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.

  • Letter to the Editor
  • Published:

A multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia

Leukemia volume 28, pages 1570–1572 (2014)Cite this article

Subjects

Therapeutic options for chronic myelomonocytic leukaemia (CMML) remain limited. Azacitidine (AZA) is approved for CMML-2 lacking proliferative features (white cell count (WCC) <13 × 109/l); however, AZA registration studies for myelodysplasia (MDS) contained small numbers of CMML patients (n=30), preventing definitive conclusions with regards to toxicity and efficacy.1, 2 Published retrospective case series of AZA therapy for CMML document overall response rates (ORR) and complete remission (CR) rates of 39–60% and 11–40%, respectively,3, 4, 5 according to International Working Group (IWG) 2006 criteria.6 On behalf of the UK National Cancer Research Network (UKNCRN) MDS Trial Subgroup, we conducted a multi-centre phase 2 trial of AZA in CMML patients with features of advanced disease, incorporating mutation analysis and methylation status.

Between January and August 2010, 32 patients with newly diagnosed or previously treated CMML7 (hydroxycarbamide and/or supportive care only) were enroled after written informed consent. Safety and tolerability, and ORR (as defined by Wattel et al.8) were co-primary end points. Secondary end points included response according to modified IWG criteria (incidence of CR, partial remission and haematological improvement),6 overall and progression-free survival (OS, PFS), time to transformation or death and biological correlates (mutation analysis of TET2, ASXL1, EZH2, CBL and NRAS genes, and gene methylation status). The trial was approved by the UK National Research Ethics Service (EudraCT 2008-006349-23 and ISRCTN 21428905). Inclusion criteria were: (1) CMML-2 and (2) CMML-1 patients with symptomatic marrow failure or proliferative disease, intermediate or high Dusseldorf score (for WCC >12 × 109/l) or int-2 or high IPSS score (for WCC <12 × 109/l), and/or symptomatic splenomegaly or systemic symptoms (including weight loss of 10% from baseline over the previous 6 months with no other explanation) or symptomatic extramedullary disease (including skin infiltration and serous effusions). Of 74 patients pre-screened for eligibility, 32 were registered for trial entry (see CONSORT Flow Diagram, Supplementary Figure 1). AZA was administered (75 mg/m2 for 7 days, 5-2-2 schedule) every 28 days, for a minimum of six cycles. Responders and patients with stable disease were allowed to continue therapy until loss of response/progressive disease or development of unacceptable toxicities. Assessment of spleen size was by clinical examination. Toxicities were determined as per National Cancer Institute-Common Toxicity Criteria (Version 3.0). Patients remained on follow-up until 12 months after the last patient’s last dose of treatment (median follow-up 12.8 months, range 0.6–30.3).

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. Fenaux P, Mufti GJ, Hellstrom-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  PubMed Central  PubMed  Google Scholar 

  2. Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh LS, Lee SL et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 2005; 11: 3604–3608.

    Article  CAS  PubMed  Google Scholar 

  3. Costa R, Abdulhaq H, Haq B, Shadduck RK, Latsko J, Zenati M et al. Activity of azacitidine in chronic myelomonocytic leukemia. Cancer 2011; 117: 2690–2696.

    Article  CAS  PubMed  Google Scholar 

  4. Thorpe M, Montalvao A, Pierdomenico F, Moita F, Almeida A . Treatment of chronic myelomonocytic leukemia with 5-Azacitidine: a case series and literature review. Leuk Res 2012; 36: 1071–1073.

    Article  CAS  PubMed  Google Scholar 

  5. Ades L, Sekeres MA, Wolfromm A, Teichman ML, Tiu RV, Itzykson R et al. Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res 2013; 37: 609–613.

    Article  CAS  PubMed  Google Scholar 

  6. Cheson B, Greenberg P, Bennett J, Lowenberg B, Wijermans P, Nimer S 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  PubMed  Google Scholar 

  7. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn. IARC Press: Lyon, France, 2008.

    Google Scholar 

  8. Wattel E, Guerci A, Hecquet B, Economopoulos T, Copplestone A, Mahe B et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Francais des Myelodysplasies and European CMML Group. Blood 1996; 88: 2480–2487.

    CAS  PubMed  Google Scholar 

  9. Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 2009; 113: 6182–6192.

    Article  CAS  PubMed  Google Scholar 

  10. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010; 42: 722–726.

    Article  CAS  PubMed  Google Scholar 

  11. Score J, Hidalgo-Curtis C, Jones AV, Winkelmann N, Skinner A, Ward D et al. Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Blood 2012; 119: 1208–1213.

    Article  CAS  PubMed  Google Scholar 

  12. Braun T, Itzykson R, Renneville A, de Renzis B, Dreyfus F, Laribi K et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 2011; 118: 3824–3831.

    Article  CAS  PubMed  Google Scholar 

  13. 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 

Download references

Acknowledgements

This trial was funded by Cancer Research UK (Grant Award Number C24417/A10418) and Celgene (UK) Ltd. Celgene (UK) provided study drug. Methylation studies were funded by a grant from Yorkshire Cancer Research (Grant Award Number L335) and on-going support from Leukaemia & Lymphoma Research, UK. We would like to thank staff at the 13 UK centres who recruited patients to this study.

Author information

Authors and Affiliations

  1. Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow, UK

    M W Drummond

  2. Department of Hematology, East Kent Hospitals, Canterbury, UK

    C Pocock

  3. Leeds Institute for Cancer Studies and Pathology, University of Leeds, Leeds, UK

    M Boissinot

  4. Worcestershire Acute Hospitals NHS Trust and University of Birmingham, Birmingham, UK

    J Mills

  5. Clinical Trials Research Unit, University of Leeds, Leeds, UK

    J Brown, S Hartley & A Szubert

  6. Institute of Biomedical Research, University of Birmingham, Birmingham, UK

    P Cauchy & P N Cockerill

  7. Faculty of Medicine, University of Southampton, Southampton, UK

    N C P Cross

  8. Department of Hematology, University Hospital of Wales, Cardiff, UK

    J Kell

  9. Department of Hematology, St James's Institute of Oncology, Leeds, UK

    D T Bowen

Authors
  1. M W Drummond
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Pocock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Boissinot
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Mills
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Cauchy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N C P Cross
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Hartley
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Kell
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Szubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P N Cockerill
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D T Bowen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M W Drummond.

Ethics declarations

Competing interests

MWD, JK and DTB have received advisory board and speaker fees from Celgene. The remaining 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

Cite this article

Drummond, M., Pocock, C., Boissinot, M. et al. A multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia. Leukemia 28, 1570–1572 (2014). https://doi.org/10.1038/leu.2014.85

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.85

This article is cited by

Search

Advanced search

Quick links