Skip to main content

Advertisement

Log in

The absolute lymphocyte count can predict the overall survival of patients with non-small cell lung cancer on nivolumab: a clinical study

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Introduction

The neutrophil-to-lymphocyte (ANC/ALC) ratio is associated with worse prognosis in patients with NSCLC on immunotherapies, but the role of ALC remains unclear. The previous radiation therapy causes lymphopenia, and given approaches of combining radiation with immunotherapies, it is critical to better understand the impact of peripheral lymphocytes.

Patients and methods

We evaluated retrospectively 22 patients with advanced NSCLC treated with nivolumab at Boston Medical Center from January 2014 to September 2016 and correlated the peripheral blood counts with the overall survival (OS) and overall time on treatment. We assessed the effect of the previous radiation on peripheral blood counts and clinical outcomes.

Results

Baseline ALC and ANC/ALC ratios are positively and negatively correlated, respectively, with the OS on nivolumab. The ALC and ALC/WBC ratios at 6 weeks on treatment are positively associated with the OS. Kaplan–Meier analysis at baseline and at 6 weeks showed significantly increased OS in the group of patients with the highest ALC. The previous radiation therapy was positively correlated with the ANC and negatively correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab.

Conclusion

Our finding that ALC at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. Our result that the previous radiation is associated with higher ANC and lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. New Engl J Med. 2016;375(18):1767–78.

    Article  CAS  PubMed  Google Scholar 

  2. Elias R, Karantanos T, Sira E, Hartshorn KL. Immunotherapy comes of age: immune aging and checkpoint inhibitors. J Geriatr Oncol. 2017;8(3):229–35.

    Article  PubMed  Google Scholar 

  3. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. New Engl J Med. 2015;373(2):123–35.

    Article  CAS  PubMed  Google Scholar 

  4. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. New Engl J Med. 2015;373(17):1627–39.

    Article  CAS  PubMed  Google Scholar 

  5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed  Google Scholar 

  6. Patel SP, Kurzrock R. PD-L1 Expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847–56.

    Article  CAS  PubMed  Google Scholar 

  7. Ferrucci PF, Ascierto PA, Pigozzo J, Del Vecchio M, Maio M, Antonini Cappellini GC, et al. Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Ann Oncol. 2016;27(4):732–8.

    Article  CAS  PubMed  Google Scholar 

  8. Ferrucci PF, Gandini S, Battaglia A, Alfieri S, Di Giacomo AM, Giannarelli D, et al. Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients. Br J Cancer. 2015;112(12):1904–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zaragoza J, Caille A, Beneton N, Bens G, Christiann F, Maillard H, et al. High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma. Br J Dermatol. 2016;174(1):146–51.

    Article  CAS  PubMed  Google Scholar 

  10. Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung cancer. 2017;111:176–81.

    Article  PubMed  Google Scholar 

  11. Bumma N, Jeyakumar G, Kim S, Galasso C, Thakur MK, Gadgeel SM, et al. Neutrophil lymphocyte ratio (NLR) as a predictive biomarker for PD-1/PD-L1 directed therapy in metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2017;35(15_suppl):e20633-e.

    Article  Google Scholar 

  12. Russo A, Scimone A, Picciotto M, Toscano G, Raiti F, Sava S, et al. Association between baseline absolute neutrophil count (ANC), derived neutrophil-to-lymphocyte ratio (dNLR), and platelet-to-lymphocyte ratio (PLR) and response to nivolumab (Nivo) in non-small cell lung cancer (NSCLC): a preliminary analysis. J Clin Oncol. 2017;35(15_suppl):e14617-e.

    Article  Google Scholar 

  13. Labomascus S, Fughhi I, Bonomi P, Fidler MJ, Borgia JA, Basu S, et al. Neutrophil to lymphocyte ratio as predictive of prolonged progression free survival (PFS) and overall survival (OS) in patients with metastatic non-small cell lung cancer (NSCLC) treated with second-line PD-1 immune checkpoint inhibitors. J Clin Oncol. 2017;35(15_suppl):e14530-e.

    Article  Google Scholar 

  14. Cortinovis SCPBPLMIASCSCD. Baseline lymphopenia should not be used as exclusion criteria in early clinical trials investigating immune checkpoint blockers (PD-1/PD-L1 inhibitors). Ann Oncol. 2016;27(suppl_4):12.

    Google Scholar 

  15. Tang C, Wang X, Soh H, Seyedin S, Cortez MA, Krishnan S, et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2(9):831–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. De Ruysscher D, Waer M, Vandeputte M, Aerts R, Vantongelen K, van der Schueren E. Changes of lymphocyte subsets after local irradiation for early stage breast cancer and seminoma testis: long-term increase of activated (HLA-DR +) T cells and decrease of “naive” (CD4-CD45R) T lymphocytes. Eur J Cancer. 1992;28(10):1729–34.

    Article  Google Scholar 

  17. Raben M, Walach N, Galili U, Schlesinger M. The effect of radiation therapy on lymphocyte subpopulations in cancer patients. Cancer. 1976;37(3):1417–21.

    Article  CAS  PubMed  Google Scholar 

  18. Campian JL, Ye X, Brock M, Grossman SA. Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Cancer Invest. 2013;31(3):183–8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hosmer DW, Lemeshow S, May S. Applied survival analysis: regression modeling of time to event data. Hoboken, New Jersey, United States: John Wiley & Sons; 2008. https://doi.org/10.1002/9780470258019.

    Book  Google Scholar 

  20. Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen TH, Zhang YC, Tan YT, An X, Xue C, Deng YF, et al. Tumor-infiltrating lymphocytes predict prognosis of breast cancer patients treated with anti-Her-2 therapy. Oncotarget. 2017;8(3):5219–32.

    PubMed  Google Scholar 

  22. Fortes C, Mastroeni S, Mannooranparampil TJ, Passarelli F, Zappala A, Annessi G, et al. Tumor-infiltrating lymphocytes predict cutaneous melanoma survival. Melanoma Res. 2015;25(4):306–11.

    Article  PubMed  Google Scholar 

  23. Bai X, Zhang Q, Wu S, Zhang X, Wang M, He F, et al. Characteristics of tumor infiltrating lymphocyte and circulating lymphocyte repertoires in pancreatic cancer by the sequencing of T cell receptors. Sci Rep. 2015;5:13664.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Choueiri TK, Fishman MN, Escudier B, McDermott DF, Drake CG, Kluger H, et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma. Clin Cancer Res. 2016;22(22):5461–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gros A, Tran E, Parkhurst MR, Anna P, Ilyas S, Prickett TD, et al. Selection of circulating PD-1 + lymphocytes from cancer patients enriches for tumor-reactive and mutation-specific lymphocytes: J Immunother. Cancer. 2015;3(Suppl 2):O2. https://doi.org/10.1186/2051-1426-3-S2-O2.

    Article  Google Scholar 

  27. Gruber I, Landenberger N, Staebler A, Hahn M, Wallwiener D, Fehm T. Relationship between circulating tumor cells and peripheral T-cells in patients with primary breast cancer. Anticancer Res. 2013;33(5):2233–8.

    CAS  PubMed  Google Scholar 

  28. Nakamura Y, Kitano S, Takahashi A, Tsutsumida A, Namikawa K, Tanese K, et al. Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget. 2016;7(47):77404–15.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18(7):895–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to T. Karantanos.

Ethics declarations

Conflict of interest

Authors do not have any conflicts of interest to disclose.

Research involving human participants and/or animals

Our research did not involve human participants or animals.

Informed consent

No informed consent was needed based on the IRB approval (H-35716) of our retrospective study by the office of the institutional review board of Boston University.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karantanos, T., Karanika, S., Seth, B. et al. The absolute lymphocyte count can predict the overall survival of patients with non-small cell lung cancer on nivolumab: a clinical study. Clin Transl Oncol 21, 206–212 (2019). https://doi.org/10.1007/s12094-018-1908-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-018-1908-2

Keywords

Navigation