Retrospective Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Nov 15, 2023; 15(11): 1900-1912
Published online Nov 15, 2023. doi: 10.4251/wjgo.v15.i11.1900
Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma
Sirish Dharmapuri, Umut Özbek, Hiren Jethra, Tomi Jun, Thomas U Marron, Anwaar Saeed, Yi-Hsiang Huang, Mahvish Muzaffar, Matthias Pinter, Lorenz Balcar, Claudia Fulgenzi, Suneetha Amara, Arndt Weinmann, Nicola Personeni, Bernhard Scheiner, Tiziana Pressiani, Musharraf Navaid, Bertram Bengsch, Sonal Paul, Uqba Khan, Dominik Bettinger, Naoshi Nishida, Yehia Ibrahim Mohamed, Arndt Vogel, Anuhya Gampa, James Korolewicz, Antonella Cammarota, Ahmed Kaseb, Peter R Galle, Anjana Pillai, Ying-Hong Wang, Alessio Cortellini, Masatoshi Kudo, Antonio D’Alessio, Lorenza Rimassa, David James Pinato, Celina Ang
Sirish Dharmapuri, Thomas U Marron, Celina Ang, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Umut Özbek, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Hiren Jethra, Department of Data Analytics Harrisburg, Harrisburg University of Science and Technology, Harrisburd, PA 17101, United States
Tomi Jun, SEMA4, Stamford, CT 06902, United States
Anwaar Saeed, Division of Medical Oncology Kansas, University of Kansas Cancer Center, Kansas, MO 66160, United States
Yi-Hsiang Huang, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
Mahvish Muzaffar, Suneetha Amara, Musharraf Navaid, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27858, United States
Matthias Pinter, Lorenz Balcar, Bernhard Scheiner, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1090, Austria
Claudia Fulgenzi, James Korolewicz, Alessio Cortellini, Antonio D’Alessio, David James Pinato, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital London, London W12 0HS, United Kingdom
Arndt Weinmann, Department of Hepatology, Johannes Gutenberg-University Medical Centre, Niedersachsen 30625, Germany
Nicola Personeni, Medical Oncology Unit, ASST Garda, Via Lungomella Valsecchi, Brescia, Manerbio 25025, Italy
Nicola Personeni, Tiziana Pressiani, Antonella Cammarota, Lorenza Rimassa, Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano 20089, Italy
Bertram Bengsch, Dominik Bettinger, Department of Medicine II, Univ Med Ctr Freiburg, Hugstetter Str 55, University Hospital Freiburg, Freiburg D-79106, Germany
Sonal Paul, Department of Oncology Baltimore, LifeBridge Health, Baltimore, MD 21215, United States
Uqba Khan, Division of Hematology and Oncology, Weill Cornell Medical College, NY 10065, United States
Naoshi Nishida, Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka 577-8502, Japan
Yehia Ibrahim Mohamed, Ahmed Kaseb, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
Arndt Vogel, Department of Gastroenterology Hepatology and Endocrinology, HannoverArndt Vogel, Medical School Hannover, Carl-Neubergstr., Hannover 30659, Germany
Anuhya Gampa, Department of Hepatology, Rush University Medical Group 1725 W Harrison St Ste 158, Chicago, IL 60612, United States
Antonella Cammarota, Lorenza Rimassa, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20072, Italy
Peter R Galle, Department of Internal Medicine I and Cirrhosis Center Mainz, University Medical Center Mainz, Johannes Gutenberg Univ Mainz, Med Klin and Poliklin, Mainz D-55131, Germany
Anjana Pillai, Department of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
Ying-Hong Wang, Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
Author contributions: Dharmapuri S contributed to study concept and design, acquisition of data, analysis, and interpretation of data and drafting of the manuscript; Özbek U and Jethra H performed statistical analysis; Jun T, Marron TU, Saeed A, Huang YH, Muzaffar M, Pinter M, Balcar L, Fulgenzi C, Amara S, Weinmann A, Personeni N, Scheiner B, Pressiani T, Navaid M, Bengsch B, Paul S, Khan U, Bettinger D, Nishida N, Mohamed YI, Vogel A, Gampa A, Korolewicz J, Cammarota C, Kaseb A, Galle PR, Pillai A, Wang YH, Cortellini A, Kudo M, D’Alessio A and Rimassa L performed acquisition of data; Pinato DJ and Ang C contributed to study concept and design, analysis and interpretation of data, drafting of the manuscript, and study supervision; Both contributed equally and should be considered joint senior authors. All authors performed critical revision of the manuscript for important intellectual content.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Mount Sinai Health System and locally by the ethical committee of each participating site.
Informed consent statement: The retrospective nature of the study, along with the absence of patient identifiers and most patients being deceased, made it impracticable to obtain individual consent from the patients included in the analysis.
Conflict-of-interest statement: Rimassa L report consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Merck Serono, Roche, Servier; travel expenses from AstraZeneca; research grants (to institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. Pressiani T reports consulting fees from Bayer, Ipsen, AstraZeneca; travel expenses from Roche; research grants (to institution) from Roche, Bayer, Astra Zeneca. Personeni N reports consulting fees from Amgen, Merck KGaA, Boehringer Ingelheim, IQVIA, Servier, Sanofi Aventis; lecture fees from Janssens, Astra Zeneca, Incyte; research grants (to institution) from Servier, Basilea; travel expenses from Amgen, Servier. Pinter M is an investigator for Bayer, BMS, Lilly, and Roche, he received speaker honoraria from Bayer, BMS, Eisai, and MSD, he is a consultant for Bayer, BMS, Ipsen, Eisai, Lilly, Roche, and MSD, and he received travel support from Bayer, BMS, and Roche. Scheiner B received travel support from AbbVie, Ipsen and Gilead. Bettinger D received consulting fees from Bayer Healthcare, Boston Scientific, and Shionogi. Lectures: Falk Foundation. A.C. received consulting fees from MSD, BMS, AstraZeneca, and Roche; speakers’ fee from AstraZeneca, MSD, Novartis, and Astellas. Pinato DJ received lecture fees from ViiV Healthcare and Bayer Healthcare, and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and Astra Zeneca; and received research funding (to institution) from MSD and BMS. Saeed A receives consulting fee from AstraZeneca; Bristol-Myers Squibb; Daiichi Sankyo/Astra Zeneca; Exelixis; Five Prime Therapeutics; Pfize, speakers fee from Daiichi Sankyo/Astra Zeneca and research funding from Actuate Therapeutics (Inst); Astellas Pharma (Inst); AstraZeneca/MedImmune (Inst); Bristol-Myers Squibb (Inst); Clovis Oncology (Inst); Daiichi Sankyo/UCB Japan (Inst); Exelixis (Inst); Five Prime Therapeutics (Inst); KAHR Medical (Inst); Merck Sharp and Dohme (Inst); Seattle Genetics (Inst). Khan U receives honoraria from Cardinal Health, consulting fee from Bard Peripheral Vascular and travel expenses paid for by Bard Peripheral Vascular; Cardinal Health. Huang YH is a consultant for Bayer; Bristol-Myers Squibb; Eisai; Gilead Sciences; Lilly; MSD; Roche and received speaker honoraria from Bayer; Bristol-Myers Squibb; Eisai; Gilead Sciences; Lilly; MSD; Roche. Kesab AO receives honoraria from AstraZeneca; Bayer Health; Bristol-Myers Squibb; Eisai; Exelixis; Genentech/Roche; Merck and research funding from Adaptimmune (Inst); Bayer/Onyx (Inst); Bristol-Myers Squibb (Inst); Genentech (Inst); Hengrui Pharmaceutical (Inst); Merck (Inst). Pillai A received consulting fee from AstraZeneca; Eisai; Exelixis; Genentech; Replimune, research funding from Target Pharmasolutions and speaker honoraria from Simply Speaking PAH. All remaining authors have declared no conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sirish Dharmapuri, MD, Assistant Professor, Tisch Cancer Institute, Icahn school of Medicine at Mount Sinai, No. 425 West 59th Street, New York, NY 10029, United States. sirish.dharmapuri@gmail.com
Received: May 21, 2023
Peer-review started: May 21, 2023
First decision: August 15, 2023
Revised: September 14, 2023
Accepted: October 23, 2023
Article in press: October 23, 2023
Published online: November 15, 2023
Abstract
BACKGROUND

A well-recognized class effect of immune checkpoint inhibitors (ICI) is immune-related adverse events (IrAEs) ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI. Deaths are reported in < 5% of patients treated with ICI. There are, however, no reliable markers to predict the onset and severity of IrAEs. We tested the association between neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) at baseline with development of clinically significant IrAEs (grade ≥ 2) in hepatocellular carcinoma (HCC) patients treated with ICI.

AIM

To test the association between NLR and PLR at baseline with development of clinically significant IrAEs (grade ≥ 2) in HCC patients treated with ICI.

METHODS

Data was extracted from an international database from a consortium of 11 tertiary-care referral centers. NLR = absolute neutrophil count/absolute lymphocyte count (ALC) and PLR = platelet count/ALC. Cutoff of 5 was used for NLR and 300 for PLR based on literature. We also tested the association between antibiotic and steroid exposure to IrAEs.

RESULTS

Data was collected from 361 patients treated between 2016-2020 across the United States (67%), Asia (14%) and Europe (19%). Most patients received Nivolumab (n = 255, 71%). One hundred sixty-seven (46%) patients developed at least one IrAE, highest grade 1 in 80 (48%), grade ≥ 2 in 87 (52%) patients. In a univariable regression model PLR > 300 was significantly associated with a lower incidence of grade ≥ 2 IrAEs (OR = 0.40; P = 0.044). Similarly, a trend was observed between NLR > 5 and lower incidence of grade ≥ 2 IrAEs (OR = 0.58; P = 0.097). Multivariate analyses confirmed PLR > 300 as an independent predictive marker of grade ≥ 2 IrAEs (OR = 0.26; P = 0.011), in addition to treatment with programmed cell death ligand 1 (PD-1)/cytotoxic T lymphocyte-associated protein-4 (OR = 2.57; P = 0.037) and PD-1/tyrosine kinase inhibitor (OR = 3.39; P = 0.01) combinations. Antibiotic use was not associated with IrAE incidence (OR = 1.02; P = 0.954). Patients treated with steroids had a > 2-fold higher incidence of grade ≥ 2 IrAEs (OR = 2.74; P < 0.001), although 74% were prescribed steroids for the treatment of IrAEs.

CONCLUSION

Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs, lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI. This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Keywords: Neutrophil-lymphocyte ratio, Platelet-lymphocyte ratio, Inflammatory biomarkers, Immunotherapy, Immune toxicity

Core Tip: In this study of hepatocellular carcinoma (HCC) patients treated with immune checkpoint inhibitors (ICI), the association between two biomarkers, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), and immune-related adverse events (IrAEs) was examined. Data from 361 patients showed that a higher PLR (> 300) was significantly associated with a lower incidence of grade ≥ 2 IrAEs. A trend was observed between a higher NLR (> 5) and lower incidence of grade ≥ 2 IrAEs. Multivariate analyses confirmed PLR as an independent predictive marker for grade ≥ 2 IrAEs. These findings suggest that NLR and PLR could be potential predictive markers for IrAEs in HCC patients receiving ICI treatment.