This is the third and final blog post in the posts focused on the FLT3 gene, FLT3 gene mutations, and functional consequences linked to FLT3 gene mutations.
In this last post, I will present the test for detecting FLT3 gene mutations and how and when those tests are connected to the FLT3 inhibitors. Also, I will shortly present the two FLT3 inhibitors. Here are links to all three blog posts:
What Is LeukoStrat CDx FLT3 Mutation Assay?
LeukoStrat CDx FLT3 Mutation Assay is an in vitro diagnostic test designed to detect internal tandem duplications (ITD) and tyrosine kinase domain (TKD) mutations D835 and I836 in the FLT3 gene in genomic DNA extracted from mononuclear cells obtained from peripheral blood or bone marrow aspirates of patients diagnosed with acute myelogenous leukemia (AML). LeukoStrat CDx FLT3 Mutation Assay is developed by Invivoscribe [citation].
What Is D835?
FLT3 D835 (also known as Asp835 or D835) is a specific amino acid residue found in the intracellular domain of the FLT3 receptor. The D835 residue is located in the activation loop of the FLT3 receptor, a region that plays a crucial role in activating the enzymatic activity of the receptor. Some mutations in the FLT3 gene, such as the D835Y mutation, can cause the constitutive activation of the FLT3 receptor, leading to the uncontrolled proliferation and survival of leukemic cells.
What Is I836?
FLT3 I836 (also known as Ile836 or I836) is a specific amino acid residue found in the intracellular domain of the FLT3 receptor. The I836 residue is located in the activation loop of the FLT3 receptor, which is a region that plays a key role in activating the enzymatic activity of the receptor. Some mutations in the FLT3 gene, such as the I836F mutation, can cause the constitutive activation of the FLT3 receptor, leading to the uncontrolled proliferation and survival of leukemic cells.
How LeukoStrat CDx FLT3 Mutation Assay Works?
Peripheral blood or bone marrow samples are collected, from which cells are harvested. After DNA extraction, a PCR amplification reaction is initiated.
In the case of TKD testing, an additional enzyme reaction is performed after PCR amplification. Amplified products are detected with capillary electrophoresis.
Obtained amplified products are further analyzed. The ratio of signal from mutation against a background signal from wild type is measured.
An FLT3 mutation is detected if the mutant: wild-type signal ratio meets or exceeds the cutoff of 0.05 [citation, citation].
What Type of Technology Does LeukoStrat CDx FLT3 Mutation Assay Use?
LeukoStrat CDx FLT3 Mutation Assay uses PCR (polymerase chain reaction) technology [citation].
When and in What Situations LeukoStrat CDx FLT3 Mutation Assay Is Indicated to Be Used?
LeukoStrat CDx FLT3 Mutation Assay is used as an aid in the selection of patients with AML for whom RYDAPT® (midostaurin) treatment is being considered. It can be used as a screening test for these mutations, but also along the course of therapy, to determine the right course of therapeutic action [citation].
What Is Rydapt (Midostaurin, PKC412)?
Rydapt (midostaurin, also known as PKC412, which was an experimental name) is a type of medication that inhibits the activity of FLT-3 kinase, among other kinases, which can be used in combination with other chemotherapy agents to treat AML in adult patients [citation]. A bit more about midostaurin can be found here.
What Is Xospata (Gilterinib, ASP2215)?
Xospata (gilternib, also known as ASP2215, which was an experimental name) is a type of medication that inhibits the activity of FLT-3 kinase, which is used as a single agent in treating AML in adult patients. It is usually used in patients which have experienced disease relapse [citation].
What Type of Drugs Are Rydapt and Xospata?
Rydapt and Xospata are FLT-3 tyrosine kinase inhibitors, which act by lowering or abolishing its activation in treating AML.
When Rydapt and Xospata Are Indicted?
Rydapt is indicated in newly diagnosed AML patients who are FLT-3 positive as detected by an FDA-approved test [citation]. Rydapt is indicated to be used in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.
Rydapt is also indicated to be used in the case of aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).
Xospata is a kinase inhibitor indicated for treating adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation as detected by an FDA-approved test [citation].
What Is the Relationship Between These Drugs (Rydapt and Xospata) and LeukoStrat CDx FLT3 Mutation Assay?
LeukoStrat CDx FLT3 Mutation Assay is a test to detect ITD (internal tandem duplication) and TKD (tyrosine kinase domain) FLT-3 mutations. This is an FDA-approved test that precedes the initiation of Rydapt and Xospata therapy.
When a specific cut-off value of FLT-3 mutation is detected by this test, Rydapt and Xospat therapy can be initiated [citation].