Pre-Treatment Peripheral Blood Parameters as Prognostic Biomarkers in Cancer Patients Receiving Immune Checkpoint Inhibitors
Abstract
Background: Immune checkpoint inhibitors have significantly improved outcomes in select cancers; however, not all patients respond to these therapies, and the duration of the response varies among responders. Markers predictive of the response to immunotherapy, such as PD-L1 expression determined by immunohistochemical staining of tumor sections and microsatellite status, have been identified. Some of these are used in companion diagnostics approved for clinical practice. Additional easy-to-use biomarkers may help clinicians to predict the efficacy of these drugs in individual patients.
Materials and Methods: A retrospective review of the medical records of patients with metastatic cancer treated with immune checkpoint inhibitors in our cancer center was performed to identify the clinical and hematologic parameters associated with survival outcomes.
Results: Among the 163 patients included in the study, most had lung cancer, followed by kidney cancer, melanoma, and bladder cancer. Most patients (61.3%) were male and had good performance status. Nivolumab and pembrolizumab were immune checkpoint inhibitors utilized in 85.9% of cases. Age, sex, and primary cancer type were not associated with survival outcomes. Among the peripheral blood parameters evaluated, lymphocytopenia was the strongest predictor of adverse survival outcomes in univariate analysis and the only clinical or hematologic biomarker that retained significance for overall survival (OS) prediction in multivariate analysis.
Conclusion: Among the clinical and hematologic parameters routinely used in the clinic, a lymphocyte count below 1 x 109/ L was predictive of adverse OS in patients with metastatic cancers receiving immune checkpoint inhibitors.
1. Boutros M, Attieh F, Chartouni A, Jalbout J, et al. Beyond the Horizon: A Cutting-Edge Review of the Latest Checkpoint Inhibitors in Cancer Treatment. Cancer Invest. 2023;41(9): 757-773.
2. Fahey CC, Gracie TJ, Johnson DB. Immune checkpoint inhibitors: maximizing benefit whilst minimizing toxicity. Expert Rev Anticancer Ther. 2023; 23(7): 673-683.
3. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018; 378(19): 1789-1801.
4. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015; 373(13): 1270-1.
5. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 378(22): 2078-2092.
6. Dyrskjøt L, Hansel DE, Efstathiou JA, et al. Bladder cancer. Nat Rev Dis Primers. 2023; 9(1): 58.
7. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127.
8. Nishio M, Ohe Y, Ikeda S, et al. First-line nivolumab plus ipilimumab in metastatic non-small cell lung cancer: 5-year outcomes in Japanese patients from CheckMate 227 Part 1. Int J Clin Oncol 2023; 28(10): 1354-1368.
9. Eso Y, Shimizu T, Takeda H, et al. Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol. 2020; 55(1): 15-26.
10. Boyiadzis MM, Kirkwood JM, Marshall JL, et al. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer. 2018; 6(1): 35.
11. Yoon HH, Jin Z, Kour O, et al. Association of PD-L1 Expression and Other Variables With Benefit From Immune Checkpoint Inhibition in Advanced Gastroesophageal Cancer: Systematic Review and Meta-analysis of 17 Phase 3 Randomized Clinical Trials. JAMA Oncol. 2022; 8(10): 1456-1465.
12. Palles C, Martin L, Domingo E, et al. The clinical features of polymerase proof-reading associated polyposis (PPAP) and recommendations for patient management. Fam Cancer. 2022; 21(2): 197-209.
13. Voutsadakis IA. High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology. Cancer Treat Res Commun. 2023; 36: 100746.
14. Policicchio A, Mercier J, Digklia A, et al. Platelet and Neutrophil Counts as Predictive Markers of Neoadjuvant Therapy Efficacy in Rectal Cancer. J Gastrointest Cancer. 2019; 50(4): 894-900.
15. Mercier J, Voutsadakis IA. The platelets-neutrophils to lymphocytes ratio: a new prognostic marker in metastatic colorectal cancer. J Gastrointest Oncol. 2018; 9(3): 478-486.
16. Stravodimou A, Voutsadakis IA. Pretreatment thrombocytosis as a prognostic factor in metastatic breast cancer. Int J Breast Cancer. 2013; 2013: 289563.
17. Arora S, Velichinskii R, Lesh RW, et al. Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors. Adv Ther. 2019; 36(10): 2638-2678.
18. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015; 372(26): 2509-20.
19. Huang Y, Li GM. DNA mismatch repair in the chromatin context: Mechanisms and therapeutic potential. DNA Repair (Amst). 2020; 93: 102918.
20. Win AK, Macinnis RJ, Dowty JG, et al. Criteria and prediction models for mismatch repair gene mutations: a review. J Med Genet. 2013; 50(12): 785-93.
21. Voutsadakis IA. Polymerase epsilon mutations and concomitant β2-microglobulin mutations in cancer. Gene. 2018; 647: 31-38.
22. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-8.
23. Liu Y, Liu Z, Yang Y, et al. The prognostic and biology of tumour-infiltrating lymphocytes in the immunotherapy of cancer. Br J Cancer. 2023; 129(7): 1041-1049.
24. Presti D, Dall'Olio FG, Besse B, et al. Tumor infiltrating lymphocytes (TILs) as a predictive biomarker of response to checkpoint blockers in solid tumors: A systematic review. Crit Rev Oncol Hematol. 2022; 177: 103773.
25. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015; 26(2): 259-71.
26. Gataa I, Mezquita L, Rossoni C, et al. Tumour-infiltrating lymphocyte density is associated with favourable outcome in patients with advanced non-small cell lung cancer treated with immunotherapy. Eur J Cancer. 2021; 145: 221-229.
27. Hanna GJ, Lizotte P, Cavanaugh M, et al. Frameshift events predict anti-PD-1/L1 response in head and neck cancer. JCI Insight. 2018; 3(4): e98811.
28. Zhang W, Li S, Zhang C, et al. Tumor-infiltrating lymphocytes predict efficacy of immunotherapy in advanced non-small cell lung cancer: a single-center retrospective cohort study. Acta Oncol. 2023; 62(8): 853-860.
29. Peled M, Onn A, Herbst RS. Tumor-Infiltrating Lymphocytes-Location for Prognostic Evaluation. Clin Cancer Res. 2019; 25(5): 1449-1451.
30. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795): 1960-4.
31. Voutsadakis IA. Prediction of Immune checkpoint inhibitors benefit from routinely measurable peripheral blood parameters. Chin Clin Oncol. 2020;9(2):19.
32. Diehl A, Yarchoan M, Hopkins A, et al. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget 2017 Dec 14; 8(69): 114268-114280.
33. Sun R, Champiat S, Dercle L, et al. Baseline lymphopenia should not be used as exclusion criteria in early clinical trials investigating immune checkpoint blockers (PD-1/PD-L1 inhibitors). Eur J Cancer. 2017; 84: 202-211.
34. Césaire M, Rambeau A, Clatot F, et al. Impact of lymphopenia on efficacy of nivolumab in head and neck cancer patients. Eur Arch Otorhinolaryngol. 2023; 280(5): 2453-2461.
35. Zhao Q, Bi Y, Xue J, et al. Prognostic value of absolute lymphocyte count in patients with advanced esophageal cancer treated with immunotherapy: a retrospective analysis. Ann Transl Med. 2022; 10(13): 744.
36. Postow MA, Chasalow SD, Kuk D, et al. Absolute lymphocyte count as a prognostic biomarker for overall survival in patients with advanced melanoma treated with ipilimumab. Melanoma Res. 2020; 30(1): 71-75.
37. Ménétrier-Caux C, Ray-Coquard I, Blay JY, et al. Lymphopenia in Cancer Patients and its Effects on Response to Immunotherapy: an opportunity for combination with Cytokines? J Immunother Cancer. 2019; 7(1): 85.
2. Fahey CC, Gracie TJ, Johnson DB. Immune checkpoint inhibitors: maximizing benefit whilst minimizing toxicity. Expert Rev Anticancer Ther. 2023; 23(7): 673-683.
3. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018; 378(19): 1789-1801.
4. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015; 373(13): 1270-1.
5. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 378(22): 2078-2092.
6. Dyrskjøt L, Hansel DE, Efstathiou JA, et al. Bladder cancer. Nat Rev Dis Primers. 2023; 9(1): 58.
7. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127.
8. Nishio M, Ohe Y, Ikeda S, et al. First-line nivolumab plus ipilimumab in metastatic non-small cell lung cancer: 5-year outcomes in Japanese patients from CheckMate 227 Part 1. Int J Clin Oncol 2023; 28(10): 1354-1368.
9. Eso Y, Shimizu T, Takeda H, et al. Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol. 2020; 55(1): 15-26.
10. Boyiadzis MM, Kirkwood JM, Marshall JL, et al. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer. 2018; 6(1): 35.
11. Yoon HH, Jin Z, Kour O, et al. Association of PD-L1 Expression and Other Variables With Benefit From Immune Checkpoint Inhibition in Advanced Gastroesophageal Cancer: Systematic Review and Meta-analysis of 17 Phase 3 Randomized Clinical Trials. JAMA Oncol. 2022; 8(10): 1456-1465.
12. Palles C, Martin L, Domingo E, et al. The clinical features of polymerase proof-reading associated polyposis (PPAP) and recommendations for patient management. Fam Cancer. 2022; 21(2): 197-209.
13. Voutsadakis IA. High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology. Cancer Treat Res Commun. 2023; 36: 100746.
14. Policicchio A, Mercier J, Digklia A, et al. Platelet and Neutrophil Counts as Predictive Markers of Neoadjuvant Therapy Efficacy in Rectal Cancer. J Gastrointest Cancer. 2019; 50(4): 894-900.
15. Mercier J, Voutsadakis IA. The platelets-neutrophils to lymphocytes ratio: a new prognostic marker in metastatic colorectal cancer. J Gastrointest Oncol. 2018; 9(3): 478-486.
16. Stravodimou A, Voutsadakis IA. Pretreatment thrombocytosis as a prognostic factor in metastatic breast cancer. Int J Breast Cancer. 2013; 2013: 289563.
17. Arora S, Velichinskii R, Lesh RW, et al. Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors. Adv Ther. 2019; 36(10): 2638-2678.
18. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015; 372(26): 2509-20.
19. Huang Y, Li GM. DNA mismatch repair in the chromatin context: Mechanisms and therapeutic potential. DNA Repair (Amst). 2020; 93: 102918.
20. Win AK, Macinnis RJ, Dowty JG, et al. Criteria and prediction models for mismatch repair gene mutations: a review. J Med Genet. 2013; 50(12): 785-93.
21. Voutsadakis IA. Polymerase epsilon mutations and concomitant β2-microglobulin mutations in cancer. Gene. 2018; 647: 31-38.
22. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-8.
23. Liu Y, Liu Z, Yang Y, et al. The prognostic and biology of tumour-infiltrating lymphocytes in the immunotherapy of cancer. Br J Cancer. 2023; 129(7): 1041-1049.
24. Presti D, Dall'Olio FG, Besse B, et al. Tumor infiltrating lymphocytes (TILs) as a predictive biomarker of response to checkpoint blockers in solid tumors: A systematic review. Crit Rev Oncol Hematol. 2022; 177: 103773.
25. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015; 26(2): 259-71.
26. Gataa I, Mezquita L, Rossoni C, et al. Tumour-infiltrating lymphocyte density is associated with favourable outcome in patients with advanced non-small cell lung cancer treated with immunotherapy. Eur J Cancer. 2021; 145: 221-229.
27. Hanna GJ, Lizotte P, Cavanaugh M, et al. Frameshift events predict anti-PD-1/L1 response in head and neck cancer. JCI Insight. 2018; 3(4): e98811.
28. Zhang W, Li S, Zhang C, et al. Tumor-infiltrating lymphocytes predict efficacy of immunotherapy in advanced non-small cell lung cancer: a single-center retrospective cohort study. Acta Oncol. 2023; 62(8): 853-860.
29. Peled M, Onn A, Herbst RS. Tumor-Infiltrating Lymphocytes-Location for Prognostic Evaluation. Clin Cancer Res. 2019; 25(5): 1449-1451.
30. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795): 1960-4.
31. Voutsadakis IA. Prediction of Immune checkpoint inhibitors benefit from routinely measurable peripheral blood parameters. Chin Clin Oncol. 2020;9(2):19.
32. Diehl A, Yarchoan M, Hopkins A, et al. Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget 2017 Dec 14; 8(69): 114268-114280.
33. Sun R, Champiat S, Dercle L, et al. Baseline lymphopenia should not be used as exclusion criteria in early clinical trials investigating immune checkpoint blockers (PD-1/PD-L1 inhibitors). Eur J Cancer. 2017; 84: 202-211.
34. Césaire M, Rambeau A, Clatot F, et al. Impact of lymphopenia on efficacy of nivolumab in head and neck cancer patients. Eur Arch Otorhinolaryngol. 2023; 280(5): 2453-2461.
35. Zhao Q, Bi Y, Xue J, et al. Prognostic value of absolute lymphocyte count in patients with advanced esophageal cancer treated with immunotherapy: a retrospective analysis. Ann Transl Med. 2022; 10(13): 744.
36. Postow MA, Chasalow SD, Kuk D, et al. Absolute lymphocyte count as a prognostic biomarker for overall survival in patients with advanced melanoma treated with ipilimumab. Melanoma Res. 2020; 30(1): 71-75.
37. Ménétrier-Caux C, Ray-Coquard I, Blay JY, et al. Lymphopenia in Cancer Patients and its Effects on Response to Immunotherapy: an opportunity for combination with Cytokines? J Immunother Cancer. 2019; 7(1): 85.
| Files | ||
| Issue | Vol 19 No 1 (2025) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v19i1.17819 | |
| Keywords | ||
| Immunotherapy; Biomarkers; Hematologic parameters; Complete blood count; Lymphocytopenia | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Bernardo D, Murugan N, Voutsadakis I. Pre-Treatment Peripheral Blood Parameters as Prognostic Biomarkers in Cancer Patients Receiving Immune Checkpoint Inhibitors. Int J Hematol Oncol Stem Cell Res. 2025;19(1):7-16.
