Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib

Abstract

We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.

Chemotherapy-induced anemia: etiology, pathophysiology, and implications for contemporary practice

“…Administration of FLT3 tyrosine kinase inhibitors following chemotherapy may selectively induce myelosuppression of neoplastic cells, but not bone marrow progenitor cells. 12 Arginine vasopressin, eryptosis inhibitors, transforming growth factor beta inhibitors, and drugs that disrupt the HIF-1α pathway may help to preserve and stimulate erythropoiesis as well as to protect renal tubular and endothelial cells. 39,[107][108][109] Roxadustat, a reversible HIF prolyl hydroxylase inhibitor, increases expression of both erythropoietin as well as erythropoietin receptors and is under investigation to reduce red blood cell transfusion requirements.…”

“…10 Unfortunately, chemotherapy affects all rapidly dividing cells, including the particularly sensitive erythroid progenitor cells in a process known as eryptosis. 12 Analogous to apoptosis of nucleated cells, erythrocytes undergo eryptosis to destroy and remove defective erythrocytes, thereby preventing hemolysis and subsequent hemoglobin release. 13 Eryptosis and resultant erythrocyte deficiency contributes to anemia and is exacerbated by inadequate compensatory erythropoiesis.…”

Myelotoxicity Assessment During Induction Chemotherapy in Patients With Acute Myeloid Leukemia

“…Проте, цитостатична мієлосупресія залишається найчастішим і найсуворішим побічним ефектом хіміотерапії (ХТ), її клінічним проявом є периферична панцитопенія. Спостерігається масове виснаження клітинпопередниць кісткового мозку, що призводить до розвитку нейтропенії, тромбоцитопенії та анемії [1,5,7].…”

Hitting the snooze button: Inducing quiescence with the FLT3 inhibitor quizartinib protects hematopoietic progenitors from chemotherapy

“…We continued our investigation with quizartinib in C57BL/6 mice and found that the induced quiescence of MPPs was also evident, and therefore was not an effect associated with the c-Cbl mutation. 2 Furthermore, the quizartinib-induced quiescence was found to be robust enough to protect these cells from the toxic effects of the chemotherapeutics, fluorouracil (5-FU) and gemcitabine (See Fig. 1).…”

“…1 In our recent study we described a combination therapy that prevents myelosuppression by protecting multipotent progenitors (MPPs) in the bone marrow. 2 Quizartinib (AC220) is a potent small molecule inhibitor of FMS-Like Tyrosine kinase 3 (FLT3), originally designed to treat acute myeloid leukemia (AML) patients with FLT3-ITD (-Internal Tandem Duplication) mutations. 3 Quizartinib is also effective in combatting wild type FLT3-driven leukemia that occurs in mice with a mutation in the RING finger domain of c-Cbl.…”