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Low-dose decitabine as part of a modified Bu-Cy conditioning regimen improves survival in AML patients with active disease undergoing allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 56, pages 1674–1682 (2021)Cite this article

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Abstract

Relapse is the major cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Effective preventive intervention in high-risk AML may be crucial. In this study, we investigated the clinical efficacy and safety of low dose decitabine (DAC) as part of a modified Busulfan-Cyclophosphamide (Bu-Cy) regimen for high-risk AML patients undergoing allo-HSCT to reduce relapse rate. Fifty-nine patients received DAC (20 mg/m2/d, i.v.) for 5 days, followed by modified Bu-Cy (DAC group). A matched-pair control (CON) group of 177 patients (matched 1:3) received modified Bu-Cy only. The differences were more substantial among patients with active disease: 2-year OS, 80.7% (DAC) versus 43.5% (CON), P = 0.011 and 2-year LFS, 64.9% (DAC) versus 39.2% (CON), P = 0.024. Median time to relapse was 8 months (DAC) versus 5 months (CON) for the entire groups and 6.5 months (DAC) versus 3.5 months (CON) for patients with active disease. In summary, our data indicated that the conditioning regimen containing low dose DAC may confer a survival advantage in high-risk AML patients with active disease undergoing allo-HSCT, and a prospective randomized trial is warranted to confirm these observations.

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Fig. 1: Drug cytotoxicity in human AML cell lines.
Fig. 2: Probability of overall and leukemia-free survival of all AML patients.
Fig. 3: Probability of overall and leukemia-free survival of AML patients with active disease.
Fig. 4: Cumulative Incidence: Relapse of AML patients with active disease.
Fig. 5: Probability of overall and leukemia-free survival of AML patients with FLT3-ITD mutation.

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References

  1. Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood. 2016;127:62–70.

    Article  CAS  Google Scholar 

  2. Barrett AJ, Battiwalla M. Relapse after allogeneic stem cell transplantation. Expert Rev Hematol. 2010;3:429–41.

    Article  Google Scholar 

  3. Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.

    Article  Google Scholar 

  4. Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A, et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia. 2006;20:322–8.

    Article  CAS  Google Scholar 

  5. Bacigalupo A, Sormani MP, Lamparelli T, Gualandi F, Occhini D, Bregante S, et al. Reducing transplant-related mortality after allogeneic hematopoietic stem cell transplantation. Haematologica. 2004;89:1238–47.

    PubMed  Google Scholar 

  6. Cornelissen JJ, van Putten WL, Verdonck LF, Theobald M, Jacky E, Daenen SM, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood. 2007;109:3658–66.

    Article  CAS  Google Scholar 

  7. Momparler RL. Molecular, cellular and animal pharmacology of 5-aza-2’-deoxycytidine. PharmacolTher. 1985;30:287–99.

    CAS  Google Scholar 

  8. Valdez BC, Li Y, Murray D, Corn P, Champlin RE, Andersson BS. 5-Aza-2’-deoxycytidine sensitizes busulfan-resistant myeloid leukemia cells by regulating expression of genes involved in cell cycle checkpoint and apoptosis. Leuk Res. 2010;34:364–72.

    Article  CAS  Google Scholar 

  9. 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 

  10. Valdez BC, Tang X, Li Y, Murray D, Liu Y, Popat U, et al. Epigenetic modification enhances the cytotoxicity of busulfan and 4-hydroperoxycyclophosphamide in AML cells. Exp Hematol. 2018;67:49–59.

    Article  CAS  Google Scholar 

  11. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.

    Article  CAS  Google Scholar 

  12. Lee SJ, Vogelsang G, Flowers MED. Chronic graft-versus-host disease. Biol Blood MarrowTransplant. 2003;9:215–33.

    Article  CAS  Google Scholar 

  13. Kaplan EL, Meier P. Nonparametric estimator from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

    Article  Google Scholar 

  14. Vijayaraghavalu S, Labhasetwar V. Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyltransferase 1 (DNMT1) depletion. Cancer Lett. 2013;331:122–9.

    Article  CAS  Google Scholar 

  15. Li K, Hu C, Mei C, Ren Z, Vera JC, Zhuang Z, et al. Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target. J Transl Med. 2014;12:167–80.

    Article  Google Scholar 

  16. Sigalotti L, Altomonte M, Colizzi F, Degan M, Rupolo M, Zagonel V, et al. 5-Aza-2’-deoxycytidine (decitabine) treatment of hematopoietic malignancies: a multimechanism therapeutic approach? Blood. 2003;101:4644–6.

    Article  CAS  Google Scholar 

  17. Almstedt M, Pfeifer D, Lubbert M. Cancer testis antigens residing on the X-chromosome are preferentially derepressed in myeloid leukemic cells by the DNA demethylating agent 5-aza-2 0 -deoxycytidine (DAC). Blood. 2008;112:abstr 2247.

    Article  Google Scholar 

  18. Klar AS, Gopinadh J, Kleber S, Wadle A, Renner C. Treatment with 5-aza-2’-deoxycytidine induces expression of NY-ESO-1 and facilitates cytotoxic T lymphocyte-mediated tumor cell killing. Plos ONE. 2015;10:e139221–139235.

    Article  Google Scholar 

  19. Jing Y, Shen X, Mei Q, Han W. Spotlight on decitabine for myelodysplastic syndromes in Chinese patients. Onco Targets Ther. 2015;8:2783–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Cany J, Roeven MWH, Hoogstad-van Evert JS, Hobo W, Maas F, Franco Fernandez R, et al. Decitabine enhances targeting of AML cells by CD34(+) progenitor-derived NK cells in NOD/SCID/IL2Rg(null) mice. Blood. 2018;131:202–14.

    Article  CAS  Google Scholar 

  21. Wang LX, Mei ZY, Zhou JH, Yao YS, Li YH, Xu YH, et al. Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. Plos ONE. 2013;8:e62924–e62935.

    Article  CAS  Google Scholar 

  22. Ma Y, Qu C, Dai H, Yin J, Li Z, Chen J, et al. Maintenance therapy with decitabine after allogeneic hematopoietic stem cell transplantation to prevent relapse of high-risk acute myeloid leukemia. Bone Marrow Transplant. 2020;55:1206–8.

    Article  Google Scholar 

  23. Ravandi F, Issa JP, Garcia-Manero G, O’Brien S, Pierce S, Shan J, et al. Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities. Cancer 2009;115:5746–51.

    Article  CAS  Google Scholar 

  24. Lübbert M, Rüter BH, Claus R, Schmoor C, Schmid M, Germing U, et al. A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica. 2012;97:393–401.

    Article  Google Scholar 

  25. Song G, Valdez BC, Li Y, Liu Y, Champlin RE, Andersson BS. Synergistic toxicity of sorafenib with busulfan and nucleoside analogs in human FMS-like tyrosine kinase 3 internal tandem duplications-positive acute myeloid leukemia cells. Biol Blood Marrow Transplant. 2014;20:1687–95.

    Article  CAS  Google Scholar 

  26. Im AP, Sehgal AR, Carroll MP, Smith BD, Tefferi A, Johnson DE, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia. 2014;28:1774–83.

    Article  CAS  Google Scholar 

  27. Bejar R, Lord A, Stevenson K, Bar-Natan M, Pérez-Ladaga A, Zaneveld J, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014;124:2705–12.

    Article  CAS  Google Scholar 

  28. Giralt S, Davis M, O’Brien S, van Besien K, Champlin R, de Vos D, et al. Studies of decitabine with allogeneic progenitor cell transplantation. Leukemia. 1997;11:S32–S34.

    PubMed  Google Scholar 

  29. de Lima M, Ravandi F, Shahjahan M, Andersson B, Couriel D, Donato M, et al. Long-term follow-up of a phase I study of high-dose decitabine, busulfan, and cyclophosphamide plus allogeneic transplantation for the treatment of patients with leukemias. Cancer 2003;97:1242–7.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by research grants from National Natural Science Foundation of China (81873443, 82070162, 81900175, 81400155, 81700139), Jiangsu Provincial Medical Talent (ZDRCA2016045), Major Natural Science Research Projects in institutions of higher education of Jiangsu Province (19KJA210002), The Key Science Research Project of Jiangsu Commission of Health (K2019022), Translational Research Grant of NCRCH (2020ZKZC04) and Natural Science Foundation of Jiangsu Province (BK20190181, BK20201169), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)

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  1. These authors contributed equally: Xiaowen Tang, Benigno C. Valdez, Yunju Ma

  2. These authors jointly supervised this work: Xiaowen Tang, Depei Wu

Authors and Affiliations

  1. National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China

    Xiaowen Tang, Yunju Ma, Qianqian Zhang, Changju Qu, Haiping Dai, Jia Yin, Zheng Li, Ting Xu, Yang Xu, Jia Chen, Xiaming Zhu, Zixing Chen & Depei Wu

  2. Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China

    Xiaowen Tang, Yunju Ma, Qianqian Zhang, Changju Qu, Haiping Dai, Jia Yin, Zheng Li, Ting Xu, Yang Xu, Jia Chen, Xiaming Zhu, Zixing Chen & Depei Wu

  3. Department of Stem Cell Transplantation & Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX, USA

    Benigno C. Valdez & Borje S. Andersson

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Correspondence to Xiaowen Tang or Depei Wu.

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Tang, X., Valdez, B.C., Ma, Y. et al. Low-dose decitabine as part of a modified Bu-Cy conditioning regimen improves survival in AML patients with active disease undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 56, 1674–1682 (2021). https://doi.org/10.1038/s41409-021-01238-5

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