Companion Diagnostics (CDx)

AML is the most common form of Leukemia in adults, and 1 out of 3 diagnosed with AML are expected to have presence of FLT3 activating mutations.  The presence of FLT3 activating mutations in AML portends a poor prognosis, and some treatment regimens and targeted drug trials are only accessible to patients who test positive for the mutation.^1,2  Therefore, a false negative FLT3 test result can have serious implications for the patient.  Due to the significant impact FLT3 testing may have on AML patient lives, the LeukoStrat CDx FLT3 Mutation Assay represents one of the most critically important biomarker tests for patients with AML.

CDx are critical tools enabling the identification of biomarkers that indicate the patients most likely to benefit (or alternately not benefit) from specific or combinatorial targeted therapies.  For cancer patients, a CDx might detect a biomarker that is predictive of a treatment regimen’s effect on an individualized patient cancer based on the underlying genetics or biology of that patient.  Screening patients for known biomarkers assists in ascertaining optimal, individualized treatment options for patients.  In doing so, patients known not to benefit from a drug (due to the absent biomarker) are further spared unnecessary treatments and the possible negative side effects.

Internal tandem duplications (ITD) and point mutations in the tyrosine kinase domain (TKD) of the FLT3 gene both result in constitutive auto-phosphorylation and activation of the FLT3 receptor, which may associate with AML disease.  In recent years, management of AML disease improved with the development of tyrosine kinase inhibitors (TKIs) that are now approved as targeted therapies for ITD and/or TKD mutations in the FLT3 gene.

The most prevalent and clinically significant type of FLT3 mutation is an Internal Tandem Duplication (ITD) in and around the juxtamembrane domain of the receptor.  FLT3 ITD are a heterogeneous type of mutation in location, size, and number and are characterized by an aggressive phenotype with high prevalence of relapse. Clinical studies have found FLT3 ITD mutations are associated with higher numbers of leukemic cells, increased incidence of relapse, and decreased overall survival.  The second most common mutation type in the FLT3 gene is a TKD point mutation in the codon for an aspartate (D835) or an isoleucine (I836) residue that is located in the activation loop of the FLT3 protein.  FLT3 TKD mutations are caused by nucleic acid substitutions and/or deletions that result in a change in the amino acid sequence in this highly conserved catalytic center.