A Review of FLT3 Kinase Inhibitors in AML

Abstract

Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood. The prevalence of FLT3 gene mutations is high and escalates the probability of relapse and mortality. The survival rates for AML patients, particularly those over 65, are low. FLT3 mutation screening at diagnosis is mandatory, and FLT3 inhibitors are crucial in treating AML patients with mutations. There are two categories of FLT3 mutations: FLT3-ITD located in the juxtamembrane domain and FLT3-TKD in the tyrosine kinase domain. FLT3-ITD is the most common type, affecting nearly a quarter of patients, whereas FLT3-TKD only affects 6–8% of patients. FLT3 inhibitors are now crucial in treating AML patients with FLT3 mutations. When dealing with FLT3-mutated AML, the recommended course of treatment typically involves chemotherapy and midostaurin, followed by allogeneic hematopoietic cell transplantation (HCT) to maximize the likelihood of success. Maintenance therapy can lower the risk of relapse, and gilteritinib is a better option than salvage chemotherapy for relapsed or refractory cases. Clinical trials for new or combined therapies are the most effective approach. This review discusses treatment options for patients with FLT3-mutated AML, including induction chemotherapy and options for relapsed or refractory disease. Additional treatment options may become available as more studies are conducted based on the patient’s condition and susceptibility.

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

“…The FLT‐3 inhibitors (FLT‐3i) are used in the treatment of AML. 156 First‐generation of FLT‐3i are multikinase inhibitors (e.g., sunitinib), with low potency, with many off‐target effects, and with reduced specificity for FLT‐3. 156 , 158 On the other hand, second‐generation ones (e.g., quizartinib, gilteritinib) are much more specific for FLT‐3, and potent.…”

“… 156 First‐generation of FLT‐3i are multikinase inhibitors (e.g., sunitinib), with low potency, with many off‐target effects, and with reduced specificity for FLT‐3. 156 , 158 On the other hand, second‐generation ones (e.g., quizartinib, gilteritinib) are much more specific for FLT‐3, and potent. 156 , 158 However, their benefits are limited, and there are several known resistance mechanisms that lead to the failure of these drugs.…”

“… 156 , 158 On the other hand, second‐generation ones (e.g., quizartinib, gilteritinib) are much more specific for FLT‐3, and potent. 156 , 158 However, their benefits are limited, and there are several known resistance mechanisms that lead to the failure of these drugs. 155 , 159 Therefore, new alternatives are needed, and PROTACs could be one of them.…”

“…154,155 Between 20% and 30% of newly diagnosed patients with this acute leukemia have mutations in the FLT-3 gene. 156,157 The occurrence of these mutations leads to a constitutive activation of this protein, involved in processes of proliferation, differentiation, and survival of blood cells. 156,157 For example, the internal tandem duplication (ITD) represents the most common type of FLT-3 mutation (FLT-3-ITD; approximately 25% of all AML cases) and is a common driver mutation associated with high leukemic burden and poor prognosis in AML patients.…”

Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations

“…Several small-molecule FLT3 inhibitors have been developed for the treatment of AML. The first-generation FLT3 inhibitors, such as midostaurin (1), 9 sunitinib (2), 10 and sorafenib (3), 11 have been used as first-line targeted therapy (Figure 1). However, the toxicity issue limited the wide clinical application owing to lacking kinome selectivity.…”