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

by Selleckchem | Jul 16 2023

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.

Comments:

FLT3 mutations are genetic alterations that are found in approximately 30% of newly diagnosed patients with acute myeloid leukemia (AML). There are two main categories of FLT3 mutations: internal tandem duplications (ITD) and tyrosine kinase domain (TKD) mutations. Among these, FLT3-ITD mutations are particularly clinically significant.

Patients with FLT3-ITD mutations often present with a higher disease burden and tend to have inferior overall survival compared to those without the mutation. This is primarily due to the high relapse rates that occur after achieving remission. However, the development of targeted therapies known as FLT3 inhibitors has significantly improved clinical outcomes over the past decade.

Currently, two FLT3 inhibitors have been approved for use in patients with AML. Midostaurin is approved for use in the frontline setting and is administered in combination with intensive chemotherapy. Gilteritinib, on the other hand, is approved as a monotherapy for patients in the relapsed or refractory setting.

In addition to the approved FLT3 inhibitors, ongoing studies have shown promising results when combining FLT3 inhibitors with other treatment approaches. For example, the addition of FLT3 inhibitors to hypomethylating agents and venetoclax has demonstrated superior responses in several completed and ongoing studies.

Despite the advances in FLT3-targeted therapies, the responses to FLT3 inhibitors are often of limited duration due to the emergence of resistance. One challenge in eradicating FLT3-mutated leukemic cells is the protective environment provided by the bone marrow. Furthermore, prior exposure to FLT3 inhibitors can lead to the development of alternative FLT3 mutations as well as activating mutations in downstream signaling pathways. These mutations promote resistance to currently available therapies.

To address these challenges, multiple novel therapeutic strategies are being investigated. These include the use of BCL-2, menin, and MERTK inhibitors, which target different aspects of AML biology. Additionally, FLT3-directed bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapy directed against FLT3 are being explored as potential treatment options.

Overall, the development of FLT3 inhibitors has significantly improved the clinical outcomes for AML patients with FLT3 mutations. However, the emergence of resistance remains a challenge, and ongoing research aims to develop novel therapeutic approaches to overcome resistance and improve long-term outcomes for patients with FLT3-mutated AML.