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:

Myelodysplastic syndrome

The myelodysplastic syndromes flow cytometric score: a three-parameter prognostic flow cytometric scoring system

Leukemia volume 30, pages 658–665 (2016)Cite this article

Subjects

Abstract

The prognosis of myelodysplastic syndromes (MDS) is currently estimated by using the revised International Prognostic Scoring System (IPSS-R). Several studies have shown that further refinement of prognostication for MDS can be achieved by adding flow cytometric parameters. However, widespread implementation of flow cytometry for the prognosis of MDS is hampered by complexity of the analysis. Therefore, the aim of this study was to construct a robust and practical flow cytometric score that could be implemented as a routine procedure. To achieve this, bone marrow aspirates of 109 MDS patients were analyzed by flow cytometry. A second cohort consisting of 103 MDS patients was used to validate the MDS flow cytometric score (MFS). The parameters forming the MFS were sideward light scatter and CD117 expression of myeloid progenitor cells and CD13 expression on monocytes. Three MFS risk categories were formed. Patients with MDS and intermediate MFS scores had significantly better overall survival (OS) compared with the patients with high MFS scores. The MFS further refined prognostication within the IPSS-R low-risk category, by identifying patients with worse OS in case of high MFS. In conclusion, a practical three parameter flow cytometric prognostic score was constructed enabling further refinement of prognostication of MDS.

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
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  PubMed  Google Scholar 

  2. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120: 2454–2465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wells DA, Benesch M, Loken MR, Vallejo C, Myerson D, Leisenring WM et al. Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndromes correlates with the IPSS and with outcome after hematopoietic stem cell transplantation. Blood 2003; 102: 394–403.

    Article  CAS  PubMed  Google Scholar 

  4. van de Loosdrecht AA, Westers TM, Westra AH, Dräger AM, van der Velden VH, Ossenkoppele GJ . Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry. Blood 2008; 111: 1067–1077.

    Article  CAS  PubMed  Google Scholar 

  5. Matarraz S, López A, Barrena S, Fernandez C, Jensen E, Flores-Montero J et al. Bone marrow cells from myelodysplastic syndromes show altered immunophenotypic profiles that may contribute to the diagnosis and prognostic stratification of the disease: a pilot study on a series of 56 patients. Cytometry B Clin Cytom 2010; 78: 154–168.

    PubMed  Google Scholar 

  6. Alhan C, Westers TM, Cremers EM, Cali C, Witte BI, Ossenkoppele GJ et al. High flow cytometric scores identify adverse prognostic subgroups within the revised international prognostic scoring system for myelodysplastic syndromes. Br J Haematol 2014; 167: 100–109.

    Article  PubMed  Google Scholar 

  7. Scott BL, Wells DA, Loken MR, Myerson D, Leisenring WM, Deeg HJ . Validation of a FC scoring system as a prognostic indicator for post transplantation outcome in patients with myelodysplastic syndrome. Blood 2008; 112: 2861–2866.

    Article  Google Scholar 

  8. Chu SC, Wang TF, Li CC, Kao RH, Li DK, Su YC et al. Flow cytometric scoring system as a diagnostic and prognostic tool in myelodysplastic syndromes. Leuk Res 2011; 35: 868–873.

    Article  PubMed  Google Scholar 

  9. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth edn. IARC Press: Lyon, 2008.

    Google Scholar 

  10. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.

    Article  CAS  PubMed  Google Scholar 

  11. Shaffer LG, McGowan-Jordan J, Schmid M (eds). ISCN: An International System for Human Cytogenetic Nomenclature. S Karger: Basel, Switzerland, 2013.

    Google Scholar 

  12. Valent P, Horny HP, Bennet JM, Fonatsch C, Germing U, Greenberg P et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference. Leuk Res 2007; 31: 727–736.

    Article  PubMed  Google Scholar 

  13. Malcovati L, Hellström-Lindberg E, Bowen D, Adès L, Cermak J, Del Cañizo C et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 2013; 122: 2943–2964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Westers TM, Alhan C, Chamuleau ME, van der Vorst MJ, Eeltink C, Ossenkoppele GJ et al. Aberrant immunophenotype of blasts in myelodysplastic syndromes is a clinically relevant biomarker in predicting response to growth factor treatment. Blood 2010; 115: 1779–1784.

    Article  CAS  PubMed  Google Scholar 

  15. Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007; 25: 3503–3510.

    Article  PubMed  Google Scholar 

  16. van de Loosdrecht AA, Alhan C, Béné MC, Della Porta MG, Dräger AM, Feuillard J et al. Standardization of flow cytometry in myelodysplastic syndromes: report from the first European LeukemiaNet working conference on flow cytometry in myelodysplastic syndromes. Haematologica 2009; 94: 1124–1134.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Westers TM, Ireland R, Kern W, Alhan C, Balleisen JS, Bettelheim P et al. Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group. Leukemia 2012; 26: 1730–1741.

    Article  CAS  PubMed  Google Scholar 

  18. Loken MR, Shah VO, Dattilio KL, Civin CI . Flow cytometric analysis of human bone marrow. II. Normal B lymphocyte development. Blood 1987; 70: 1316–1324.

    CAS  PubMed  Google Scholar 

  19. Terwijn M, Feller N, van Rhenen A, Kelder A, Westra G, Zweegman S et al. Interleukin-2 receptor alpha-chain (CD25) expression on leukaemic blasts is predictive for outcome and level of residual disease in AML. Eur J Cancer 2009; 45: 1692–1699.

    Article  CAS  PubMed  Google Scholar 

  20. Cutler JA, Wells DA, van de Loosdrecht AA, de Baca ME, Kalnoski MH, Zehentner BK et al. Phenotypic abnormalities strongly reflect genotype in patients with unexplained cytopenias. Cytometry B Clin Cytom 2011; 80: 150–157.

    Article  PubMed  Google Scholar 

  21. Zhang HP, Singer B . Recursive Partitioning in the Health Sciences. Springer: New York, 1999.

    Book  Google Scholar 

  22. Zhao F, Chen Y, Wu Q, Wang Z, Lu J . Prognostic value of CD117 in cancer: a meta-analysis. Int J Clin Exp Pathol 2014; 7: 1012–1021.

    PubMed  PubMed Central  Google Scholar 

  23. Ogawa M, Matsuzaki Y, Nishikawa S, Hayashi S, Kunisada T, Sudo T et al. Expression and function of c-kit in hemopoietic progenitor cells. J Exp Med 1991; 174: 63–71.

    Article  CAS  PubMed  Google Scholar 

  24. Kimura A, Nakata Y, Katoh O, Hyodo H . c-kit Point mutation in patients with myeloproliferative disorders. Leuk Lymphoma 1997; 25: 281–287.

    Article  CAS  PubMed  Google Scholar 

  25. Lorand-Metze I, Califani SM, Ribeiro E, Lima CS, Metze K . The prognostic value of maturation-associated phenotypic abnormalities in myelodysplastic syndromes. Leuk Res 2008; 32: 211–213.

    Article  CAS  PubMed  Google Scholar 

  26. Mina-Osorio P . The moonlighting enzyme CD13: old and new functions to target. Trends Mol Med 2008; 14: 361–371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Aggarwal S, van de Loosdrecht AA, Alhan C, Ossenkoppele GJ, Westers TM, Bontkes HJ . Role of immune responses in the pathogenesis of low-risk MDS and high-risk MDS: implications for immunotherapy. Br J Haematol 2011; 153: 568–581.

    Article  CAS  PubMed  Google Scholar 

  28. Ghosh M, Gerber C, Rahman MM, Vernier KM, Pereira FE, Subramani J et al. Molecular mechanisms regulating CD13-mediated adhesion. Immunology 2014; 142: 636–647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Guzman-Rojas L, Rangel R, Salameh A, Edwars JK, Dondossola E, Kim Y et al. Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment. Proc Natl Acad Sci USA 2012; 109: 1637–1642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Alhan C, Westers TM, van der Helm LH, Eeltink C, Huls G, Witte BI et al. Absence of aberrant myeloid progenitors by flow cytometry is associated with favorable response to azacitidine in higher risk myelodysplastic syndromes. Cytometry B Clin Cytom 2014; 86: 207–215.

    Article  PubMed  Google Scholar 

  31. Schanz J, Steidl C, Fonatsch C, Pfeilstöcker M, Nösslinger T, Tuechler H et al. Coalesced multicentric analysis of 2,351 patients with myelodysplastic syndromes indicates an underestimation of poor-risk cytogenetics of myelodysplastic syndromes in the international prognostic scoring system. J Clin Oncol 2011; 29: 1963–1970.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Della Porta MG, Picone C, Tenore A, Yokose N, Malcovati L, Cazzola M et al. Prognostic significance of reproducible immunophenotypic markers of marrow dysplasia. Haematologica 2014; 99: e8–e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ogata K, Della Porta MG, Malcovati L, Picone C, Yokose N, Matsuda A et al. Diagnostic utility of flow cytometry in low-grade myelodysplastic syndromes: a prospective validation study. Haematologica 2009; 94: 1066–1074.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Della Porta MG, Picone C, Pascutto C, Malcovati L, Tamura H, Handa H et al. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNet study. Haematologica 2012; 97: 1209–1217.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Kelly Schouten and Kristin Vandenberghe (Department of Hematology, Cancer Center Amsterdam (CCA), VU University Medical Center, Amsterdam, The Netherlands) for technical assistance.

Author contributions

CA drafted the manuscript, performed and analyzed experiments. TMW performed and analyzed experiments and revised the manuscript and validated the final version of the manuscript. CC performed and analyzed experiments. BIW guided the statistical analysis, revised the manuscript and validated the final version of the manuscript. EMPC and GJO validated the final version of the manuscript. AAL designed the study, provided bone marrow samples, revised the manuscript and validated the final version of the manuscript.

Author information

Authors and Affiliations

  1. Department of Hematology, Cancer Center Amsterdam (CCA), VU University Medical Center, Amsterdam, The Netherlands

    C Alhan, T M Westers, E M P Cremers, C Cali, G J Ossenkoppele & A A van de Loosdrecht

  2. Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands

    B I Witte

Authors
  1. C Alhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T M Westers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E M P Cremers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Cali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B I Witte
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G J Ossenkoppele
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A A van de Loosdrecht
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Alhan.

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

Alhan, C., Westers, T., Cremers, E. et al. The myelodysplastic syndromes flow cytometric score: a three-parameter prognostic flow cytometric scoring system. Leukemia 30, 658–665 (2016). https://doi.org/10.1038/leu.2015.295

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.295

This article is cited by

Search

Advanced search

Quick links