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Quizartinib is a kinase inhibitor approved by the FDA for the treatment of newly diagnosed acute myeloid leukemia that meets certain requirements. The brand name of Quizartinib is Vanflyta. Daiichi Sankyo Company received the approval for Vanflyta on July 20, 2023. Acute Myeloid Leukemia (AML) is a type of cancer that causes uncontrolled growth and proliferation of hematopoietic cells. Quizartinib works for Acute Myeloid Leukemia with specific criteria. It is used for the treatment of FLT3 internal tandem duplication-positive AML. Quizartinib inhibits the FLT3 kinase activity and prevents its autophosphorylation which would have led to cell proliferation. In this article, we will see what is FLT3 internal tandem duplication-positive Acute Myeloid Leukemia, the mechanism of action of Quizartinib, and the adverse effects of Quizartinib.
What is FLT3 internal tandem duplication-positive Acute Myeloid Leukemia
- The FLT3 gene provides instructions for making the FLT3 protein, which is a receptor tyrosine kinase expressed on the surface of certain cells, including hematopoietic stem cells. FLT3 plays a crucial role in regulating the growth, survival, and differentiation of these cells.
- In FLT3 ITD-positive AML, a specific mutation occurs in the FLT3 gene, resulting in the insertion of duplicated sequences within the gene. This internal tandem duplication leads to an abnormal form of the FLT3 protein with enhanced kinase activity.
- The FLT3 protein normally transmits signals within the cell through a series of intracellular pathways, including the Ras/Raf/MAPK and PI3K/AKT pathways. In FLT3 ITD-positive AML, the mutated FLT3 protein constitutively activates these signaling pathways even in the absence of normal stimuli. This leads to continuous and unregulated signaling, promoting cell survival and proliferation.
- The persistent activation of FLT3 signaling pathways results in uncontrolled proliferation of hematopoietic progenitor cells, particularly myeloid progenitors. This leads to the overproduction of immature and dysfunctional myeloid cells, which fail to mature into normal blood cells.
- FLT3 ITD-positive AML is associated with a block in the normal process of myeloid cell differentiation. The immature cells (blasts) accumulate in the bone marrow and peripheral blood, preventing the production of functional red blood cells, platelets, and mature white blood cells.
- AML with FLT3 ITD mutations is often associated with an aggressive disease course and poor prognosis. The high proliferation rate and resistance to apoptosis (programmed cell death) contribute to the rapid expansion of leukemic cells, leading to the replacement of normal hematopoietic cells.
Mechanism of action of Quizartinib
- Quizartinib works by inhibiting FLT3 kinase activity thereby preventing the further autophosphorylation which leads to cell proliferation.
- Quizartinib is orally administered, and it is well-absorbed. It undergoes extensive metabolism in the liver, primarily through the CYP3A4 enzyme.
- The metabolism of quizartinib produces active metabolites. The main metabolite, AC886, is also pharmacologically active. Both quizartinib and its metabolites are eliminated primarily through feces.
- Quizartinib is a potent and selective inhibitor of FLT3, a receptor tyrosine kinase that plays a crucial role in the regulation of hematopoiesis. FLT3-ITD mutations lead to constitutive activation of FLT3, contributing to the development and progression of AML.
- Quizartinib binds to and inhibits the activity of FLT3, specifically targeting the mutant FLT3-ITD. By doing so, quizartinib downregulates aberrant FLT3 signaling pathways, which include the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways.
- Inhibition of FLT3 signaling by quizartinib promotes apoptosis (programmed cell death) in leukemic cells. This is particularly relevant in FLT3-ITD-positive AML, where the constitutive activation of FLT3 contributes to cell survival and proliferation.
- Quizartinib induces cell cycle arrest, preventing the uncontrolled proliferation of leukemic cells. This contributes to the anti-leukemic effects of the drug.
Adverse Effects of Quizartinib
- QT Prolongation, Torsades de Pointes, and Cardiac Arrest
Contraindications of Quizartinib
VANFLYTA is contraindicated in patients with severe hypokalemia, severe hypomagnesemia, long QT
syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes
