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  • Original Article
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Post-transplant Events

Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT

Abstract

Patients with hematopoietic malignancies relapsing after allogeneic hematopoietic SCT (allo-HSCT) have a poor prognosis. We retrospectively analyzed the patients who received azacitidine in our center in the course of treatment of their post-transplant relapse. We identified 31 patients. Relapse occurred at a median of 3.7 (1.7–37.6) months following allo-HSCT. Patients received a median number of three cycles (1–12) of azacitidine (7 days, 75 mg/m2 daily). Thirty-nine percent of patients had either a monosomal karyotype or a complex karyotype. Eleven patients (35%) received at least one DLI. Eleven patients responded to azacitidine, with four patients achieving a CR (13%). Median time to best response was 92 (35–247) days, with a median duration of 209 (64–751) days. One-year estimated survival rate was 14%. In conclusion, azacitidine may reinduce durable remissions in very few patients with AML or myelodysplastic syndrome. The toxicity related to azacitidine was high, although it may be difficult to distinguish between treatment-related side effects, namely due to cytopenia and toxicity due to the relapse or disease progression itself. Early administration of azacitidine after transplant followed by DLI should be considered as a pre-emptive therapy for potential relapse in patients with minimal residual disease or high-risk myeloid malignancies.

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References

  1. Mielcarek M, Storer BE, Flowers MED, Storb R, Sandmaier BM, Martin PJ . Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2007; 13: 1160–1168.

    Article  Google Scholar 

  2. Pollyea DA, Artz AS, Stock W, Daugherty C, Godley L, Odenike OM et al. Outcomes of patients with AML and MDS who relapse or progress after reduced intensity allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2007; 40: 1027–1032.

    Article  CAS  Google Scholar 

  3. Hosing C, Saliba RM, Shahjahan M, Estey EH, Couriel D, Giralt S et al. Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia. Bone Marrow Transplant 2005; 36: 157–162.

    Article  CAS  Google Scholar 

  4. Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol Off 2002; 20: 405–412.

    Article  CAS  Google Scholar 

  5. Loren AW, Porter DL . Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation. Bone Marrow Transplant 2008; 41: 483–493.

    Article  CAS  Google Scholar 

  6. Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol Off 2006; 24: 3895–3903.

    Article  CAS  Google Scholar 

  7. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol Off 2010; 28: 562–569.

    Article  CAS  Google Scholar 

  8. Maurillo L, Venditti A, Spagnoli A, Gaidano G, Ferrero D, Oliva E et al. Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program. Cancer 2012; 118: 1014–1022.

    Article  CAS  Google Scholar 

  9. Frikeche J, Clavert A, Delaunay J, Brissot E, Grégoire M, Gaugler B et al. Impact of the hypomethylating agent 5-azacytidine on dendritic cells function. Exp Hematol 2011; 39: 1056–1063.

    Article  CAS  Google Scholar 

  10. Pinto A, Maio M, Attadia V, Zappacosta S, Cimino R . Modulation of HLA-DR antigens expression in human myeloid leukaemia cells by cytarabine and 5-aza-2′-deoxycytidine. Lancet 1984; 2: 867–868.

    Article  CAS  Google Scholar 

  11. Flotho C, Claus R, Batz C, Schneider M, Sandrock I, Ihde S et al. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leuk Off J Leuk Soc Am Leuk Res Fund UK 2009; 23: 1019–1028.

    CAS  Google Scholar 

  12. Atanackovic D, Luetkens T, Kloth B, Fuchs G, Cao Y, Hildebrandt Y et al. Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia. Am J Hematol 2011; 86: 918–922.

    Article  CAS  Google Scholar 

  13. Goodyear O, Agathanggelou A, Novitzky-Basso I, Siddique S, McSkeane T, Ryan G et al. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood 2010; 116: 1908–1918.

    Article  CAS  Google Scholar 

  14. Sánchez-Abarca LI, Gutierrez-Cosio S, Santamaría C, Caballero-Velazquez T, Blanco B, Herrero-Sánchez C et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood 2010; 115: 107–121.

    Article  Google Scholar 

  15. Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood 2012; 119: 3361–3369.

    Article  CAS  Google Scholar 

  16. Choi J, Ritchey J, Prior JL, Holt M, Shannon WD, Deych E et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 2010; 116: 129–139.

    Article  CAS  Google Scholar 

  17. 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 

  18. Guillaume T, Gaugler B, Chevallier P, Delaunay J, Ayari S, Clavert A et al. Escalated lymphodepletion followed by donor lymphocyte infusion can induce a graft-versus-host response without overwhelming toxicity. Bone Marrow Transplant 2012; 47: 1112–1117.

    Article  CAS  Google Scholar 

  19. Kim D-Y, Lee J-H, Park Y-H, Lee J-H, Kim S-D, Choi Y et al. Feasibility of hypomethylating agents followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome. Bone Marrow Transplant 2012; 47: 374–379.

    Article  CAS  Google Scholar 

  20. Damaj G, Duhamel A, Robin M, Beguin Y, Michallet M, Mohty M et al. Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Société Française de Greffe de Moelle et de Thérapie-Cellulaire and the Groupe-Francophone des Myélodysplasies. J Clin Oncol Off 2012; 30: 4533–4540.

    Article  CAS  Google Scholar 

  21. Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood 2012; 119: 1599–1606.

    Article  CAS  Google Scholar 

  22. Jabbour E, Giralt S, Kantarjian H, Garcia-Manero G, Jagasia M, Kebriaei P et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer 2009; 115: 1899–1905.

    Article  CAS  Google Scholar 

  23. Lübbert M, Bertz H, Wäsch R, Marks R, Rüter B, Claus R et al. Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting. Bone Marrow Transplant 2010; 45: 627–632.

    Article  Google Scholar 

  24. Czibere A, Bruns I, Kröger N, Platzbecker U, Lind J, Zohren F et al. 5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after allo-SCT: a retrospective analysis. Bone Marrow Transplant 2010; 45: 872–876.

    Article  CAS  Google Scholar 

  25. Craddock C, Quek L, Goardon N, Freeman S, Siddique S, Raghavan M et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leuk Off J Leuk Soc Am Leuk Res Fund UK 2013; 27: 1028–1036.

    CAS  Google Scholar 

  26. Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T et al. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leuk Off J Leuk Soc Am Leuk Res Fund UK 2013; 27: 1229–1235.

    CAS  Google Scholar 

  27. Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leuk Off J Leuk Soc Am Leuk Res Fund UK 2012; 26: 381–389.

    CAS  Google Scholar 

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Acknowledgements

We thank the Association pour la Recherche sur le Cancer (Grant no. 3175 to MM), the Fondation de France, the Fondation contre la Leucémie, the Agence de Biomédecine, the Association Cent pour Sang la Vie, the Association Laurette Fuguain, the IRGHET and the Ligue contre le Cancer (Comités Départementaux de l’Inter région Grand-Ouest Bretagne, Centre, Pays-de-Loire, Poitou-Charentes) for their generous and continuous support for our clinical and basic research work. This work was also supported by educational grants from the Association for Training, Education and Research in Hematology, Immunology and Transplantation (ATERHIT). Our group is supported by several grants from the French National Cancer Institute (PHRC, INCa to MM).

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Correspondence to B Tessoulin.

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MM received lectures honoraria and research support from Celgene whose product is discussed in this article. All other authors report no conflict of interest.

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Tessoulin, B., Delaunay, J., Chevallier, P. et al. Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT. Bone Marrow Transplant 49, 567–571 (2014). https://doi.org/10.1038/bmt.2013.233

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