The FMS-like tyrosine kinase 3 internal tandem duplication, or FLT3 ITD, represents a specific genetic change frequently identified in patients with Acute Myeloid Leukemia (AML). This alteration affects the FLT3 gene, which normally plays a role in the growth and development of blood cells. When the ITD mutation is present, it disrupts the normal regulation of this gene, leading to uncontrolled signaling within the affected cells. This genetic subtype of AML is one of the most common, occurring in approximately one-quarter of all new diagnoses. Identifying this mutation is important because it influences the course of the disease and determines the use of specialized, targeted treatments.
Understanding the FLT3 Gene and ITD Mutation
The FLT3 gene produces a receptor tyrosine kinase protein that resides on the surface of hematopoietic cells and transmits signals into the cell. Under normal conditions, this protein acts like a switch, activating only when a specific signaling molecule, called the FLT3 ligand, binds to it. This activation triggers downstream pathways that carefully regulate the proliferation, survival, and differentiation of early blood cells in the bone marrow. The process is tightly controlled to ensure a balanced production of mature blood components.
The FLT3 ITD mutation introduces a duplication of a short segment of DNA within the gene’s juxtamembrane domain. This internal tandem duplication causes a structural change in the resulting FLT3 protein, which destabilizes its regulatory mechanism. The protein can no longer turn itself off effectively, resulting in a state of permanent, ligand-independent activation. This is often described as the protein being constitutively “on,” constantly signaling the cell to grow and divide.
This uncontrolled signaling pathway drives the rapid and excessive production of immature white blood cells, known as leukemic blast cells. The constant stream of growth signals generated by the mutated protein prevents these cells from maturing into functional blood cells. Instead, the bone marrow quickly fills with these non-functional blasts, leading to the condition known as Acute Myeloid Leukemia. The FLT3 ITD mutation is a powerful driver of this disease, making it a direct target for specialized therapeutic intervention.
Clinical Significance and Diagnostic Testing
The presence of the FLT3 ITD mutation has a significant bearing on the disease’s characteristics and outcome for the patient. AML with this mutation is associated with a more aggressive disease course, including a higher white blood cell count and a greater percentage of blast cells in the blood and bone marrow at diagnosis. This genetic alteration is associated with a higher likelihood of disease relapse and a less favorable long-term outlook when treated with conventional chemotherapy alone.
The identification of the FLT3 ITD mutation is now a standard practice upon diagnosis of AML, as it is a necessary step for risk stratification and treatment planning. Testing is performed rapidly on samples from the bone marrow or peripheral blood, often using molecular techniques such as Polymerase Chain Reaction (PCR) or Next-Generation Sequencing (NGS). These methods are designed to detect the presence of the duplication and calculate its relative abundance.
A particularly important factor in determining the disease’s aggressiveness is the allelic ratio (AR), which represents the proportion of the mutated FLT3 gene copies compared to the normal copies. A high allelic ratio, generally defined as \(\ge\)0.5, is linked to a greater disease burden and a higher risk of adverse outcomes. Conversely, a low allelic ratio may be associated with a less aggressive presentation. This ratio provides important information that helps clinicians select the most appropriate and intensive therapy, including the potential for stem cell transplantation.
Targeted Therapies for FLT3 ITD Positive AML
The discovery of the FLT3 ITD mutation paved the way for the development of targeted drugs specifically designed to counteract its effects, known as FLT3 inhibitors (FLT3i). These small molecule drugs work by fitting into the active site of the mutated FLT3 protein, effectively blocking the constant activation signal.
The first generation of FLT3 inhibitors, such as midostaurin, demonstrated the effectiveness of this targeted approach. Midostaurin is approved for use in newly diagnosed FLT3-mutated AML and is administered in combination with standard induction and consolidation chemotherapy regimens. This combination therapy has shown improved outcomes compared to chemotherapy alone for this patient population.
Second-generation FLT3 inhibitors, including gilteritinib and quizartinib, offer improved potency and specificity against the FLT3 ITD protein. Gilteritinib, for example, is approved for patients whose disease has returned or not responded to initial therapy (relapsed or refractory AML). It is particularly effective because it targets both the ITD mutation and other related FLT3 mutations, providing a more comprehensive blockade of the aberrant signaling. Gilteritinib, when used as a single agent in the relapsed setting, has shown a benefit in overall survival compared to traditional salvage chemotherapy.
The use of these targeted therapies extends beyond the initial treatment phase and the relapsed setting. FLT3 inhibitors are also investigated for use as maintenance therapy following intensive treatment, including after stem cell transplantation. The goal of maintenance therapy is to sustain remission by continuously suppressing any residual leukemic cells that harbor the FLT3 mutation. Ongoing research is exploring the optimal combination of these inhibitors with other agents, such as venetoclax, to further enhance the depth and duration of response across all treatment settings.