The presence of severe lymphopenia at the initiation of consolidative immune checkpoint inhibitor (ICI) therapy after definitive chemoradiation was found to be an independent predictor of shorter progression-free survival (PFS) among patients with unresectable, locally advanced non-small cell lung cancer (NSCLC), according to the results of a study published in Lung Cancer.

The current standard of care for the treatment of unresectable, locally advanced NSCLC is chemoradiation followed by consolidative ICI therapy. Lymphopenia has been associated with poor outcomes in other cancer types treated with ICIs, but it is not yet known what role it may play in NSCLC.

This single-center, retrospective cohort study included 78 patients with unresectable, locally advanced NSCLC who received definitive chemoradiation followed by consolidative ICI therapy between 2015 and 2019. Patients were stratified by the presence of severe lymphopenia, which was defined as absolute lymphocyte count (ALC) ≤0.5 x 109 cells/L.

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The median age at baseline was 66 years; 55% of patients were men, and 73% were White. The median dose of radiation delivered was 63 Gy, and 94% of patients received durvalumab for their ICI therapy, with the remaining receiving ipilimumab plus nivolumab in a clinical trial. Baseline ALC was normal among 90% of patients, with 1 patient having severe lymphopenia.

Chemoradiation decreased the median ALC from 1.52 x 109 cells/L to 0.72 x 109 cells/L (P <.001), with 23% of patients developing severe lymphopenia. Chemoradiation also increased the neutrophil-to-lymphocyte ratio (NLR) from a median of 3.6 at baseline to 4.3, and 51% of patients had an NLR >4 before beginning ICI therapy.

Lower baseline ALC (P =.001) and higher NLR at baseline (P =.002) and before ICI therapy (P <.001) were associated with severe lymphopenia.

Patients with severe lymphopenia at the start of ICI therapy demonstrated shorter PFS than patients without severe lymphopenia. The median PFS was 217 days among patients with severe lymphopenia compared with 570 days among patients without (P <.001).

Multivariate analysis demonstrated that severe lymphopenia at ICI initiation was an independent predictor of shorter PFS (hazard ratio [HR], 4.90; 95% CI, 1.70-14.2; P =.003). Improved PFS was significantly associated with total delivered Gy (HR, 0.84; 95% CI, 0.73-0.96; P =.01). The investigators did not find NLR to be associated with PFS in univariate analysis.

The authors concluded that “these data encourage the cautious use of factors that may incite treatment-related lymphopenia and emphasize the importance of identifying lymphopenic patients before the initiation of ICIs.” They added that future prospective studies are needed to validate their findings.


Friedes C, Chakrabarti T, Olson S, et al. Association of severe lymphopenia and disease progression in unresectable locally advanced non-small cell lung cancer treated with definitive chemoradiation and immunotherapy. Lung Cancer. 2021;154:36-43. doi:10.1016/j.lungcan.2021.01.022