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Optimizing FLT3 Inhibitor Monotherapy in Acute Myeloid Leukemia

Amro Elshoury, MBChB; Jeffrey Baron, PharmD, BCOP; Amanda Przespolewski, DO; and Eunice S. Wang, MD
Published Online: Dec 27,2017

Amro Elshoury, MBCHB
Abstract

Acute myeloid leukemia (AML) therapy is guided mainly by cytogenetic profile, such as chromosomal duplication or deletion, and molecular mutations. FLT3 mutations are the most common genetic abnormalities detected in patients with AML and are usually associated with a high relapse rate and short overall survival. Given the dismal outcomes in patients with FLT3-mutant AML, a great effort has been underway over the last several years to develop clinically effective FLT3 inhibitors. In May 2017, the FLT3 inhibitor midostaurin was approved for the upfront treatment of newly diagnosed patients with FLT3-mutant AML in combination with cytarabine-based induction and consolidation therapy. Currently, several other tyrosine kinase inhibitors are being evaluated in patients with FLT3-mutated AML, either as a monotherapy or in combination with systemic chemotherapy. This review aims to explore the current and future directions of FLT3 inhibitor monotherapy in various clinical settings for FLT3-mutant AML, including frontline and relapsed disease as well as maintenance following allogeneic stem cell transplantation.

Clinical Significance of Aberrant FLT3 Signaling in Acute Myeloid Leukemia 

Acute myeloid leukemia (AML) therapy is guided mainly by the molecular and cytogenetic profile. FLT3 mutations are the most common genetic abnormalities detected in patients with AML (30%) and are encoded by a gene located on chromosome 13q12.1 There are 2 main types of FLT3 mutations.2 The first type is composed of internal tandem duplications (FLT3-ITD mutations) in or near the juxtamembrane domain of the receptor, which occurs predominantly in cytogenetically normal AML. The second type is composed of missense point mutations resulting in substitutions of single amino acids, mostly aspartic acid 835, in the activation loop of the tyrosine kinase domain (FLT3-TKD mutations). Both types of mutations lead to constitutive activation of FLT3 kinase in a ligandindependent manner with subsequent activation of multiple downstream signaling pathways, including STATs, MAP, and PI3K/AKT kinase pathways; this leads to uncontrolled cell proliferation and survival.3 Although, patients with FLT3-mutant AML can achieve remission with standard induction chemotherapy in a frequency comparable to FLT3-wild type AML, responses are usually transient with a high relapse rate and shorter overall survival (OS). Patients with FLT3-mutant AML with a high allelic burden are an exception, as they are usually refractory to standard induction chemotherapy.4 

Given the dismal outcomes in patients with FLT3-mutant AML, a great effort has been underway over the last several years to develop clinically effective FLT3 inhibitors. In May 2017, the FLT3 inhibitor midostaurin was approved for the upfront treatment of newly diagnosed patients with FLT3 mutations in combination with cytarabine-based induction and consolidation therapy. Currently, several other tyrosine kinase inhibitors (TKIs) are being evaluated in patients with FLT3-mutated AML, either as a monotherapy or in combination with systemic chemotherapy. This review aims to explore the current and future directions of FLT3-inhibitor monotherapy in various clinical settings for FLT3-mutant AML, including frontline and relapsed disease as well as maintenance following allogeneic stem cell transplantation.



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Optimizing FLT3 Inhibitor Monotherapy in Acute Myeloid Leukemia
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