Introduction: A major issue with current cancer treatment is the harmful depletion of the haematopoietic system that occurs as a result of chemotherapy. We have previously identified that treatment with AC220 (quizartinib), a second-generation FLT3 inhibitor, induces a transient quiescence in early progenitor cells in a murine model. We investigated this phenomenon further to determine whether AC220-induced quiescence could protect wildtype (WT) progenitors from chemotherapy-induced depletion. Furthermore, we investigated the selectivity of this protective effect for WT against leukaemic bone marrow in chimeric mouse models.
Methods: B6 mice were dosed via oral gavage with AC220 or vehicle to determine quiescence (via flow cytometric Ki67 expression and cell cycle analysis) and the resultant sensitivity to the chemotherapeutic agent 5-FU. FLT3-dependent (FLT3-ITD mutant) and FLT3-independent (JAK2 V617F mutant) leukemic bone marrow were mixed with WT bone marrow and transplanted into irradiated recipient B6.SJL.45.1 mice. These chimeric mice were treated with multiple rounds of AC220 or vehicle plus 5-FU.
Results: B6 mice dosed with AC220 display a transient induction of quiescence in their hematopoietic progenitor cell compartment. This AC220-induced quiescence proved sufficient to induce protection from the cytotoxic actions of 5-FU such that pre-treatment with AC220 (2-18hr prior to 5-FU) led to a 4-fold increase in the number of LSK cells surviving 2 days post injection with 5-FU. Furthermore, AC220-primed B6 mice displayed significantly higher survival to serial 5-FU treatment. Findings from FLT3-ITD and JAK2 V617F chimeric mice treated with AC220-primed 5-FU will also be presented.
Conclusion: FLT3 inhibition provides a simple and effective means to protect bone marrow progenitors thus alleviating the haematopoietic side effects in patients receiving chemotherapy.