DR STONE: So FLT3 mutations are amongst the 2 most common mutations in AML. There’s NPM1 and FLT3, both about 30%. And if you selected a group of cells that have the same mutation, it’s probably important in leukemic physiology in some way, either as a founder or as a proliferation mutation.

Anyway, so FLT3 is mutated in about 30% of AMLs. FLT3 length mutation, which is an “extra” between a few and a lot of amino acids in the juxtamembrane region, that’s the one that really carries the bad prognosis if you have it. Then there’s what’s called a point mutation or a tyrosine kinase domain mutation in the 835th residue. That is probably important in the physiology but may not be a bad prognostic actor.

So because these are gain-of-function mutations and they both cause spontaneous dimerization in cell line models, you don’t need the ligand to bind to the FLT3 receptor for the FLT3 to be on. So it’s just like BCR-ABL. It’s a thermostat that’s broken. The thing is on all the time and telling these cells to grow. So it’s a gain-of-function mutation and thought to be, therefore, an ideal candidate to inhibit to disrupt the function and, therefore, prevent the growth due to that mutation.

DR CORTES: The only thing that I would add is that FLT3 is expressed in pretty much all the AML patients. It’s the mutated one that adds to the physiology and to the prognosis of patients. But the FLT3 itself — and actually, there’s been some attempt at targeting FLT3, like with monoclonal antibodies and things like that, that have been looked at.

Module 1: Current and future approaches to targeted therapy for acute myeloid leukemia (AML)

Module 2: Other clinical issues in AML management

Module 3: Case discussions