The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy.

Abstract

Simple SummaryCombining chemoradiotherapy with immunotherapy is one of the main milestones in cancer treatment. The optimal sequence to ensure the effectiveness of the treatment is unknown. We investigated the kinetics of FMS-related tyrosine kinase 3 ligand (Flt-3L), a multi-potential haemopoietic protein, and observed an increase in its concentration following bone marrow-damaging irradiation. At the same time, Flt-3L is an important regulating factor of dendritic cells, which are essential for the immune effect of lymphocytes. We observed an increase in Flt-3L levels in the first two weeks of treatment with no further increase during chemoradiotherapy. Our model explains the early variability of Flt-3L, which was related to the irradiation dose in active bone marrow and the subsequent lymphopenia. Our results argue for the earlier initiation of immunotherapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred.The optimal sequence of chemoradiotherapy with immunotherapy is still not established. The patient’s immune status may play a role in determining this order. We aim to determine the kinetics of a multi-potential haemopoietic factor FMS-related tyrosine kinase 3 ligand (Flt-3L) during chemoradiotherapy. Our pilot, a single arm prospective study, enrolled patients with rectal cancer who qualified for neoadjuvant chemoradiotherapy. Blood samples for Flt-3L were collected before and every second week of chemoradiotherapy for a complete blood count every week. The kinetics of Flt-3L were assessed using Friedman’s ANOVA. A multiple factor analysis (MFA) was performed to find relevant factors affecting levels of serum Flt-3L during chemoradiotherapy. FactoMineR and factoextra R packages were used for analysis. In the 33 patients enrolled, the level of Flt-3L increased from the second week and remained elevated until the end of treatment (p < 0.01). All patients experienced Grade ≥2 lymphopenia with a nadir detected mostly in the 5/6th week. MFA revealed the spatial partitioning of patients among the first and second dimensions (explained by 38.49% and 23.14% variance). The distribution along these dimensions represents the magnitude of early changes of Flt-3L. Patients with the lowest values of Flt-3L change showed the highest lymphocyte nadirs and lowest dose/volume parameters of active bone marrow. Our hypothesis-generating study supports the concept of early initiation of immuno-therapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred.