hôpital Purpan, Toulouse, France

    O Beyne-Rauzy

  10. Service d'Hématologie, CHU de Nancy, Nancy, France

    A Guerci

  11. Service d′Hématologie Clinique, Hôpital Clemenceau, Caen, France

    S Cheze

  12. Service d'Hématologie, Hôpital Edouard Herriot, Lyon, France

    X Thomas

  13. Service d'Hématologie, CHU de Rouen, Rouen, France

    A Stamatoullas

  14. Service d'hématologie, CHU d'Angers, Angers, France

    M Gardembas

  15. Service d'Hématologie, Centre Hospitalier de la Côte Basque, Bayonne, France

    F Bauduer

  16. Service d'Hématologie, CHU de Reims, Reims, France

    A Kolb

  17. Service d'Hématologie, CHU de Limoges, Limoges, France

    M C Chaury

  18. Fédération de Médecine Interne Hématologie, Hôpital Archet, Nice, France

    L Legros

  19. Service d'hématologie, CHU d'Amiens, Amiens, France

    G Damaj

  20. Inserm Unit 848, Institut Gustave Roussy, Villejuif, France

    P Fenaux & L Ades

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  1. R Itzykson
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  9. A Guerci
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  10. S Cheze
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  11. X Thomas
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  12. A Stamatoullas
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  13. M Gardembas
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  14. F Bauduer
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  15. A Kolb
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  16. M C Chaury
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  22. L Ades
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on behalf of the Groupe Francophone des Myelodysplasies (GFM)

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Correspondence to L Ades.

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Itzykson, R., Ayari, S., Vassilief, D. et al. Is there a role for all-trans retinoic acid in combination with recombinant erythropoetin in myelodysplastic syndromes? A report on 59 cases. Leukemia 23, 673–678 (2009). https://doi.org/10.1038/leu.2008.362

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  • DOI: https://doi.org/10.1038/leu.2008.362

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