Bendamustine induces peripheral lymphodepletion in dogs with relapsed lymphoma

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has improved outcomes for many human patients with B-cell lymphoma and provides a rational template for analogous canine patients. To date, the expansion, persistence, and activity of CAR T cells in dogs have been limited. Lymphodepletion supports CAR T-cell engraftment and antitumor activity. In human medical oncology, bendamustine has emerged as a well-tolerated lymphodepleting agent. However, prospective use of bendamustine for dogs with lymphoma has not been characterized. HYPOTHESIS/OBJECTIVES: To determine the lymphodepleting activity and tolerability of bendamustine in dogs with relapsed lymphoma. Secondary objectives included monitoring serum cytokines and short-term changes in peripheral tumor burden. ANIMALS: Eleven client-owned dogs with relapsed lymphoma. METHODS: Luminescent assays were used to assess the direct cytotoxic activity of bendamustine against canine lymphoid cell lines. A prospective rapid dose-escalation pilot trial was undertaken in 11 dogs with relapsed lymphoma to evaluate tolerability while tracking peripheral lymphocyte counts, serum cytokine concentrations, and lymph node measurements. RESULTS: Bendamustine induced concentration-dependent cytotoxicity in all cell lines tested. Two-dose bendamustine regimens up to 90 mg/m2 were generally well tolerated, with no dose-limiting toxicities observed, and resulted in peripheral lymphodepletion (pretreatment median, 880 cells/μL; posttreatment median, 310 cells/μL), an exploratory decrease in circulating interleukin-6 (pretreatment median, 5.32 pg/mL; posttreatment median, 1.33 pg/mL), and a short-term decrease in peripheral nodal burden in 8 of 11 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Bendamustine was generally well tolerated and induced lymphodepletion in our cohort. These findings support further evaluation of bendamustine as a preconditioning agent before autologous canine CAR T-cell infusion.