Global Perspectives: FLT3 Inhibitors for AML - Episode 2

Establishing the Role of FLT3 Mutations in AML


Richard F. Schlenk, MD: FLT3 mutations are late mutations in the clonal development of acute myeloid leukemia [AML]. They do not occur at the beginning of the disease, but later on. But if FLT3 mutations occur, they induce a very rapid proliferation, and this is really indicated by a high white blood cell count and high bone marrow blast count in patients with activated FLT3 mutations.

FLT3 mutations are type 1 mutation. They induce proliferation and the stop of differentiation, and FLT3 mutations can be distinguished in 2 broad groups. The first group is internal tandem duplications, which occur in the juxtamembrane domain and also in the tyrosine kinase domain-1. This can be distinguished from point mutations, and these occur in the tyrosine kinase domain. Most common is the Asp835 mutation.

If FLT3 mutations occur, they introduce enormous proliferative signal in the cell, and we see this clinically through a high white blood cell count and a high blast count. These mutations also induce a block in differentiation. However, the most important thing is the proliferation, and this is important to identify early during the disease course, because otherwise patients have a very dismal prognosis when treated too late.

FLT3 inhibitors were introduced in the treatment of acute myeloid leukemia. I think it’s now 20 years ago that the first multikinase inhibitors came up, such as midostaurin and sorafenib, and midostaurin was tested in 2008 in a double-blinded randomized study. Sorafenib has been tested in a double-blinded randomized study. These are multikinase inhibitors that are not very specific for FLT3, but they also inhibit FLT3. Later on, second-generation inhibitors came up such as quizartinib, gilteritinib, and crenolanib. These are the inhibitors that are now in clinical development in phase I trials, and they will move to phase III studies. There are 2 types of second-generation inhibitors. These are type 1 inhibitors, gilteritinib and crenolanib. They inhibit the active, but also the inactive, FLT3 receptor kinase; whereas the type 2 inhibitor, quizartinib, only inhibits the inactive form of FLT3.

The second-generation inhibitors differ in half-life, and this is quite important because quizartinib and gilteritinib have to be applied only once daily whereas crenolanib has to be applied 3 times daily. There is relayed a great difference in half-life, and there are some advantages for quizartinib and gilteritinib in that they have to be taken only once. However, as we already see in acute myeloid leukemia patients with clinical problems, crenolanib may be preferable because it can be easily put off and its half-life is very short. The effect of the drug is very limited in time.

Transcript Edited for Clarity