Acute Myeloid Leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow, characterized by the uncontrolled growth of immature white blood cells. The treatment approach for AML depends heavily on the specific genetic alterations found within the leukemia cells. Modern diagnostics test for these genetic markers, which guide therapy. Among the most frequent and impactful changes is a mutation in the FMS-like tyrosine kinase 3 (FLT3) gene. This alteration influences disease aggression and has led to the development of highly specific targeted therapies.
Understanding the FLT3 Gene and its Mutations
The FLT3 gene provides instructions for creating the FMS-like tyrosine kinase 3 protein, a receptor located on the surface of hematopoietic cells, including leukemia cells. Normally, the FLT3 receptor regulates cell survival, growth, and proliferation when it binds to its specific ligand. This signaling process is tightly controlled to ensure the healthy development of blood cells.
Mutations in the FLT3 gene are the most common genetic alterations in AML, occurring in approximately one-third of newly diagnosed adult patients. These mutations disrupt the receptor’s normal regulatory function, causing it to become constantly activated. This uncontrolled signaling leads to the rapid multiplication of immature leukemia cells, which is the disease’s hallmark.
Two primary types of FLT3 mutations are recognized, each with a distinct biological mechanism. The first, and more common, is the Internal Tandem Duplication (FLT3-ITD). In FLT3-ITD, a segment of the gene is duplicated and inserted back into the gene, typically within the juxtamembrane domain. This insertion disrupts the receptor’s self-inhibitory mechanism, resulting in continuous activation of signaling pathways that promote cell growth.
The second type is the Tyrosine Kinase Domain (FLT3-TKD) mutation, a less frequent alteration often involving a single point mutation, commonly at the D835 residue. This mutation occurs in the receptor’s kinase domain and stabilizes the enzyme’s active configuration. Both ITD and TKD mutations result in constitutive activation and drive leukemic cell proliferation, though their clinical impact differs considerably.
Impact on AML Prognosis and Risk Stratification
The presence of an FLT3 mutation significantly impacts the clinical course of AML, making genetic testing at diagnosis standard practice. Patients whose leukemia cells harbor the FLT3-ITD mutation are classified into a higher-risk category. This high-risk designation is due to the mutation’s association with adverse clinical features, such as higher white blood cell counts and a greater likelihood of disease relapse after initial treatment.
FLT3-ITD is an independent prognostic factor for shorter overall survival and reduced event-free survival compared to AML without the mutation. The severity of the poor prognosis is directly related to the mutant allele burden. This burden is the ratio of the mutated FLT3 gene to the normal (wild-type) FLT3 gene. A high allelic ratio is linked to the most aggressive disease behavior and the highest risk of relapse.
The FLT3-TKD mutation generally carries a less severe prognostic impact than FLT3-ITD, often placing patients in an intermediate-risk group. Both mutation types necessitate careful consideration in treatment planning. The European LeukemiaNet (ELN) guidelines, widely used for risk stratification, incorporate the FLT3 status to guide clinical decisions.
Identifying the FLT3 mutation early guides the intensity of therapy, often leading to more aggressive treatment strategies. For patients with FLT3-ITD, achieving a deep and durable remission is paramount. This frequently requires considering allogeneic hematopoietic stem cell transplantation (allo-HSCT). This intensive procedure offers the best chance for a long-term cure and is often considered a standard approach for medically fit, high-risk FLT3-ITD patients.
Targeted Therapy: FLT3 Inhibitors
The discovery of the FLT3 mutation as a driver of AML growth paved the way for targeted therapies designed to block the overactive receptor. These medications, known as FLT3 inhibitors (FLT3i), represent a significant advancement over traditional chemotherapy. They interfere directly with the cancer’s underlying molecular mechanism. FLT3 inhibitors fall into different classes based on their structure and selectivity, affecting their potency and the mutations they can inhibit.
One class includes multi-kinase inhibitors, such as Midostaurin, often referred to as first-generation FLT3 inhibitors. These drugs target FLT3 but also inhibit several other tyrosine kinases, sometimes leading to a broader range of side effects. Midostaurin is approved for use in newly diagnosed AML patients with an FLT3 mutation. It is administered alongside standard intensive induction chemotherapy, where its addition improves overall survival.
A second class comprises more selective and potent second-generation inhibitors, such as Gilteritinib and Quizartinib. These agents are designed to specifically target the FLT3 receptor, showing high efficacy against both FLT3-ITD and FLT3-TKD mutations. Gilteritinib is approved for use in the relapsed or refractory setting. This means it is used for patients whose disease has returned or not responded to prior treatment, and it has demonstrated superior overall survival compared to salvage chemotherapy alone.
Quizartinib, another highly selective FLT3 inhibitor, is approved for use in combination with chemotherapy for newly diagnosed FLT3-ITD positive AML, and for maintenance therapy following consolidation. Incorporating FLT3 inhibitors aims to achieve a deeper and more lasting remission, often serving as a bridge to allo-HSCT. By suppressing the leukemic clone, these targeted drugs increase the likelihood that a patient can proceed to transplant, which remains the most curative option for many FLT3-mutated AML cases.
The use of FLT3 inhibitors is dynamic, with ongoing research exploring their combination with other novel agents, such as BCL-2 inhibitors, and their role in maintenance therapy post-transplant. While resistance can emerge over time, the introduction of FLT3 inhibitors has fundamentally changed the treatment landscape. It has transformed a previously high-risk, poor-prognosis subset of AML into a disease where targeted intervention can significantly extend life.