Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Cellular Therapy

5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft

Abstract

DNA-hypomethylating agents are a viable treatment option for AML/myelodysplastic syndrome (MDS) relapse after allograft by upregulating Ags on blasts before DLI. Seventy-two patients with relapsed AML (n=62), MDS (n=8) and other myeloid neoplasms (n=2) after allograft were treated with low-dose 5-azacytidine and, if feasible, DLI. Patient characteristics: median age 62 years (range 20–75), 42% with adverse cytogenetics, 82% not in remission at transplant and 83% received fludarabine-based reduced-toxicity conditioning. Median duration from transplant to 5-azacytidine was 289 days (range 59–2133). Response criteria: CR, temporary disease control or treatment failure. A median of 2.7 courses (range 1–10) were administered; 65 out of 72 patients also received DLI (41 already before 5-azacytidine). Ten patients developed acute GVHD and two succumbed to treatment-related sepsis. CR rate was 9.7% (in two patients lasting >5 years), 44% had temporary disease control (median duration 71 days, range 31–380). Median survival from 5-azacytidine was 108 days, 21 patients proceeded to subsequent transplant. In multivariate analysis, peripheral blood blasts <1% were predictive of longer OS (P=0.03). Taken together, long-term remissions can be induced by this well-tolerated outpatient treatment, particularly in patients without peripheral blood blasts.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Finelli C, Giagounidis A et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223–232.

    Article  CAS  Google Scholar 

  2. Lübbert M, Suciu S, Baila L, Rüter BH, Platzbecker U, Giagounidis A et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 2011; 29: 1987–1996.

    Article  Google Scholar 

  3. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012; 30: 2670–2677.

    Article  CAS  Google Scholar 

  4. Graef T, Kuendgen A, Fenk R, Zohren F, Haas R, Kobbe G . Successful treatment of relapsed AML after allogeneic stem cell transplantation with azacitidine. Leuk Res 2007; 31: 257–259.

    Article  CAS  Google Scholar 

  5. 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 

  6. 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. Leukemia 2013; 27: 1229–1235.

    Article  CAS  Google Scholar 

  7. 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 

  8. 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 

  9. Lübbert M, Bertz H, Rüter B, Marks R, Claus R, Wäsch R et al. Non-intensive treatment with low-dose 5-aza-2′-deoxycytidine (DAC) prior to allogeneic blood SCT of older MDS/AML patients. Bone Marrow Transplant 2009; 44: 585–588.

    Article  Google Scholar 

  10. Bertz H, Potthoff K, Finke J . Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia. J Clin Oncol 2003; 21: 1480–1484.

    Article  Google Scholar 

  11. Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100: 4372–4380.

    Article  Google Scholar 

  12. Döhner K, Schlenk RF, Habdank M, Scholl C, Rücker FG, Corbacioglu A et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 2005; 106: 3740–3746.

    Article  Google Scholar 

  13. Breems DA, Putten WLJV, Greef GED, Zelderen-Bhola SLV, Gerssen-Schoorl KBJ, Mellink CHM et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008; 26: 4791–4797.

    Article  Google Scholar 

  14. 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. Leukemia 2012; 26: 381–389.

    Article  CAS  Google Scholar 

  15. Phillips CL, Davies SM, McMasters R, Absalon M, O’Brien M, Mo J et al. Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults. Br J Haematol 2013; 161: 406–410.

    Article  CAS  Google Scholar 

  16. De Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome. Cancer 2010; 116: 5420–5431.

    Article  CAS  Google Scholar 

  17. 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 

  18. 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 

  19. Schroeder T, Fröbel J, Cadeddu R-P, Czibere A, Dienst A, Platzbecker U et al. Salvage therapy with azacitidine increases regulatory T cells in peripheral blood of patients with AML or MDS and early relapse after allogeneic blood stem cell transplantation. Leukemia 2013; 27: 1910–1913.

    Article  CAS  Google Scholar 

  20. 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 

  21. Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, Karbach J, Pfeifer D, Jäger E et al. The DNA demethylating agent 5-aza-2′-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk Res 2010; 34: 899–905.

    Article  CAS  Google Scholar 

  22. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng Q-R et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 2014; 28: 1280–1288.

    Article  CAS  Google Scholar 

  23. Tessoulin B, Delaunay J, Chevallier P, Loirat M, Ayari S, Peterlin P et al. Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT. Bone Marrow Transplant 2014; 49: 567–571.

    Article  CAS  Google Scholar 

  24. Griffiths EA, Srivastava P, Collamat G, James SR, Ford LA, Wetzler M et al. Decitabine treatment induces NY-ESO1 promoter hypomethylation, transcription and protein expression in circulating AML blasts. Leuk Res 2013; 37: S132.

    Article  Google Scholar 

  25. Toffalori C, Riba M, Zito L, Barcella M, Spinelli O, Crucitti L et al. CIITA-dependent transcriptional downregulation of HLA Class II results in leukemia immune escape and relapse after allogeneic HSCT. EBMT Annual Meeting 2014 abstract PH-O129.

Download references

Acknowledgements

We thank Irmgard Matt for excellent support with data acquisition.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Lübbert.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Steinmann, J., Bertz, H., Wäsch, R. et al. 5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft. Bone Marrow Transplant 50, 690–695 (2015). https://doi.org/10.1038/bmt.2015.10

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.10

This article is cited by

Search

Quick links