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:

Prognostic value of monitoring a candidate immunophenotypic leukaemic stem/progenitor cell population in patients allografted for acute myeloid leukaemia

Leukemia volume 29, pages 988–991 (2015)Cite this article

Subjects

It is postulated that disease relapse in patients with acute myeloid leukaemia (AML) is consequent upon chemoresistance within leukaemic stem/progenitor cell (LSC) populations from which bulk blasts arise.1 In adults with high-risk AML, allogeneic haematopoietic cell transplantation (HCT) has become a central component of the treatment algorithm to overcome this chemoresistance, as it delivers maximal anti-leukaemic activity through both dose intensification and by the genesis of a potent graft-versus-leukaemia (GVL) effect.2, 3, 4 However, relapse still occurs in a significant proportion of allografted patients and now represents the major cause of treatment failure, particularly with reduced intensity conditioning (RIC) regimens.5 Although minimal residual disease (MRD) from the bulk leukaemic population is known to be prognostic, more accurate predictors of relapse risk might be developed from detection of putative LSC populations pre- or post transplant. However, to date an association between LSC and transplant outcome remains uncertain.

Xenotransplantation assays, which have characterised the leukaemic propagating functional properties of LSCs, cannot be applied as a routine clinical assay to track LSC residual disease in AML patients. As well as monitoring MRD from bulk leukaemic blasts,6 multiparameter flow cytometry (MFC) assays can be used to quantitate candidate immunophenotypic haematopoietic stem/progenitor populations characterised as enriched for LSC activity.7, 8 We report the first study to evaluate an immunophenotypic LSC assay as a biomarker for outcome in allografted AML patients, performed in parallel with standard MFC-MRD monitoring (using conventional leukaemic aberrant immunophenotypes) and chimerism studies for pre- and post-HCT time points in 101 adults undergoing HCT for high-risk AML or myelodysplasia. Our cohort included predominantly older patients, many of whom were allografted using a RIC regimen (RIC=73; myeloablative conditioning, MAC=28). The results are thus relevant to similar patient populations in many adult transplant centres, as RIC-HCT is increasingly used for older patients with AML/high-risk myelodysplasia.

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

Figure 1

References

  1. Dick JE . Stem cell concepts renew cancer research. Blood 2008; 112: 4793–4807.

    Article  CAS  PubMed Central  Google Scholar 

  2. Appelbaum FR . Optimising the conditioning regimen for acute myeloid leukaemia. Best Pract Res Clin Haematol 2009; 22: 543–550.

    Article  PubMed Central  Google Scholar 

  3. Estey EH . How to manage high-risk acute myeloid leukemia. Leukemia 2012; 26: 861–869.

    Article  CAS  PubMed Central  Google Scholar 

  4. Stelljes M, Krug U, Beelen DW, Braess J, Sauerland MC, Heinecke A et al. Allogeneic transplantation versus chemotherapy as postremission therapy for acute myeloid leukemia: a prospective matched pairs analysis. J Clin Oncol 2014; 32: 288–296.

    Article  Google Scholar 

  5. Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood 2012; 119: 1599–1606.

    Article  CAS  PubMed Central  Google Scholar 

  6. Grimwade D, Freeman SD . Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for "Prime Time"? Blood 2014; 124: 3345–3355.

    Article  CAS  Google Scholar 

  7. Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 2011; 19: 138–152.

    Article  CAS  Google Scholar 

  8. van Rhenen A, Moshaver B, Kelder A, Feller N, Nieuwint AW, Zweegman S et al. Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. Leukemia 2007; 21: 1700–1707.

    Article  CAS  Google Scholar 

  9. Craddock C, Quek L, Goardon N, Freeman S, Siddique S, Raghavan M et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia 2013; 27: 1028–1036.

    Article  CAS  Google Scholar 

  10. Sarry JE, Murphy K, Perry R, Sanchez PV, Secreto A, Keefer C et al. Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rgammac-deficient mice. J Clin Invest 2011; 121: 384–395.

    Article  CAS  Google Scholar 

  11. Taussig DC, Vargaftig J, Miraki-Moud F, Griessinger E, Sharrock K, Luke T et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood 2010; 115: 1976–1984.

    Article  CAS  PubMed Central  Google Scholar 

  12. Craddock C . Pharmacological methods to reduce disease recurrence. Hematology Am Soc Hematol Educ Program 2013; 2013: 63–69.

    Article  Google Scholar 

  13. Stolzel F, Hackmann K, Kuithan F, Mohr B, Fussel M, Oelschlagel U et al. Clonal evolution including partial loss of human leukocyte antigen genes favoring extramedullary acute myeloid leukemia relapse after matched related allogeneic hematopoietic stem cell transplantation. Transplantation 2012; 93: 744–749.

    Article  Google Scholar 

  14. Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med 2009; 361: 478–488.

    Article  CAS  Google Scholar 

  15. Costello RT, Mallet F, Gaugler B, Sainty D, Arnoulet C, Gastaut JA et al. Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res 2000; 60: 4403–4411.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank patients and clinical teams and Peter Richardson, Steve Dix and the West Midlands Regional Genetics laboratory led by Mike Griffiths and Susanna Akiki for sample processing. This work was supported by funding from the National Institute for Health and Research, Leukaemia and Lymphoma Research, Cancer Research UK, and the CIRM Disease Team Grant DR1-01485. PV is supported by the MRC Disease Team Award. This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0108-10093). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Author information

Authors and Affiliations

  1. Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK

    C Bradbury, A E Houlton, R Gregg, J Khan, J Ward, S Nagra, C Craddock & S D Freeman

  2. Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, UK

    A E Houlton & C Craddock

  3. West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, UK

    S Akiki, M Rindl & M Griffiths

  4. Department of Clinical Immunology, University of Birmingham, Birmingham, UK

    N Khan & S D Freeman

  5. Department of Haematology, Cardiff University, Cardiff, UK

    R Hills & A Burnett

  6. Department of Haematology, Nottingham University Hospital NHS Trust, Nottingham, UK

    N Russell

  7. MRC Molecular Haematology Unit, WIMM, University of Oxford, Oxford, UK

    P Vyas

  8. Department of Haematology, Radcliffe Hospitals NHS Trust, Oxford, UK

    P Vyas

  9. Department of Medical & Molecular Genetics, King’s College London, Faculty of Life Sciences and Medicine, London, UK

    D Grimwade

  10. Department of Haematology, Guy’s & St. Thomas’ NHS Foundation Trust, London, UK

    D Grimwade

Authors
  1. C Bradbury
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A E Houlton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Akiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Gregg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Rindl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Griffiths
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Nagra
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R Hills
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Burnett
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. N Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P Vyas
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. D Grimwade
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. C Craddock
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. S D Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S D Freeman.

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

Bradbury, C., Houlton, A., Akiki, S. et al. Prognostic value of monitoring a candidate immunophenotypic leukaemic stem/progenitor cell population in patients allografted for acute myeloid leukaemia. Leukemia 29, 988–991 (2015). https://doi.org/10.1038/leu.2014.327

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.327

This article is cited by

Search

Advanced search

Quick links