FLT3-Positive Acute Myeloid Leukemia

FLT3-positive acute myeloid leukemia is a form of blood cancer that occurs in approximately 30% of adult cases and is associated with a higher risk of the disease returning after treatment.

Table of contents

• What is FLT3-Positive AML
• Types of FLT3 Mutations
• How It Affects Prognosis
• Treatment Approaches
• FLT3 Inhibitor Medications

What is FLT3-Positive AML

FLT3-positive acute myeloid leukemia is a type of blood cancer where patients have changes, called mutations, in a gene known as FMS-like tyrosine kinase 3 (FLT3). This gene normally helps control how blood cells grow and develop. When the FLT3 gene contains mutations, it can cause blood cells to grow out of control, leading to leukemia.^[1]

The FLT3 receptor is a protein that sits on the surface of cells and belongs to a group called type III tyrosine kinases. In healthy bone marrow, FLT3 is found on early blood-forming cells called hematopoietic stem cells, which are marked by a protein called CD34. These cells are also present in other blood-forming organs like the spleen and liver.^[3]

FLT3 mutations are one of the most frequently occurring genetic changes in acute myeloid leukemia. They are found in approximately 30% of adults newly diagnosed with this disease.^[1][5]

Types of FLT3 Mutations

There are two main types of FLT3 mutations that can occur in patients with acute myeloid leukemia. The more common type is called FLT3-ITD, which stands for internal tandem duplication. This mutation occurs in about 25 to 30% of adult cases.^[5]

The second type is called FLT3-TKD, which stands for tyrosine kinase domain mutation. This type is less common, occurring in about 5 to 10% of cases. The TKD mutation involves a change in a specific part of the FLT3 gene that affects its structure.^[5]

In rare cases, a small percentage of patients can have both ITD and TKD mutations at the same time. Having both mutations together is associated with worse outcomes than having just one type of mutation.^[3]

When FLT3 mutations are present, the FLT3 protein becomes constantly active, even when it shouldn’t be. This continuous activation turns on growth signals inside the cells, particularly through pathways called STAT5-PIM and PI3K-AKT. These signals cause leukemia cells to multiply rapidly.^[4]

How It Affects Prognosis

FLT3 mutations, particularly the ITD type, are considered an independent poor prognostic factor for patients with acute myeloid leukemia. This means they are associated with a higher risk of the disease coming back and shorter survival times.^[1]

The FLT3-ITD mutation has no impact on a patient’s ability to achieve complete remission initially. However, it is strongly associated with an increased risk for relapse, decreased disease-free survival, and shorter overall survival.^[3]

Research has shown that patients with acute myeloid leukemia who have high levels of a protein called CHK1 (checkpoint kinase 1), which is activated by FLT3-ITD, have lower overall survival rates and lower disease-free survival rates compared to patients with low CHK1 levels.^[4]

In contrast, the TKD mutation is less common and has no known prognostic effect on its own.^[3]

Because of the significant impact on outcomes, it is recommended that FLT3 testing always be performed in patients with acute myeloid leukemia, especially in those who have normal results on other genetic tests. Test results should typically be available within 48 to 72 hours, at least for patients who are eligible for intensive treatment.^[3]

Treatment Approaches

The identification of FLT3 mutations has important implications for how acute myeloid leukemia is managed. The discovery and development of medications called tyrosine kinase inhibitors (TKIs) have changed the treatment approach for patients with FLT3-positive disease.^[1]

FLT3 inhibitors have shown improved outcomes in FLT3-positive acute myeloid leukemia both when used alone in patients whose disease has returned and when combined with chemotherapy as initial treatment. The combination of inhibitors and chemotherapy in the first-line setting represents a significant advancement in treating this disease.^[1]

These inhibitors are classified into first-generation and second-generation types based on how specific they are for the FLT3 protein. First-generation FLT3 inhibitors include medications such as sorafenib and midostaurin. These drugs also affect other proteins in addition to FLT3.^[5]

Second-generation inhibitors, which include quizartinib, gilteritinib, and crenolanib, are much more selective and specific for FLT3. Although they may target a few other receptors, they are very focused and powerful against FLT3 specifically.^[3]

The effectiveness of these inhibitors depends on how they attach to the FLT3 receptor and whether they work against both ITD and TKD mutations. Type 1 inhibitors are active against both FLT3-ITD and FLT3-TKD mutations, while type 2 inhibitors are only active against FLT3-ITD.^[5]

FLT3 Inhibitor Medications

Several FLT3 inhibitor medications have been tested in different treatment settings, including for patients whose disease has returned or not responded to treatment, after transplant to help prevent relapse, and in combination with intensive chemotherapy or less intensive treatment regimens.^[5]

Midostaurin was the first tyrosine kinase inhibitor approved by the FDA for the treatment of acute myeloid leukemia, receiving approval in April 2017. It is approved for patients with newly diagnosed FLT3-positive acute myeloid leukemia, used in combination with standard chemotherapy drugs (cytarabine and daunorubicin) during the initial treatment phase and with cytarabine during the consolidation phase.^[3]

The approval of midostaurin was based on results from a large clinical trial called CALGB 10603 (RATIFY), which included 717 patients aged 18 to 59 years with newly diagnosed disease. Adding midostaurin to chemotherapy resulted in patients living much longer—a median of 74.7 months compared to 25.6 months for those who received chemotherapy with placebo. The trial showed a 22% lower risk of death in patients who received midostaurin plus chemotherapy.^[3]

Gilteritinib is another FLT3 inhibitor that has been approved based on results from the ADMIRAL trial. This medication is supported for use in patients whose acute myeloid leukemia has returned or did not respond to initial treatment.^[5]

Sorafenib has shown benefit in a specific setting. Results from the SORMAIN trial support its use after transplant to help prevent the disease from returning.^[5]

Despite these advances, challenges remain. A major concern is that many patients experience disease relapse, primarily due to the development of resistance to FLT3 inhibitors. This resistance can be present from the beginning or develop over time during treatment.^[7]

Researchers are investigating combination approaches to overcome resistance and improve outcomes. Studies have shown that combining FLT3 inhibitors with other types of drugs, such as CDK7 inhibitors, may produce synergistic effects, meaning the drugs work better together than either one alone.^[7]