Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

Simple Summary Despite the recent approval of some FLT3 inhibitors by drug regulatory agencies, treatment guidelines for FLT3-mutated AML still require allogeneic transplantation as a necessary procedure to treat the disease in first or second CR, due to the high relapse incidence related to the use of these drugs. The study of the heterogeneity of leukemogenesis and resistance mechanisms related to the use of FLT3 inhibitors, alone or in combination, represents one of the additional challenges in attempting to achieve the eradication of the mutated FLT3 leukemic clone. The analysis and knowledge of these pathways might drive future approach in this setting. FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30-40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30-50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.