FLT3-ITD refers to a specific genetic alteration found in certain blood cancers, particularly acute myeloid leukemia (AML). This mutation involves an “internal tandem duplication” within the FLT3 gene, which plays a role in the uncontrolled growth of leukemia cells. Its presence directly influences how AML is diagnosed and treated, helping medical professionals classify the disease and tailor treatment plans for patients.
The Role of the FLT3 Gene Mutation
The FLT3 gene provides instructions for making a protein called FMS-like tyrosine kinase 3, or FLT3. This protein functions as a receptor on the surface of early blood cells, known as hematopoietic progenitor cells, and is involved in their normal development, survival, and proliferation. When a specific protein called FLT3 ligand binds to the FLT3 receptor, it activates a series of signals inside the cell, guiding processes like cell growth and division.
The FLT3-ITD mutation occurs when a short segment of DNA within the FLT3 gene is copied and inserted directly after the original sequence. This duplication leads to an altered FLT3 protein that is continuously active, even without the FLT3 ligand binding to it. One can imagine this like a light switch that is stuck in the “on” position, constantly signaling the cell to grow and multiply without regulation.
This constant activation of the FLT3 protein stimulates downstream signaling pathways, primarily STAT5, MAPK, and AKT signals, which promote uncontrolled cell proliferation and survival while impairing normal cell differentiation. The FLT3-ITD mutation is a common genetic alteration in AML, found in approximately 20% to 30% of cases.
Prognostic Significance in AML
The presence of an FLT3-ITD mutation significantly impacts the disease course for individuals with acute myeloid leukemia. It is considered a high-risk factor, indicating a more aggressive form of the disease. Patients with FLT3-ITD positive AML often present with higher white blood cell counts and increased blast percentages at diagnosis.
This mutation is associated with a greater likelihood of the leukemia returning after initial treatment, known as relapse. Historically, patients with FLT3-ITD mutations have experienced poorer overall survival rates compared to those without this genetic change. Even following an allogeneic stem cell transplant, patients with FLT3-ITD mutations are more prone to relapse.
Medical professionals use this prognostic information to classify the risk level of AML and make informed decisions about the intensity and type of treatment required. The effect of the FLT3 mutation can also be influenced by factors such as the allelic burden, which refers to the ratio of mutant FLT3 alleles to wild-type alleles, and the presence of other co-occurring mutations.
Diagnostic and Monitoring Procedures
Identifying the FLT3-ITD mutation typically begins at the time of initial AML diagnosis. The process usually involves collecting a bone marrow biopsy, which is the preferred specimen for mutation assessment. If a bone marrow sample is not available, peripheral blood can be used, provided there are enough leukemia cells present for accurate testing.
In the laboratory, specialized techniques are employed to detect the specific genetic abnormality. Polymerase Chain Reaction (PCR) fragment analysis is a common method used for FLT3-ITD detection. This test helps determine if the duplicated DNA sequence is present.
Next-Generation Sequencing (NGS) is another powerful technique increasingly used, which can provide more detailed information, including the specific sequence of individual ITD clones and the variant allele frequency. While NGS can be more challenging for FLT3-ITD due to its complex nature, it offers enhanced sensitivity for detecting low levels of the mutation.
Doctors may also monitor for the FLT3-ITD mutation during or after treatment to check for minimal residual disease (MRD). Detecting MRD, even at very low levels, is important because it indicates remaining leukemia cells that could lead to a relapse. This ongoing monitoring helps guide further therapeutic decisions.
Targeted Therapies and Treatment Strategies
Targeted therapy uses drugs specifically designed to attack unique features of cancer cells, in this case, the faulty FLT3 protein. For FLT3-ITD positive AML, a class of drugs known as FLT3 inhibitors has been developed. These drugs block the continuous signaling caused by the mutated FLT3 protein, thereby hindering the growth and survival of leukemia cells.
Two notable FLT3 inhibitors approved for use are midostaurin and gilteritinib. Midostaurin is often used in combination with standard chemotherapy during initial treatment for newly diagnosed FLT3-mutated AML. Clinical trials have shown that adding midostaurin to chemotherapy can improve overall survival in these patients. It is considered a multi-targeted kinase inhibitor, meaning it can block several proteins, including FLT3, that contribute to leukemia cell growth.
Gilteritinib is another FLT3 inhibitor that is more specific and potent in inhibiting mutant FLT3 compared to midostaurin. It is primarily used for patients with AML that has relapsed or is refractory to initial treatments. Gilteritinib has demonstrated superior overall survival compared to salvage chemotherapy in patients with relapsed/refractory FLT3-mutated AML. This drug is active against both ITD and TKD mutations and can be administered orally, which facilitates outpatient treatment.
Beyond initial and salvage therapies, a stem cell (bone marrow) transplant is frequently recommended for patients with FLT3-ITD positive AML to reduce the high risk of relapse. Allogeneic stem cell transplantation, which uses cells from a donor, aims to eradicate remaining leukemia cells and rebuild a healthy blood system. FLT3 inhibitors may also be used as maintenance therapy after a transplant to further reduce the chance of the disease returning.