Sleeping through the storm: Preventing myelosuppression with quizartinib

Chemotherapy-induced myelosuppression is a major complication for cancer patients, causing high rates of morbidity and mortality. Furthermore, myelosuppression is frequently managed by delaying and/or reducing the scheduled dose, and as a consequence the efficacy of treatment can be compromised. In addition, elderly patients are more susceptible to chemotherapy-induced myelosuppression because of their limited hematopoietic reserve, and as a consequence they often receive a reduced dose contributing to poorer outcomes. Current management of the three main side effects of myelosuppression: anemia, neutropenia and thrombocytopenia is costly and of limited effectiveness. Chemotherapy patients often require hospitalization to treat these side effects, thus affecting their quality of life and causing substantial financial burden to themselves and the healthcare system. We recently described an innovative approach that prevents chemotherapy-induced myelosuppression in mice through the repurposing of quizartinib, a potent inhibitor of the FLT3 receptor tyrosine kinase [1]. Quizartinib was developed to treat acute myeloid leukemia (AML) patients with FLT3 driver mutations, and clinical trials have shown considerable promise with a high number of complete composite remissions [2, 3]. Our initial studies with quizartinib involved treating Cbl RING finger mutant mice that develop a myeloproliferative disease (MPD) [4]. This disease is driven by hyper-active wild type Flt3 signaling [5], and we found that dosing these mice with quizartinib suppressed Flt3 activity, and as a consequence MPD development was prevented [4]. This study was of interest because CBL mutations are found in approximately 5% of human MPDs. From these studies of Cbl mutant mice we observed that a single dose of quizartinib induced a rapid but transient quiescence in multipotent progenitors (MPPs). MPPs are highly proliferative FLT3+ cells in the bone marrow that produce all mature blood lineages. Wildtype C57BL/6 mice were subsequently investigated, and quizartinib produced an identical effect on MPPs as seen in Cbl mutant mice. From these observations we reasoned that the transient quiescence might allow the cells to be protected from chemotherapeutic drugs that kill rapidly proliferating cells (Figure 1). A detailed study of doses and time courses revealed that a priming dose of 30 mg/ kg of quizartinib 6-18 hours before administration of the cytotoxic drug fluorouracil (5-FU) provided 10-fold protection to MPPs [1]. We also found that quizartinib provided significant protection to committed progenitors within the lineage negative, c-Kit+, Sca-1population (i.e. LK cells), as well more immature CD48progenitor/ stem cells within the lineage negative, c-Kit+, Sca-1+ population (i.e. LSK cells). As a result quizartinib priming enabled a rapid recovery of bone marrow cellularity after 5-FU treatment, and the numbers of red blood cells, lymphocytes, neutrophils and platelets in the peripheral blood followed a similar trajectory. Furthermore, mice primed with quizartinib before 5-FU retained their body weight, whereas all vehicle-primed mice showed significant weight loss. As a consequence, quizartinib priming prevented otherwise lethal myelosuppression [1] . We also showed that quizartinib provided marked Editorial