Impact of Palliative Radiation on Lymphocyte Count and Neutrophil-to-Lymphocyte Ratio in Patients Receiving PD-1 Inhibitors

Abstract

Immune checkpoint inhibitors (ICI) are increasingly used in patients receiving palliative radiation (RT). However, studies suggest that RT, and particularly protracted RT courses, may decrease circulating lymphocytes, which could adversely impact ICI efficacy. We therefore evaluated circulating lymphocytes in a contemporary cohort of melanoma, non-small cell lung cancer and renal cell carcinoma patients treated with ICI and radiation. We reviewed consecutive patients treated with palliative RT and ICI. We recorded absolute lymphocyte count (ALC), neutrophil count, and neutrophil to lymphocyte ratio (NTL) before and after palliative RT, and start of ICI. Patients who received other intervening systemic therapy were excluded. Survival was analyzed using the Kaplan-Meier method and log-rank tests. Chi-squared and non-parametric tests evaluated differences between groups. We identified 110 patients treated with PD-1 inhibitors; 38 also received CTLA-4 inhibitors (23 sequentially, 15 concurrently). The most common site irradiated was the brain (71 patients, 120 courses, 40% SRS). Among all patients, median change in ALC (dALC) and NTL (dNTL) after RT was -161 and 0.8, respectively. Changes were more pronounced after extracranial RT (dALC -384 vs. -48 for brain-directed RT p=0.01, dNTL 0.2 vs. 2.5, p=0.001), RT to the spine, lung, or chest wall vs. brain, extremity, or abdomen/pelvis (dALC -438, -384 or -470 vs. 252, 204, or -7, p=0.002, dNTL 11.6, 15.8 or 10.8 vs. 0.2, 1.2, or 3.4, p=0.05) or RT courses >5 fractions (dALC -328 vs. -11 p=0.003, dNTL 1.6 vs. 0.05, p=0.02). The association of dALC with >5 fractions RT remained significant after excluding brain-directed RT (dALC -443 vs. -26, p=0.01, dNTL 2.7 vs. 0.03, p=0.09), but not in brain-directed RT patients (dALC -128 vs 11, p=0.5, dNTL 0.5 vs 0.1, p=0.97). There was no association between timing of RT in relation to ICI on dALC and dNTL. Median survival (MS) was 319 days from PD-1 therapy onset. ALC<500 and NTL>4 at PD-1 therapy onset was associated with decreased MS (359 vs. 100 days, p<.0001, and 472 vs 250 days, p=0.01, respectively). In a MVA correcting for performance status and serum albumin, this association of ALC with survival persisted (HR 2.3, p=0.01). RT before PD-1 therapy onset was associated with ALC<500 or NTL>4 at onset when RT was extracranial (OR 3.9, p=0.0008 and 2.4, p=0.02) or >5 fractions (OR 2.9, p=0.01 and 2.3, p=0.03). There was no such association with RT performed after initiation of PD-1 therapy. Among RT patients treated <30d prior to PD-1 therapy, dALC after RT was associated with decreased MS (p=0.009). In a contemporary cohort of patients treated with palliative RT and PD-1 inhibitors, we confirm that RT can decrease ALC and increase NTL, particularly extracranial RT and more protracted regimens. These parameters are associated with worse outcomes following treatment with ICI, suggesting the need for further optimization of combined RT/ICI regimens.