ORCID

0000-0002-1587-0370 (Ismail)

Document Type

Article

Publication Date

2026

DOI

10.3390/cancers18121940

Publication Title

Cancers

Volume

18

Issue

12

Pages

1940

Abstract

Background: Baseline lymphopenia is common among advanced solid tumors and may influence the efficacy/safety of immune checkpoint inhibitors (ICIs), but large real-world evidence is limited. We evaluated the association between baseline absolute lymphocyte count (ALC) and clinical outcomes in adults with solid tumors treated with ICIs in routine practice. Methods: We performed a retrospective cohort study using TriNetX. Adults with solid tumors who received pembrolizumab, nivolumab, or atezolizumab (ICI-Naïve) between January 2015 and June 2026 were included. Baseline ALC was measured within 30 days before first treatment and was classified as lymphopenic (ALC < 1.5 × 10⁹/L) or non-lymphopenic (ALC ≥ 1.5 × 10⁹/L). Propensity score matching (1:1) yielded 5249 patients per group. The index date was the first immunotherapy date, and outcomes were assessed at 6, 12, 24, 36 months, and 5 years. The primary outcome was 24-month overall survival (OS); secondary outcomes were OS at 6 and 12 months and 6-month risks of healthcare utilization, immune-related adverse events (irAEs), and serious infections; and exploratory outcomes included OS at 36 months and 5 years. All outcomes were analyzed using Kaplan–Meier analysis, Cox proportional hazards models, and risk ratios. Subgroup analysis included OS stratified by solid tumor subtypes and prior lines of therapy. Results: After matching, patients with baseline lymphopenia had consistently worse OS. Compared with patients without lymphopenia, the lymphopenia cohort had lower OS at 6 months (HR 1.29, 95% CI 1.22–1.37), 12 months (HR 1.28, 95% CI 1.21–1.35), 24 months (HR 1.26, 95% CI 1.2–1.33), and, in exploratory analyses with substantial right censoring and limited observed follow-up, 36 months (HR 1.26, 95% CI 1.2–1.33) and 5 years (HR 1.26, 95% CI 1.2–1.33), though these estimates should be considered hypothesis-generating only. At 6 months, baseline lymphopenia was associated with a greater healthcare utilization (RR 1.05, 95% CI 1.02–1.09), a higher infection risk (RR 1.08, 95% CI 1.01–1.15), and similar rates of clinically coded irAEs (RR 1.0, 95% CI 0.93–1.09), an observation subject to competing risk from early mortality in the lymphopenic cohort. Subgroup analysis, stratified by tumor subtypes and prior lines of therapy, showed consistently lower OS in the lymphopenia group, consistent with the primary outcome results. Conclusions: In this large propensity-matched real-world analysis of 10,498 patients with diverse solid tumors, baseline lymphopenia at ICI initiation was associated with persistently inferior OS at 6, 12, and 24 months (primary and secondary endpoints), greater early healthcare utilization, and a higher serious infection risk. Critically, lymphopenic patients developed irAEs at an identical rate to non-lymphopenic patients despite worse survival, a dissociation suggesting that baseline ALC stratifies patients along mortality risk and immune activation capacity as partially independent axes. These findings could support the use of baseline ALC as a simple, universally available biomarker that informs not only survival prognosis but also the anticipated toxicity profile of ICI therapy and highlight the need for competing-risk analyses and prospective immune phenotyping to characterize this relationship fully.

Rights

© 2026 by the Authors.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Data Availability

Article states: "All data (Tables and figures) are presented in the body of the manuscript."

Original Publication Citation

Ismail, A., Balanchivadze, N., Simon, G. R., & Boumber, Y. (2026). Baseline lymphopenia predicts survival in ICI-Naïve solid tumor patients receiving immune checkpoint inhibitors: A propensity-matched real-world pan-cancer analysis. Cancers, 18(12), Article 1940. https://doi.org/10.3390/cancers18121940

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