Skip to main content

Advertisement

SpringerLink
Log in

Elevated absolute NK cell counts in peripheral blood predict good prognosis in chronic lymphocytic leukemia

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to investigate the prognostic significance of the absolute natural killer (NK) cell counts in peripheral blood in patients with chronic lymphocytic leukemia (CLL).

Methods

A total of 273 previously untreated patients with CLL from April 2004 and October 2015 were enrolled into this retrospective study. We analysed the T cell subsets of all patients and figured out the number of NK cells. Comparisons of NK cell count as continuous parameter in different groups were described using Mann–Whitney U test and the Kruskal–Wallis test. Kaplan–Meier method was used to survival analysis, and the Cox proportional hazards models were used for the estimation of prognostic factors.

Results

NK cell counts were calculated in 273 therapy-naive CLL patients, and higher number of NK cell was observed in those with Binet stage A/B, ZAP-70 < 20%, normal serum albumin and β2-microglobulin levels. Using a NK cell count cut-off of 0.40 × 109/L, patients with lower NK cell count (< 0.40 × 109/L) had a significantly shorter overall survival (OS) than those with higher NK cell count (≥ 0.40 × 109/L) (P = 0.0014). Multivariate analysis showed that NK cell counts remained its prognostic value. However, the effect of NK cell count on time to treatment was not significant.

Conclusions

Our results suggest that NK cell count is an independent prognostic marker for OS in patients with CLL and NK cell counts ≥ 0.40 × 109/L can routinely be used to identify patients with favorable survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Binet JL, Auquier A, Dighiero G et al (1981) A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48:198–206

    Article  CAS  PubMed  Google Scholar 

  • Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10:7252–7259

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Zhang Y, Zheng W et al (2008) Distinctive IgVH gene segments usage and mutation status in Chinese patients with chronic lymphocytic leukemia. Leuk Res 32:1491–1498

    Article  CAS  PubMed  Google Scholar 

  • Chen CI, Bergsagel PL, Paul H et al (2011) Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol 29:1175–1181

    Article  CAS  PubMed  Google Scholar 

  • Costello RT, Knoblauch B, Sanchez C et al (2012) Expression of natural killer cell activating receptors in patients with chronic lymphocytic leukaemia. Immunology 135:151–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cvetković RS, Perry CM (2006) Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs 66:791–820

    Article  PubMed  Google Scholar 

  • Eichhorst B, Robak T, Montserrat E et al (2015) Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 26(Suppl 5):v78–84

    Article  PubMed  Google Scholar 

  • Ferrajoli A, Lee BN, Schlette EJ et al (2008) Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111:5291–5297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foa R, Del Giudice I, Guarini A et al (2013) Clinical implications of the molecular genetics of chronic lymphocytic leukemia. Haematologica 98:675–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galustian C, Meyer B, Labarthe M-C et al (2008) The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother 58:1033–1045

    Article  PubMed  Google Scholar 

  • Hayashi T, Hideshima T, Akiyama M et al (2005) Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol 128:192–203

    Article  CAS  PubMed  Google Scholar 

  • Huang B, Sikorski R, Sampath P, Thorne SH (2011) Modulation of NKG2D-ligand cell surface expression enhances immune cell therapy of cancer. J Immunother 34:289–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huergo-Zapico L, Acebes-Huerta A, Gonzalez-Rodriguez AP et al (2014) Expansion of NK cells and reduction of NKG2D expression in chronic lymphocytic leukemia. Correlation with progressive disease. PLoS ONE 9:e108326

    Article  PubMed  PubMed Central  Google Scholar 

  • Huntington ND, Vosshenrich CAJ, Di Santo JP (2007) Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat Rev Immunol 7:703–714

    Article  CAS  PubMed  Google Scholar 

  • Kay NE, Zarling JM (1984) Impaired natural killer activity in patients with chronic lymphocytic leukemia is associated with a deficiency of azurophilic cytoplasmic granules in putative NK cells. Blood 63:305–309

    CAS  PubMed  Google Scholar 

  • Laprevotte E, Voisin G, Ysebaert L et al (2013) Recombinant human IL-15 trans-presentation by B leukemic cells from chronic lymphocytic leukemia induces autologous NK cell proliferation leading to improved anti-CD20 immunotherapy. J Immunol 191:3634–3640

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Chen B, Qin S et al (2010) A novel histone deacetylase inhibitor Chidamide induces apoptosis of human colon cancer cells. Biochem Biophys Res Commun 392:190–195

    Article  CAS  PubMed  Google Scholar 

  • MacFarlane AW, Jillab M, Smith MR et al (2017) NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors. Oncoimmunology 6:e1330235

    Article  PubMed  Google Scholar 

  • Ning Z-Q, Li Z-B, Newman MJ et al (2011) Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol 69:901–909

    Article  PubMed  Google Scholar 

  • Nückel H, Rebmann V, Dürig J et al (2005) HLA-G expression is associated with an unfavorable outcome and immunodeficiency in chronic lymphocytic leukemia. Blood 105:1694–1698

    Article  PubMed  Google Scholar 

  • Palmer S, Hanson CA, Zent CS et al (2008) Prognostic importance of T and NK-cells in a consecutive series of newly diagnosed patients with chronic lymphocytic leukaemia. Br J Haematol 141:607–614

    Article  PubMed  Google Scholar 

  • Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS (1975) Clinical staging of chronic lymphocytic leukemia. Blood 46(2):219–234

    CAS  PubMed  Google Scholar 

  • Rizzo R, Audrito V, Vacca P et al (2014) HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: impact of the HLA-G 14 bp (rs66554220) polymorphism. Haematologica 99:888–896

    Article  PubMed  PubMed Central  Google Scholar 

  • Romagnani C (2013) Signatures of human NK cell development and terminal differentiation. Front Immunol 4:1–6

  • Sarah T (2015) XVI international workshop on chronic lymphocytic leukemia 2015 6–9 September 2015 Sydney, Australia. Leuk Lymphoma 56:1–166

    Google Scholar 

  • Shi Y, Dong M, Hong X et al (2015) Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol 26:1766–1771

    Article  CAS  PubMed  Google Scholar 

  • Spits H, Artis D, Colonna M et al (2013) Innate lymphoid cells–a proposal for uniform nomenclature. Nat Rev Immunol 13:145–149

    Article  CAS  PubMed  Google Scholar 

  • Veuillen C, Aurran-Schleinitz T, Castellano R et al (2012) Primary B-CLL resistance to NK cell cytotoxicity can be overcome in vitro and in vivo by priming NK cells and monoclonal antibody therapy. J Clin Immunol 32:632–646

    Article  CAS  PubMed  Google Scholar 

  • Weiner GJ (2010) Rituximab: mechanism of action. Semin Hematol 47:115–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Własiuk P, Tomczak W, Zając M et al (2013) Total expression of HLA-G and TLR-9 in chronic lymphocytic leukemia patients. Hum Immunol 74:1592–1597

    Article  PubMed  Google Scholar 

  • Xu W, Li J-Y, Wu Y-J et al (2008) Prognostic significance of ATM and TP53 deletions in Chinese patients with chronic lymphocytic leukemia. Leuk Res 32:1071–1077

    Article  CAS  PubMed  Google Scholar 

  • Xu W, Li J-Y, Wu Y-J et al (2009) CD38 as a prognostic factor in Chinese patients with chronic lymphocytic leukaemia. Leuk Res 33:237–243

    Article  CAS  PubMed  Google Scholar 

  • Yu J, Freud AG, Caligiuri MA (2013) Location and cellular stages of natural killer cell development. Trends Immunol 34:573–582

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by National Natural Science Foundation of China (81370657, 81470328, 81770166, 81720108002), Jiangsu Province’s Medical Elite Programme (ZDRCA2016022), Project of National Key Clinical Specialty, National Science and Technology Pillar Program (2014BAI09B12), Jiangsu Provincial Special Program of Medical Science (BL2014086 and BE2017751) and National Science and Technology Major Project (2017ZX09304032).

Author information

Author notes

  1. Wen-Ting Wang and Hua-Yuan Zhu contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China

    Wen-Ting Wang, Hua-Yuan Zhu, Yu-Jie Wu, Yi Xia, Jia-Zhu Wu, Wei Wu, Jin-Hua Liang, Li Wang, Lei Fan, Jian-Yong Li & Wei Xu

  2. Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China

    Wen-Ting Wang, Hua-Yuan Zhu, Yu-Jie Wu, Yi Xia, Jia-Zhu Wu, Wei Wu, Jin-Hua Liang, Li Wang, Lei Fan, Jian-Yong Li & Wei Xu

  3. Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210029, China

    Wen-Ting Wang, Hua-Yuan Zhu, Yu-Jie Wu, Yi Xia, Jia-Zhu Wu, Wei Wu, Jin-Hua Liang, Li Wang, Lei Fan, Jian-Yong Li & Wei Xu

Authors
  1. Wen-Ting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hua-Yuan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Jie Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia-Zhu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jin-Hua Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lei Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jian-Yong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Xu.

Ethics declarations

Conflict of interest

The authors have 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

Wang, WT., Zhu, HY., Wu, YJ. et al. Elevated absolute NK cell counts in peripheral blood predict good prognosis in chronic lymphocytic leukemia. J Cancer Res Clin Oncol 144, 449–457 (2018). https://doi.org/10.1007/s00432-017-2568-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-017-2568-2

Keywords

Search

Navigation