Dosimetric Factors Associated With Lymphopenia in Metastatic Cancer Patients Receiving Palliative Radiation and PD-1 Immune Checkpoint Inhibitors

Abstract

Radiation (RT)-associated lymphopenia may adversely affect treatment outcomes, particularly in the era of immunotherapy. We sought to determine dosimetric factors (DF) correlated with lymphopenia following palliative RT in a cohort of patients with advanced cancer treated with anti-PD-1 immune checkpoint inhibitors (ICIs).We included patients with metastatic lung cancer, melanoma, or renal cell carcinoma who were treated with either pembrolizumab or nivolumab and received palliative RT to an extracranial site. Baseline and nadir absolute lymphocyte count (ALC) within 6 weeks of RT were recorded. Heart, lungs, liver, kidneys, spleen, bone, and large blood vessels (LBV) were contoured for each RT course, and various DF were extracted from the corresponding dose-volume histograms (DVHs). To model RT dose to circulating lymphocytes, we also input these DVHs into a whole-body blood flow model that simulates the spatiotemporal distribution of blood particles in organs based on blood volumes and flow rates from ICRP-89. Associations between DF with ALC nadir and ALC change were assessed with Spearman correlation coefficients. DF with the strongest correlations were dichotomized at the median and evaluated for association with grade 3+ lymphopenia (ALC < 500cells/mL) post-RT by univariable logistic regression.We analyzed 55 patients who underwent 80 total courses of palliative RT; most (94%) were treated with 3D conformal RT. Doses to whole body, bone, and LBV were negatively correlated with ALC nadir, with the strongest correlations seen at V15 (rs = -0.38, -0.43, and -0.36, P = 0.0004, 0.0001, and 0.001, respectively). Doses to other organs were not significantly correlated with ALC nadir. The modeled dose to circulating lymphocytes was also negatively correlated with ALC nadir and ALC change (for D2%, rs = -0.31 and -0.38, P = 0.005 and 0.0007, respectively). Associations between these DF and grade 3+ lymphopenia are shown in the Table.RT dose to whole body, bone, and large blood vessels were correlated with lymphopenia in patients treated with palliative RT and anti-PD-1 ICIs. The modeled dose to circulating lymphocytes in our dynamic model correlated with lymphopenia as well, validating our model and enabling future investigation into dose rate and fractionation effects. These dose parameters may help guide RT planning to minimize lymphopenia risk, though additional studies are required to elicit the relative importance of each factor.