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.

  • Correspondence
  • Published:

Sequential administration of low dose 5-azacytidine (AZA) and donor lymphocyte infusion (DLI) for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in relapse after allogeneic stem cell transplantation (SCT): a prospective study from the Belgian Hematology Society (BHS)

Bone Marrow Transplantation volume 57, pages 116–118 (2022)Cite this article

Subjects

Relapse remains the major cause of failure after allogeneic stem cell transplantation (SCT) and to date, there has been little progress in managing those relapses. Therapeutic options are still limited including supportive care, salvage chemotherapy, donor lymphocyte infusion (DLI), or second SCT [1]. Azacytidine (AZA) has shown to improve survival in patients with MDS and low blast count AML and has been therefore administered in relapsed MDS or AML after SCT [2,3,4]. Responses appear to be mainly related to an immunomodulatory effect, which consists of upregulated expression of HLA and cancer-associated antigens, and subsequent sensitization of leukemic blasts to an adaptive T-cell response. Moreover, epigenetic mechanisms induce regulatory T cells, leading to a protective effect against graft-versus-host disease (GvHD) [5,6,7]. Here are the results of a phase II prospective study conducted on the sequential administration of AZA and DLI in patients with MDS or AML relapsing after SCT.

Adult patients from 18 up to 70 years of age were eligible provided they were transplanted for AML in remission or MDS with less than 10% marrow blasts, and they developed evidence of relapse with <30% marrow blasts. For the first cycle, patients received AZA 100 mg/m2, subcutaneously (SQ) for 5 days. From cycle 2 to 6, AZA was decreased to 35 mg/m2 SQ based on the observations that low dose AZA is sufficient to exert an immunomodulatory effect [7]. DLI was planned on day 1 or 2 of cycles 2, 4, and 6 if free from GvHD to allow lymphocytes to be fully modulated by AZA. The escalating dose schedule of DLI was 5 × 107, 1 × 108, and 5 × 108 CD3+/kg in case of sibling donors, and 5 × 106, 1 × 107, and 5 × 107 CD3+/kg for unrelated donors. In case of complete response (CR) or CR with incomplete blood recovery (CRi), two additional cycles of AZA were administered. If the patient achieved partial response (PR) or stable disease (SD), AZA was continued until progression (PD) or CR. The primary endpoint was overall response rate (ORR) at 6 months, defined by the achievement of CR, CRi, or PR. Secondary endpoints included overall survival (OS), non-relapse mortality, hematological, and non-hematological toxicities, incidence of GvHD and incidence of infections. Statistical analyses were performed with SPSS 24.0 (SPSS Inc, Chicago, IL, USA) and R 3.4.1 (R Core Team (2017). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/).

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

References

  1. Thanarajasingam G, Kim HT, Cutler C, Ho VT, Koreth J, Alyea EP, et al. Outcome and prognostic factors for patients who relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:1713–8.

    Article  Google Scholar 

  2. Craddock C, Jilani N, Siddique S, Yap C, Khan J, Nagra S, et al. Tolerability and clinical activity of post-transplantation azacitidine in patients allografted for acute myeloid leukemia treated on the RICAZA trial. Biol Blood Marrow Transplant. 2016;22:385–90.

    Article  CAS  Google Scholar 

  3. 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;115:1899–905.

    Article  CAS  Google Scholar 

  4. 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;27:1229–35.

    Article  CAS  Google Scholar 

  5. 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;116:129–39.

    Article  CAS  Google Scholar 

  6. Cooper ML, Choi J, Karpova D, Vij K, Ritchey J, Schroeder MA, et al. Azacitidine mitigates graft-versus-host disease via differential effects on the proliferation of T effectors and natural regulatory T cells in vivo. J Immunol. 2017;198:3746–54.

    Article  CAS  Google Scholar 

  7. 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;119:3361–9.

    Article  CAS  Google Scholar 

  8. Craddock C, Labopin M, Robin M, Finke J, Chevallier P, Yakoub-Agha I, et al. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2016;101:879–83.

    Article  CAS  Google Scholar 

  9. Schroeder T, Rachlis E, Bug G, Stelljes M, Klein S, Steckel NK, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions—a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant. 2015;21:653–60.

    Article  CAS  Google Scholar 

  10. 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;45:872–6.

    Article  CAS  Google Scholar 

  11. Schroeder T, Rautenberg C, Krüger W, Platzbecker U, Bug G, Steinmann J, et al. Treatment of relapsed AML and MDS after allogeneic stem cell transplantation with decitabine and DLI-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group. Ann Hematol. 2018;97:335–42.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Celgene provided azacytidine to all included patients and supported study with a restricted grant. We thank Myriam Labopin, MD, Ph.D., Saint-Antoine, Paris, France who helped us with the statistical analysis.

Author information

Author notes

  1. These authors contributed equally: Xavier Poiré, Carlos Graux.

Authors and Affiliations

  1. Section of Hematology, Cliniques Universitaires St-Luc, Université Catholique de Louvain, Brussels, Belgium

    Xavier Poiré

  2. Section of Hematology, CHU UCL Namur-Godinne, Université Catholique de Louvain, Yvoir, Belgium

    Carlos Graux

  3. Data Management Office, Belgian Hematology Society, Liège, Belgium

    Aurélie Ory & Julie Herman

  4. Section of Hematology, Centre Hospitalier Universitaire de Liège, Université de Liège, Liège, Belgium

    Frédéric Baron & Yves Beguin

  5. Department of Hematology, University Hospitals of Leuven and KU Leuven, Leuven, Belgium

    Hélène Schoemans

  6. Section of Hematology, Institut Jules Bordet, Université libre de Bruxelles, Brussels, Belgium

    Philippe Lewalle

  7. Department Clinical Hematology, Universitair Ziekenhuis Brussel, Brussels, Belgium

    Ann De Becker

  8. Department of Hematology, AZ Delta, Roeselare, Belgium

    Dries Deeren

  9. Department of Hematology, Antwerp University Hospital, Edegem, Belgium

    Zwi Berneman

  10. Department of Hematology, Ghent University Hospital, Ghent, Belgium

    Tessa Kerre

  11. Department of Hematology, ZNA Stuivenberg, Antwerp, Belgium

    Pierre Zachée

  12. Department of Hematology, AZ Sint Jan, Brugge, Belgium

    Dominik Selleslag

Authors
  1. Xavier Poiré
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos Graux
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aurélie Ory
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julie Herman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frédéric Baron
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hélène Schoemans
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Philippe Lewalle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ann De Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dries Deeren
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zwi Berneman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tessa Kerre
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Pierre Zachée
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Dominik Selleslag
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yves Beguin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XP and CG wrote the paper. AO and JH collected the data. XP analyzed the data and performed the statistical analysis. XP, CG, FB, HS, PL, ADB, DD, ZB, TK, PZ, DS, and YB provided the data. FB, HS, PL, ADB, DD, ZB, TK, PZ, DS, and YB approved the paper.

Corresponding author

Correspondence to Xavier Poiré.

Ethics declarations

Competing interests

FB has received travel grants and/or speaker honoraria from Celgene, AbbVie, Novartis, Pfizer and Sanofi. HS has received travel grants and/or speaker/advisor honoraria from Incyte, Janssen, Novartis, Jazz Pharmaceuticals, Takeda Celgene, AbbVie, MSD, and Therakos. YB has received travel grants and/or speaker/consulting honoraria from Celgene, AbbVie, Novartis, Pfizer, Janssens-Cilag, Amgen and Sanofi. The study was supported by a grant from Celgene Inc.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Poiré, X., Graux, C., Ory, A. et al. Sequential administration of low dose 5-azacytidine (AZA) and donor lymphocyte infusion (DLI) for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in relapse after allogeneic stem cell transplantation (SCT): a prospective study from the Belgian Hematology Society (BHS). Bone Marrow Transplant 57, 116–118 (2022). https://doi.org/10.1038/s41409-021-01464-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-021-01464-x

This article is cited by

Search

Advanced search

Quick links