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Review
. 2020 Jan 8:12:151-163.
doi: 10.2147/CMAR.S196568. eCollection 2020.

Profile of Quizartinib for the Treatment of Adult Patients with Relapsed/Refractory FLT3-ITD-Positive Acute Myeloid Leukemia: Evidence to Date

Luke Fletcher  1   2 , Sunil K Joshi  1   2   3 , Elie Traer  1   2
Affiliations
Review

Profile of Quizartinib for the Treatment of Adult Patients with Relapsed/Refractory FLT3-ITD-Positive Acute Myeloid Leukemia: Evidence to Date

Luke Fletcher et al. Cancer Manag Res. .

Abstract

Acute myeloid leukemia (AML) is a clonal hematologic neoplasm characterized by rapid, uncontrolled cell growth of immature myeloid cells (blasts). There are numerous genetic abnormalities in AML, many of which are prognostic, but an increasing number are targets for drug therapy. One of the most common genetic abnormalities in AML are activating mutations in the FMS-like tyrosine kinase 3 receptor (FLT3). As a receptor tyrosine kinase, FLT3 was the first targetable genetic abnormality in AML. The first generation of FLT3 inhibitors were broad-spectrum kinase inhibitors that inhibited FLT3 among other proteins. Although clinically active, first-generation FLT3 inhibitors had limited success as single agents. This led to the development of a second generation of more selective FLT3 inhibitors. This review focuses on quizartinib, a potent second-generation FLT3 inhibitor. We discuss the clinical trial development, mechanisms of resistance, and the recent FDA decision to deny approval for quizartinib as a single agent in relapsed/refractory AML.

Keywords: AML; FLT3; QuANTUM; clinical trials; quizartinib; resistance.

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Conflict of interest statement

Dr. Elie Traer reports consulting honorarium from Astellas, Agios, Daiichi Sankyo, Abbvie, and ImmunoGen, outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
(A) Representative FLT3 receptor indicating location of internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations. (B) The crystal structure of the FLT3 kinase domain is shown in blue (Griffith, J. et al (2004) Mol Cell 13: 169–178) with the ATP binding site in yellow (where FLT3 inhibitors bind). The activation loop (salmon) with most commonly mutated residues (magenta), and the F691 gatekeeper residue (white) are highlighted to show the close interaction of these domains. The juxtamembrane domain is also shown (gray) in relation to the kinase domain.
See this image and copyright information in PMC

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