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Baseline Lymphopenia Predicts Survival in ICI-Naïve Solid Tumor Patients Receiving Immune Checkpoint Inhibitors: A Propensity-Matched Real-World Pan-Cancer Analysis
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Department of Medicine, Eastern Virginia Medical School at Old Dominion University, Norfolk, VA 23507, USA
2
Virginia Oncology Associates, Norfolk, VA 23502, USA
3
Department of Medical Oncology, Ohio Health, Columbus, OH 43228, USA
4
Department of Medical Oncology, Ohio Health, Delaware, OH 43015, USA
*
Authors to whom correspondence should be addressed.
Cancers 2026, 18(12), 1940; https://doi.org/10.3390/cancers18121940 (registering DOI)
Submission received: 21 May 2026
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Revised: 11 June 2026
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Accepted: 12 June 2026
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Published: 14 June 2026
(This article belongs to the Section Cancer Immunology and Immunotherapy)
Simple Summary
Many people with advanced cancer have low lymphocyte counts, but it is unclear how this common blood test should influence decisions about immune checkpoint inhibitor treatment. In this study, we used a large United States electronic health record network to examine adults with multiple solid tumor types who received pembrolizumab, nivolumab, or atezolizumab. We compared patients who started immunotherapy with low lymphocyte counts to similar patients with normal counts, carefully balancing other factors that might affect outcomes. We found that patients with low counts before treatment had consistently shorter survival, needed more hospital care early after treatment, and may have had more serious infections, without a clear increase in immune-related side effects. These results suggest that a simple, widely available blood test can help identify higher-risk patients starting immunotherapy and may guide how closely they are monitored and supported.
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.
