Fms-like tyrosine kinase 3 (FLT3) is a cell-surface receptor protein found on hematopoietic progenitor cells, the early-stage cells that develop into various blood cells. Normally, FLT3 acts as a signaling receptor, regulating the survival, growth, and differentiation of these precursors. The FLT3 gene, which provides instructions for making this protein, is one of the most frequently altered genes in patients diagnosed with Acute Myeloid Leukemia (AML). Mutations are found in approximately 20% to 30% of adult AML cases, establishing its clinical importance in this aggressive blood cancer. The presence of an FLT3 mutation provides a clear molecular target for specific drug therapies and influences the prognosis and treatment strategy for patients.
The Biology of the FLT3 Mutation
The FLT3 protein functions as a tyrosine kinase receptor, an enzyme that activates internal cell signaling pathways when a ligand attaches. This binding causes two FLT3 receptors to join (dimerization), triggering enzyme activity and initiating signals that promote cell proliferation and inhibit apoptosis.
The most common FLT3 gene alterations fall into two types, both leading to uncontrolled cell growth. The first and most prevalent is the FLT3 Internal Tandem Duplication (FLT3-ITD), an in-frame insertion of extra genetic material within the juxtamembrane domain of the receptor. This insertion disrupts the protein’s natural regulatory mechanism, causing the receptor to signal continuously without needing the external ligand.
The second type is the less frequent FLT3 Tyrosine Kinase Domain (FLT3-TKD) point mutation, often involving the D835 residue. This mutation directly alters the enzyme’s active site, also leading to continuous activation. Both ITD and TKD mutations result in persistent downstream signaling through pathways like STAT5, PI3K/AKT, and RAS, driving the proliferation of leukemic blast cells.
Diagnostic Testing and Risk Assessment
Identifying the presence and type of an FLT3 mutation is mandatory for AML diagnosis, as results determine patient risk and guide treatment. Mutations are typically detected using molecular assays on bone marrow or peripheral blood samples. Traditional methods like Polymerase Chain Reaction (PCR) identify the presence and size of the FLT3-ITD insertion.
Next-Generation Sequencing (NGS) is increasingly important, offering a highly sensitive approach that detects both ITD and TKD mutations simultaneously. The FLT3-ITD mutation is associated with a significantly poorer prognosis, indicating a high risk of relapse and reduced overall survival compared to wild-type FLT3. Conversely, the FLT3-TKD mutation often has a less detrimental prognostic impact, sometimes comparable to patients without the mutation.
Risk stratification is further refined by measuring the FLT3-ITD allelic ratio (AR), the proportion of mutated FLT3 gene copies relative to normal copies. A high allelic ratio (AR of 0.5 or greater) is linked to a higher leukemic burden and a worse clinical outcome. The AR provides a quantitative measure of mutation severity and helps define the necessary therapeutic intensity. NGS sensitivity also allows for assessing measurable residual disease (MRD), detecting small numbers of persistent leukemic cells after treatment, which predicts post-treatment relapse risk.
Targeted Therapy: FLT3 Inhibitors
FLT3 inhibitors are targeted therapies designed to block the activity of the mutated receptor. These small-molecule inhibitors fit into the FLT3 protein’s active site, preventing the constitutive signaling that drives leukemic cell growth. Inhibitors are classified into two generations based on their specificity and potency.
First-Generation Inhibitors
First-generation inhibitors, such as midostaurin and sorafenib, are multi-kinase inhibitors, blocking several tyrosine kinases besides FLT3. This broad inhibition can lead to a wider range of side effects due to off-target activity. Midostaurin was the first FLT3 inhibitor approved for newly diagnosed AML patients, effective against both ITD and TKD mutations. Common side effects include rash and gastrointestinal issues.
Second-Generation Inhibitors
Second-generation inhibitors, such as gilteritinib and quizartinib, were designed to be more potent and highly selective for the FLT3 receptor. Gilteritinib is effective against both FLT3-ITD and FLT3-TKD mutations and is approved for relapsed or refractory FLT3-mutated AML. Its increased selectivity generally results in fewer off-target toxicities, though common adverse effects include febrile neutropenia, anemia, and elevated liver enzymes. Quizartinib is another potent, selective inhibitor showing efficacy, particularly against FLT3-ITD mutations.
These targeted drugs directly counteract the molecular driver of the cancer. However, leukemic cells can develop resistance, often through the activation of alternative signaling pathways like AXL or the acquisition of new mutations. Ongoing development of newer FLT3 inhibitors and combination strategies aims to overcome these resistance mechanisms to achieve durable remissions.
Combining Treatment Strategies
FLT3 inhibitors are integrated directly into the overall protocol for AML management, rather than being used as standalone treatments. For newly diagnosed patients, the FLT3 inhibitor midostaurin is combined with standard intensive chemotherapy, such as anthracycline and cytarabine, during both the induction and consolidation phases. This combination approach improves long-term survival outcomes compared to chemotherapy alone.
The high-risk nature of FLT3-ITD-mutated AML means that allogeneic hematopoietic stem cell transplant (SCT) remains a primary consolidation strategy for eligible patients who achieve remission. SCT replaces the patient’s diseased blood-forming system with a healthy donor’s, offering the best chance for a cure. Combining FLT3 inhibitors with initial chemotherapy aims to achieve a deeper remission, making the patient a better candidate for the subsequent transplant.
Following SCT, patients with FLT3-ITD AML face a substantial risk of relapse. Maintenance therapy with FLT3 inhibitors is standard practice in this setting. Drugs like gilteritinib or sorafenib are administered orally after the transplant to eliminate minimal residual disease (MRD). Clinical trials show that this post-transplant maintenance therapy significantly improves both overall survival and relapse-free survival in this high-risk population. Current research focuses on optimizing the timing and duration of these combinations and addressing acquired drug resistance.