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:

Acute myeloid leukemia

Mitoxantrone, etoposide and cytarabine following epigenetic priming with decitabine in adults with relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms: a phase 1/2 study

Leukemia volume 31, pages 2560–2567 (2017)Cite this article

Subjects

Abstract

DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. We therefore conducted a phase 1/2 study of mitoxantrone, etoposide and cytarabine following ‘priming’ with 5–10 days of decitabine (dec/MEC) in 52 adults (median age 55 (range: 19–72) years) with relapsed/refractory acute myeloid leukemia (AML) or other high-grade myeloid neoplasms. During dose escalation in cohorts of 6–12 patients, all dose levels were well tolerated. As response rates appeared similar with 7 and 10 days of decitabine, a 7-day course was defined as the recommended phase 2 dose (RP2D). Among 46 patients treated at/above the RP2D, 10 (22%) achieved a complete remission (CR), 8 without measurable residual disease; five additional patients achieved CR with incomplete platelet recovery, for an overall response rate of 33%. Seven patients (15%) died within 28 days of treatment initiation. Infection/neutropenic fever, nausea and mucositis were the most common adverse events. While the CR rate compared favorably to a matched historic control population (observed/expected CR ratio=1.77), CR rate and survival were similar to two contemporary salvage regimens used at our institution (G-CLAC (granulocyte colony-stimulating factor (G-CSF); clofarabine; cytarabine) and G-CLAM (G-CSF; cladribine; cytarabine; mitoxantrone)). Thus, while meeting the prespecified efficacy goal, we found no evidence that dec/MEC is substantially better than other cytarabine-based regimens currently used for relapsed/refractory AML.

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

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Ferrara F, Schiffer CA . Acute myeloid leukaemia in adults. Lancet 2013; 381: 484–495.

    Article  PubMed  Google Scholar 

  2. Döhner H, Weisdorf DJ, Bloomfield CD . Acute myeloid leukemia. N Engl J Med 2015; 373: 1136–1152.

    Article  PubMed  Google Scholar 

  3. Amadori S, Arcese W, Isacchi G, Meloni G, Petti MC, Monarca B et al. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol 1991; 9: 1210–1214.

    Article  CAS  PubMed  Google Scholar 

  4. Leopold LH, Willemze R . The treatment of acute myeloid leukemia in first relapse: a comprehensive review of the literature. Leuk Lymphoma 2002; 43: 1715–1727.

    Article  CAS  PubMed  Google Scholar 

  5. Ravandi F . Relapsed acute myeloid leukemia: why is there no standard of care? Best Pract Res Clin Haematol 2013; 26: 253–259.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Thol F, Schlenk RF, Heuser M, Ganser A . How I treat refractory and early relapsed acute myeloid leukemia. Blood 2015; 126: 319–327.

    Article  CAS  PubMed  Google Scholar 

  7. Shih AH, Abdel-Wahab O, Patel JP, Levine RL . The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 2012; 12: 599–612.

    Article  CAS  PubMed  Google Scholar 

  8. Abdel-Wahab O, Levine RL . Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood 2013; 121: 3563–3572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Estey EH . Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia. Leukemia 2013; 27: 1803–1812.

    Article  CAS  PubMed  Google Scholar 

  10. Roboz GJ . Epigenetic targeting and personalized approaches for AML. Hematol Am Soc Hematol Educ Program 2014; 2014: 44–51.

    Article  Google Scholar 

  11. Wouters BJ, Delwel R . Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood 2016; 127: 42–52.

    Article  CAS  PubMed  Google Scholar 

  12. Qin T, Youssef EM, Jelinek J, Chen R, Yang AS, Garcia-Manero G et al. Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res 2007; 13: 4225–4232.

    Article  CAS  PubMed  Google Scholar 

  13. Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS ONE 2010; 5: e9001.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kurimoto M, Matsuoka H, Hanaoka N, Uneda S, Murayama T, Sonoki T et al. Pretreatment of leukemic cells with low-dose decitabine markedly enhances the cytotoxicity of gemtuzumab ozogamicin. Leukemia 2013; 27: 233–235.

    Article  CAS  PubMed  Google Scholar 

  15. Leonard SM, Perry T, Woodman CB, Kearns P . Sequential treatment with cytarabine and decitabine has an increased anti-leukemia effect compared to cytarabine alone in xenograft models of childhood acute myeloid leukemia. PLoS ONE 2014; 9: e87475.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Scandura JM, Roboz GJ, Moh M, Morawa E, Brenet F, Bose JR et al. Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML. Blood 2011; 118: 1472–1480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Song LX, Xu L, Li X, Chang CK, Zhang Y, Wu LY et al. Clinical outcome of treatment with a combined regimen of decitabine and aclacinomycin/cytarabine for patients with refractory acute myeloid leukemia. Ann Hematol 2012; 91: 1879–1886.

    Article  CAS  PubMed  Google Scholar 

  18. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.

    Article  PubMed  Google Scholar 

  19. Walter RB, Othus M, Borthakur G, Ravandi F, Cortes JE, Pierce SA et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol 2011; 29: 4417–4423.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354–365.

    Article  CAS  PubMed  Google Scholar 

  21. Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 2011; 29: 1190–1197.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Araki D, Wood BL, Othus M, Radich JP, Halpern AB, Zhou Y et al. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: time to move toward a minimal residual disease-based definition of complete remission? J Clin Oncol 2016; 34: 329–336.

    Article  PubMed  Google Scholar 

  23. Becker PS, Kantarjian HM, Appelbaum FR, Petersdorf SH, Storer B, Pierce S et al. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol 2011; 155: 182–189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Holowiecki J et al. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol 2008; 80: 115–126.

    Article  CAS  PubMed  Google Scholar 

  25. Jaglal MV, Duong VH, Bello CM, Al Ali NH, Padron E, Fernandez HF et al. Cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) compared to standard induction in acute myeloid leukemia from myelodysplastic syndrome after azanucleoside failure. Leuk Res 2014; 38: 443–446.

    Article  CAS  PubMed  Google Scholar 

  26. Ravandi F, Ritchie EK, Sayar H, Lancet JE, Craig MD, Vey N et al. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol 2015; 16: 1025–1036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Estey E, Kornblau S, Pierce S, Kantarjian H, Beran M, Keating M . A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. Blood 1996; 88: 756.

    CAS  PubMed  Google Scholar 

  28. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109: 52–57.

    Article  CAS  PubMed  Google Scholar 

  29. Walter RB, Appelbaum FR, Tallman MS, Weiss NS, Larson RA, Estey EH . Shortcomings in the clinical evaluation of new drugs: acute myeloid leukemia as paradigm. Blood 2010; 116: 2420–2428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ye XN, Zhou XP, Wei JY, Xu GX, Li Y, Mao LP et al. Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms. Leuk Lymphoma 2016; 57: 1311–1318.

    Article  CAS  PubMed  Google Scholar 

  31. Li J, Chen Y, Zhu Y, Zhou J, Xu Y, Li Y et al. Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia. Oncotarget 2015; 6: 6448–6458.

    PubMed  PubMed Central  Google Scholar 

  32. Müller-Tidow C, Tschanter P, Röllig C, Thiede C, Koschmieder A, Stelljes M et al. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA Trial of the Study Alliance Leukemia. Leukemia 2016; 30: 555–561.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The conduct of the clinical trial was partially funded by Protocol Specific Research Support from the Fred Hutchinson/University of Washington Cancer Consortium Cancer Center Support Grant of the National Institutes of Health (P30-CA015704). ABH and SAB are supported by a fellowship training grant from the National Heart, Lung and Blood Institute/National Institutes of Health (NHLBI/NIH: T32-HL007093). RBW is a Leukemia & Lymphoma Society Scholar in Clinical Research.

Author information

Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    A B Halpern, E M Huebner, E L Pogosova-Agadjanyan, K F Orlowski, B L Scott, P S Becker, M-E M Percival, E H Estey, D L Stirewalt & R B Walter

  2. Division of Hematology/Department of Medicine, University of Washington, Seattle, WA, USA

    A B Halpern, P S Becker, P C Hendrie, M-E M Percival, E H Estey & R B Walter

  3. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    M Othus

  4. Hematology/Oncology Fellowship Program, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S A Buckley

  5. Department of Medicine/Division of Hematology, University of Washington, Seattle, WA, USA

    B L Scott & D L Stirewalt

  6. Department of Pharmacy Services, University of Washington, Seattle, WA, USA

    T L Chen

  7. Department of Epidemiology, University of Washington, Seattle, WA, USA

    R B Walter

Authors
  1. A B Halpern
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Othus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E M Huebner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S A Buckley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E L Pogosova-Agadjanyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K F Orlowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B L Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P S Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P C Hendrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T L Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M-E M Percival
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E H Estey
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D L Stirewalt
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R B Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A B Halpern.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Halpern, A., Othus, M., Huebner, E. et al. Mitoxantrone, etoposide and cytarabine following epigenetic priming with decitabine in adults with relapsed/refractory acute myeloid leukemia or other high-grade myeloid neoplasms: a phase 1/2 study. Leukemia 31, 2560–2567 (2017). https://doi.org/10.1038/leu.2017.165

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2017.165

This article is cited by

Search

Advanced search

Quick links