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:

Is there a need for morphologic exam to detect relapse in AML if multi-parameter flow cytometry is employed?

Leukemia volume 31, pages 2536–2537 (2017)Cite this article

Subjects

For many years, examination of the bone marrow in acute myeloid leukemia (AML) was largely limited to morphology. The WHO criterion for the diagnosis remains a marrow with ⩾20% blasts as assessed morphologically,1 while a diagnosis of relapse requires the presence, also based on morphology, of ⩾5% myeloblasts.2 The 5% requirement reflects observations that normal subjects can have up to 5% blasts as identified morphologically.

In contrast to the 5% sensitivity of morphologic exam, multi-parameter flow cytometry (MFC) can currently detect one abnormal myeloblast among 1000–10 000 white cells for a sensitivity of 0.1–0.01%,3 although there is debate about the relative advantages and disadvantages of the two principal methodologies: detection of patient-specific leukemia-associated immunophenotypes (LAIP) and use of a fixed antibody panel to distinguish normal cells from abnormal leukemia cells, irrespective of diagnostic leukemia immunophenotype (‘different-from-normal method’, the method used here).3 In contrast to enumerating blasts, MFC can in many cases define more than one LAIP, thus increasing MFC’s sensitivity.3 The 50–500-fold greater sensitivity of MFC suggests that if morphologic exam demonstrates ⩾5% blasts, MFC will essentially invariably be positive except when the excess blasts identified morphologically reflect active regeneration of normal marrow; in these cases, perhaps more common in children, the negative MFC result provides the more accurate predictor of subsequent clinical outcome.4 Under these circumstances it seems reasonable to consider dispensing with morphologic exam in cases where MFC is negative. This is particularly true since morphology is time consuming, subjective and adds further expense; at our institution results of morphologic exam are usually reported at least 1 day after results of MFC. Furthermore, although MFC has, fairly enough, been criticized for lack of standardization and hence reproducibility, it is not obvious that morphologic enumeration of marrow blast percent is entirely reproducible either. Under the ELN’s recommendation for examination of 500 cells,5 disagreement on identification of only 10 cells is needed to convert a report of 6% blasts (relapse) to 4% blasts (no relapse). A repeat marrow examination may not totally address the problem given the heterogeneity of the marrow as an organ. Even ignoring disagreement on identification of individual cells, 95% confidence intervals for 20/500 blasts (4%) and 30/500 (6%) blasts overlap: 2–6% and 4–8%. Obviously MFC evaluates several orders of magnitude more cells than morphology with consequently smaller confidence intervals.

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

References

  1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391–2405.

    Article  CAS  PubMed  Google Scholar 

  2. Cheson BD, Bennett JM, Kopecky KJ, Buchner 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 

  3. Grimwade D, Freeman SD . Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for ‘prime time’? Hematology Am Soc Hematol Educ Program 2014; 2014: 222–233.

    Article  PubMed  Google Scholar 

  4. Inaba H, Coustan-Smith E, Cao X, Pounds SB, Shurtleff SA, Wang KY et al. Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia. J Clin Oncol 2012; 30: 3625–3632.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129: 424–447.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wood B . 9-color and 10-color flow cytometry in the clinical laboratory. Arch Pathol Lab Med 2006; 130: 680–690.

    PubMed  Google Scholar 

  7. Terwijn M, van Putten WL, Kelder A, van der Velden VH, Brooimans RA, Pabst T et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol 2013; 31: 3889–3897.

    Article  PubMed  Google Scholar 

  8. Chen X, Xie H, Wood BL, Walter RB, Pagel JM, Becker PS et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol 2015; 33: 1258–1264.

    Article  PubMed  Google Scholar 

  9. Buckley SA, Wood BL, Othus M, Hourigan CS, Ustun C, Linden MA et al. Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis. Haematologica 2017; 102: 865–873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Estey E, Pierce S . Routine bone marrow exam during first remission of acute myeloid leukemia. Blood 1996; 87: 3899–3902.

    CAS  PubMed  Google Scholar 

  11. O'Donnell MR, Abboud CN, Altman J, Appelbaum FR, Arber DA, Attar E et al. NCCN Clinical Practice Guidelines acute myeloid leukemia. J Natl Compr Canc Netw 2012; 10: 984–1021.

    Article  CAS  PubMed  Google Scholar 

  12. Wood BL . Flow cytometric monitoring of residual disease in acute leukemia. Methods Mol Biol 2013; 999: 123–136.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Author contributions

YZ, BLW and EE designed the research, performed the analyses and wrote the paper. YZ, CS and KG provided data for the analyses. RBW, PSB, M-EP, MB, PH, JA and FRA reviewed the letter and made suggestions. All authors approved the final submission.

Author information

Authors and Affiliations

  1. Division of Hematopathology, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA

    Y Zhou & B L Wood

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

    R B Walter, P S Becker, M-E Percival, K Gardner, P Hendrie, J Abkowitz & E Estey

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

    R B Walter, P S Becker, M-E Percival, M Bar, C Shaw, F R Appelbaum & E Estey

  4. Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA

    M Bar & F R Appelbaum

Authors
  1. Y Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B L Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R B Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P S Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M-E Percival
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Bar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Gardner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Hendrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Abkowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F R Appelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E Estey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Estey.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, Y., Wood, B., Walter, R. et al. Is there a need for morphologic exam to detect relapse in AML if multi-parameter flow cytometry is employed?. Leukemia 31, 2536–2537 (2017). https://doi.org/10.1038/leu.2017.263

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2017.263

Search

Advanced search

Quick links