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.
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References
Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. New Engl J Med. 2016;375(18):1767–78.
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.
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.
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.
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.
Patel SP, Kurzrock R. PD-L1 Expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847–56.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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.
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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
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DOI: https://doi.org/10.1007/s12094-018-1908-2