Investigating the Mechanism of FMS-Like Tyrosine Kinase 3 (FLT3) Inhibitors in Acute Myeloid Leukemia (AML): A Basic and Clinical Research

Background & Objectives: The FMS-like tyrosine kinase 3 (FLT3) pathways can play a significant role in cellular proliferation, survival, and differentiation. In this respect, patients with acute myeloid leukemia (AML) with mutated FLT3 suffer from high levels of disease burden at presentation and dismal prognosis. In this respect, several FLT3 inhibitors have been developed and used to treat patients affected with FLT3-mutated AML in all disease contexts including induction, consolidation, maintenance, relapse, and hematopoietic cell transplantation (HCT).Methodology: To this end, a search was conducted in relevant English articles in the literature published in the database of PubMed using the keywords of AML, FLT3 Inhibitors, FLT3-ITD, FLT3 _TKI, Treatment.Findings: The findings showed that numerous inhibitors of FLT3 signaling had been recognized and also reported in clinical trials, both alone and with chemotherapy, which could improve clinical outcomes in patients with AML with FLT3 mutations. The first-generation type I inhibitor such as midostaurin also had benefits and the second-generation type I inhibitors such as gilteritinib was reported favorable as new combinations of diverse therapies had been advocated to increase the effect of FLT3 inhibitors and to prevent resistance or even control it. Accordingly, FLT3 tyrosine kinase inhibitors (TKI) were found as a new therapeutic option in internal tandem duplications (FLT3-ITD) AML, and clinical trials were also being conducted with various types of TKI either alone, combined with chemotherapy, or as maintenance after allogenic stem cell transplantation. Conclusion: FLT3 inhibitors had significant anti-leukemic activities in clinical trials; however, sustained remissions using these inhibitors as monotherapy had not been obtained. Furthermore, efficacy of TKI treatment of relapsed or refractory FLT3-ITD AML was limited and needed improvements; e.g., through the introduction of the second-generation inhibitors targeting constitutively active FLT3.

Investigating the Mechanism of FMS-Like Tyrosine Kinase 3 (FLT3) Inhibitors in Acute Myeloid Leukemia (AML): A Basic and Clinical Research Keywords:

AML , FLT3 Inhibitors , FLT3-ITD , FLT3 _TKI , Treatment