The FMS-like tyrosine kinase 3 gene (FLT3) marker is present in 25-30% of all AML patients and indicates a poorer prognosis. The testing landscape is evolving and FLT3 diagnostic testing is now used in efficacy-based patient stratification, safety-based patient stratification and ongoing monitoring to assess treatment. Professor of oncology Mark Levis (John Hopkins University) an expert at targeting the FLT3 signaling pathway has highlighted the need for an internationally standardized FLT3 mutation assay. More recently, associate Professor Dr Todd Kelly (University of Utah) has emphasized the change in clinical utility of FLT3 from a purely prognostic marker to a selective marker essential for care.
Since 2017 one FLT3 inhibitor has been granted FDA clearance (Rydapt®), another granted fast-track status (gilteritinib) and myriad additional studies are currently ongoing.
One interesting study is an Italian non-interventional study of FLT3 mutated AML Patients (FLAM) NCT03547258. The primary objective of this study is to analyze how FLT3 mutational status evolves during the management of the disease looking at the percentage of patients with no FLT3 mutations at diagnosis who relapse with a new FLT3 mutation detected, and the percentage of FLT3 positive AML patients, that after having obtained a Complete Remission, relapse with a FLT3 negative status. The percentage change rate would be important for companion diagnostic reimbursement (budget impact) and could be used to address patient losses from non-optimal retest rates, although this could necessitate a change in testing strategy to include retesting for FLT mutation status at relapse. The recent successful UK technology appraisal for midostaurin TA523 for untreated AML included a resource impact statement that referred to the cost of repeat testing. A significant impact on resources was not expected because of the small treatment population (around 300 people in England) despite the requirement for FLT3 gene mutation analysis earlier than current practice i.e. within 7 days instead of 2 to 4 weeks. The cost of companion diagnostics is especially relevant if re-testing is applied to patients who are FLT3 WT at diagnosis but who become FLT3 ITD/TKD by relapse. That implies re-testing the 75% of FLT3 WT at diagnosis rather than just the 25% of FLT mutated at diagnosis.
The new molecular testing guidance from the College of American Pathology and American Society for Hematology recommend molecular testing guidelines in AML and describe the FLT3 mutation tests in patients at diagnosis as essential. At Diaceutics we support quality testing to identify all patients eligible for treatment. Given the rare nature of AML, the likely impact of additional costs for companion diagnostics is insignificant in comparison to (i) the impact made on the additional lives saved for those patients who are identified and treated with these newly approved targeted therapies and (ii) the cost savings to payers from reduced burden of illness and reduction in wasteful use of costly drug treatments for those patients unlikely to benefit from these therapies.