Radiation-Induced Lymphopenia: In Silico Replications of Preclinical Studies Suggest Importance of Dose to Lymphoid Organs.

Abstract

Purpose: To develop a computational framework to investigate the implications of lymphocyte recirculation for understanding radiation-induced lymphopenia (RIL) and to compare model predictions with preclinical in vivo studies.

Methods and materials: A whole-body compartmental model of lymphocyte migration in mice was developed, and unknown rate parameters were fitted to published experimental data. Using a stochastic representation of the model in combination with detailed mouse phantom meshes, implicit lymphocyte trajectories were computed. In parallel, a module was developed to reproduce small animal irradiation plans using either photon or proton beams. Combining these computational tools, we calculated the dose distribution of the recirculating lymphocyte pool in different irradiation scenarios and simulated the subsequent redistribution of viable lymphocytes. The relative importance of irradiation of secondary lymphoid organs (SLOs) versus the blood was investigated through in silico replications of 3 preclinical studies in which mice were locally irradiated.

Results: Lymphocyte recirculation between the blood and SLOs attenuates lymphocyte depletion in 1 compartment by distributing the loss throughout the system. Because only a relatively small fraction (∼17% for mice) of the recirculating lymphocyte pool is in the blood at any given time, with most lymphocytes in the SLOs, the effect of SLO irradiation is greater than that of the blood. Predicted depletion trends correlated with those observed in preclinical studies but underestimated the degree of lymphopenia. The finding that proton beams can avert lymphopenia after whole-brain irradiation by sparing head and neck lymph nodes was reproduced.

Conclusions: The occurrence of RIL is associated with worse outcomes in patients with cancer but remains poorly understood. Therefore, a computational framework to replicate preclinical studies was developed to systematically investigate this phenomenon. Our simulations indicate that irradiation of SLOs contributes more to lymphocyte dose than blood irradiation. However, the expected cytotoxicity associated with the replicated preclinical studies could not fully account for the degree of lymphopenia observed.