Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions

Abstract

FLT3 mutations are present in 30% of newly diagnosed patients with acute myeloid leukemia. Two broad categories of FLT3 mutations are ITD and TKD, with the former having substantial clinical significance. Patients with FLT3-ITD mutation present with a higher disease burden and have inferior overall survival, due to high relapse rates after achieving remission. The development of targeted therapies with FLT3 inhibitors over the past decade has substantially improved clinical outcomes. Currently, two FLT3 inhibitors are approved for use in patients with acute myeloid leukemia: midostaurin in the frontline setting, in combination with intensive chemotherapy; and gilteritinib as monotherapy in the relapsed refractory setting. The addition of FLT3 inhibitors to hypomethylating agents and venetoclax offers superior responses in several completed and ongoing studies, with encouraging preliminary data. However, responses to FLT3 inhibitors are of limited duration due to the emergence of resistance. A protective environment within the bone marrow makes eradication of FLT3mut leukemic cells difficult, while prior exposure to FLT3 inhibitors leads to the development of alternative FLT3 mutations as well as activating mutations in downstream signaling, promoting resistance to currently available therapies. Multiple novel therapeutic strategies are under investigation, including BCL-2, menin, and MERTK inhibitors, as well as FLT3-directed BiTEs and CAR-T therapy.

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

“…131 In recent years, targeting FLT3 has been an integral component of treatment regimens for FLT3-ITD/ TKD-mutated AML patients, leading to significantly extended survival rates. 132 Despite the clinical availability of FLT3 inhibitors, their impact on survival outcomes remains modest. 133 In 2023, Yashar et al reported that combining an LSD1 inhibitor GSK-2879552 and an FLT3 inhibitor Quizartinib exhibited a synergistic effect in inducing cell death in FLT3 mutant AML (Table 2).…”

“…FLT3 mutations are common genetic alterations detected in AML, with approximately 30% of newly diagnosed patients . In recent years, targeting FLT3 has been an integral component of treatment regimens for FLT3-ITD/TKD-mutated AML patients, leading to significantly extended survival rates . Despite the clinical availability of FLT3 inhibitors, their impact on survival outcomes remains modest …”

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

“…FMS-like tyrosine kinase-3 (FLT3) is one of many human tyrosine kinases [45,46]. Tyrosine kinases belong to a group of enzymes that catalyze the phosphorylation of select tyrosine residues in target proteins using ATP.…”

“…FLT3-ITD mutated AML displays heterogeneity, which can be attributed to variations in ITD length, insertion site, mutant-to-wild type allele ratio (AR), overall karyotype, and co-occurring mutations, particularly NPM1 [45]. Regardless of other factors, the presence of FLT3-ITD mutation alone in patients newly diagnosed is associated with unfavorable outcomes in terms of relapse-free (RFS) and overall survival (OS) compared to patients with wild-type FLT3 (WT-FLT3) [45,49,53]. It should be pointed out that until recently, the impact of an FLT3 mutation on the prognosis of patients struggling with AML was considered to be dependent on the ratio of mutated to wild-type allele [54].…”

“…Given the high frequency of FLT3 mutations in AML and their correlation with poor prognosis, in recent years, extensive research focusing on the development of targeted therapies was conducted, aiming to enhance patient outcomes. Due to these studies, FLT3i can be categorized using two classification systems: first-and second-generation based on their specificity, and Type I and II inhibitors based on their mechanism of action [45,57]. Each FLT3i inhibits receptor autophosphorylation and downstream signaling activation by interacting with the ATP-binding site of the intracellular tyrosine kinase domain.…”