Understanding mechanisms of resistance to FLT3 inhibitors in adult FLT3-mutated acute myeloid leukemia to guide treatment strategy
Martina Ruglioni, Stefania Crucitta, Giovanna Irene Luculli, Gaspare Tancredi, Maria Livia Del Giudice, Sandra Mechelli, Sara Galimberti, Romano Danesi, Marzia Del Re
Abstract
The presence of FLT3 mutations, including the most common FLT3-ITD (internal tandem duplications) and FLT3-TKD (tyrosine kinase domain), is associated with an unfavorable prognosis in patients affected by acute myeloid leukemia (AML). In this setting, in recent years, new FLT3 inhibitors have demonstrated efficacy in improving survival and treatment response. Nevertheless, the development of primary and secondary mechanisms of resistance poses a significant obstacle to their efficacy. Understanding these mechanisms is crucial for developing novel therapeutic approaches to overcome resistance and improve the outcomes of patients. In this context, the use of novel FLT3 inhibitors and the combination of different targeted therapies have been studied. This review provides an update on the molecular alterations involved in the resistance to FLT3 inhibitors, and describes how the molecular monitoring may be used to guide treatment strategy in FLT3-mutated AML. • Different mechanisms of resistance have been identified in FLT3-mutated AML patients treated with FLT3 inhibitors. • Novel FLT3 inhibitors and the combination of target-therapies have been used to overcome such resistance. • The analysis of circulating-free DNA by NGS may allow the detection of the FLT3 resistance mutations in patients.