Hematological ratios, immune-related adverse events and mortality in patients treated with immune checkpoint inhibitors

Sophie Lekkerkerker; Karin A H Kaasjager; Saskia Haitjema; Cornelia Hulsbergen-Veelken; Karin H Herbschleb; Marianne C Verhaar; Meriem Khairoun; Gurbey Ocak

doi:10.1371/journal.pone.0336491

Hematological ratios, immune-related adverse events and mortality in patients treated with immune checkpoint inhibitors

Sophie Lekkerkerker
, Karin A H Kaasjager
, Saskia Haitjema
, Cornelia Hulsbergen-Veelken
, Karin H Herbschleb
, Marianne C Verhaar
, Meriem Khairoun
, Gurbey Ocak^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: Although immune checkpoint inhibitors improve survival in patients with malignancies, a substantial number of patients treated with these agents experience immune-related adverse events. It is unknown whether inflammation-related hematological ratios are associated with immune-related adverse events or mortality.

OBJECTIVE: We aimed to investigate the association between pretreatment inflammation-related hematological ratios and the occurrence of immune-related adverse events and mortality in patients receiving checkpoint inhibitors.

METHODS: Patients treated with checkpoint inhibitors within a tertiary hospital in the Netherlands were studied using routine care data between January 2013 and May 2020. Cox regression analysis was performed to assess the association between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocytes and platelets ratio (NLPR), and systemic immune-inflammation index (SII) and outcomes (immune-related adverse events or mortality).

RESULTS: Among 664 patients treated with checkpoint inhibitors, 397 (59.8%) patients developed an immune-related adverse event and 363 (54.7%) patients died during a median follow-up period of 17 months (interquartile range 7-30 months). Hematological ratios were not associated with immune-related adverse events. However, highest tertiles as compared with lowest tertiles of all hematological ratios were independently associated with mortality (NLR: adjusted hazard ratio (HR) 2.23, 95% CI 1.69-2.95; PLR: adjusted HR 1.88, 95% CI 1.43-2.47; NLPR: adjusted 1.59, 95% CI 1.22-2.06; SII: adjusted HR 2.33, 95% CI 1.77-3.08).

CONCLUSION: In this study, pretreatment inflammation-based hematological ratios were not associated with future immune-related adverse events in patients treated with checkpoint inhibitors. However, elevated hematological ratios were associated with an increased mortality risk.

Original language	English
Article number	e0336491
Pages (from-to)	1-13
Number of pages	13
Journal	PLoS ONE
Volume	20
Issue number	11 November
DOIs	https://doi.org/10.1371/journal.pone.0336491
Publication status	Published - 12 Nov 2025

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title = "Hematological ratios, immune-related adverse events and mortality in patients treated with immune checkpoint inhibitors",

abstract = "BACKGROUND: Although immune checkpoint inhibitors improve survival in patients with malignancies, a substantial number of patients treated with these agents experience immune-related adverse events. It is unknown whether inflammation-related hematological ratios are associated with immune-related adverse events or mortality.OBJECTIVE: We aimed to investigate the association between pretreatment inflammation-related hematological ratios and the occurrence of immune-related adverse events and mortality in patients receiving checkpoint inhibitors.METHODS: Patients treated with checkpoint inhibitors within a tertiary hospital in the Netherlands were studied using routine care data between January 2013 and May 2020. Cox regression analysis was performed to assess the association between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocytes and platelets ratio (NLPR), and systemic immune-inflammation index (SII) and outcomes (immune-related adverse events or mortality).RESULTS: Among 664 patients treated with checkpoint inhibitors, 397 (59.8\%) patients developed an immune-related adverse event and 363 (54.7\%) patients died during a median follow-up period of 17 months (interquartile range 7-30 months). Hematological ratios were not associated with immune-related adverse events. However, highest tertiles as compared with lowest tertiles of all hematological ratios were independently associated with mortality (NLR: adjusted hazard ratio (HR) 2.23, 95\% CI 1.69-2.95; PLR: adjusted HR 1.88, 95\% CI 1.43-2.47; NLPR: adjusted 1.59, 95\% CI 1.22-2.06; SII: adjusted HR 2.33, 95\% CI 1.77-3.08).CONCLUSION: In this study, pretreatment inflammation-based hematological ratios were not associated with future immune-related adverse events in patients treated with checkpoint inhibitors. However, elevated hematological ratios were associated with an increased mortality risk.",

author = "Sophie Lekkerkerker and Kaasjager, \{Karin A H\} and Saskia Haitjema and Cornelia Hulsbergen-Veelken and Herbschleb, \{Karin H\} and Verhaar, \{Marianne C\} and Meriem Khairoun and Gurbey Ocak",

note = "Publisher Copyright: {\textcopyright} 2025 Lekkerkerker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2025",

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doi = "10.1371/journal.pone.0336491",

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T1 - Hematological ratios, immune-related adverse events and mortality in patients treated with immune checkpoint inhibitors

AU - Lekkerkerker, Sophie

AU - Kaasjager, Karin A H

AU - Haitjema, Saskia

AU - Hulsbergen-Veelken, Cornelia

AU - Herbschleb, Karin H

AU - Verhaar, Marianne C

AU - Khairoun, Meriem

AU - Ocak, Gurbey

N1 - Publisher Copyright: © 2025 Lekkerkerker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2025/11/12

Y1 - 2025/11/12

N2 - BACKGROUND: Although immune checkpoint inhibitors improve survival in patients with malignancies, a substantial number of patients treated with these agents experience immune-related adverse events. It is unknown whether inflammation-related hematological ratios are associated with immune-related adverse events or mortality.OBJECTIVE: We aimed to investigate the association between pretreatment inflammation-related hematological ratios and the occurrence of immune-related adverse events and mortality in patients receiving checkpoint inhibitors.METHODS: Patients treated with checkpoint inhibitors within a tertiary hospital in the Netherlands were studied using routine care data between January 2013 and May 2020. Cox regression analysis was performed to assess the association between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocytes and platelets ratio (NLPR), and systemic immune-inflammation index (SII) and outcomes (immune-related adverse events or mortality).RESULTS: Among 664 patients treated with checkpoint inhibitors, 397 (59.8%) patients developed an immune-related adverse event and 363 (54.7%) patients died during a median follow-up period of 17 months (interquartile range 7-30 months). Hematological ratios were not associated with immune-related adverse events. However, highest tertiles as compared with lowest tertiles of all hematological ratios were independently associated with mortality (NLR: adjusted hazard ratio (HR) 2.23, 95% CI 1.69-2.95; PLR: adjusted HR 1.88, 95% CI 1.43-2.47; NLPR: adjusted 1.59, 95% CI 1.22-2.06; SII: adjusted HR 2.33, 95% CI 1.77-3.08).CONCLUSION: In this study, pretreatment inflammation-based hematological ratios were not associated with future immune-related adverse events in patients treated with checkpoint inhibitors. However, elevated hematological ratios were associated with an increased mortality risk.

AB - BACKGROUND: Although immune checkpoint inhibitors improve survival in patients with malignancies, a substantial number of patients treated with these agents experience immune-related adverse events. It is unknown whether inflammation-related hematological ratios are associated with immune-related adverse events or mortality.OBJECTIVE: We aimed to investigate the association between pretreatment inflammation-related hematological ratios and the occurrence of immune-related adverse events and mortality in patients receiving checkpoint inhibitors.METHODS: Patients treated with checkpoint inhibitors within a tertiary hospital in the Netherlands were studied using routine care data between January 2013 and May 2020. Cox regression analysis was performed to assess the association between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocytes and platelets ratio (NLPR), and systemic immune-inflammation index (SII) and outcomes (immune-related adverse events or mortality).RESULTS: Among 664 patients treated with checkpoint inhibitors, 397 (59.8%) patients developed an immune-related adverse event and 363 (54.7%) patients died during a median follow-up period of 17 months (interquartile range 7-30 months). Hematological ratios were not associated with immune-related adverse events. However, highest tertiles as compared with lowest tertiles of all hematological ratios were independently associated with mortality (NLR: adjusted hazard ratio (HR) 2.23, 95% CI 1.69-2.95; PLR: adjusted HR 1.88, 95% CI 1.43-2.47; NLPR: adjusted 1.59, 95% CI 1.22-2.06; SII: adjusted HR 2.33, 95% CI 1.77-3.08).CONCLUSION: In this study, pretreatment inflammation-based hematological ratios were not associated with future immune-related adverse events in patients treated with checkpoint inhibitors. However, elevated hematological ratios were associated with an increased mortality risk.

U2 - 10.1371/journal.pone.0336491

DO - 10.1371/journal.pone.0336491

M3 - Article

C2 - 41223165

SN - 1932-6203

VL - 20

SP - 1

EP - 13

JO - PLoS ONE

JF - PLoS ONE

IS - 11 November

M1 - e0336491

ER -

Hematological ratios, immune-related adverse events and mortality in patients treated with immune checkpoint inhibitors

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