Evaluating Single-Agent Use of FLT3 Inhibition in AML

Transcript:Harry Erba, MD, PhD: There are 2 general classes of FLT3 inhibitors based on the mechanism of action. The type 1, which binds to the ATP [adenosine triphosphate] binding site, will inhibit both FLT3 ITD [internal tandem duplication] and TKD [tyrosine kinase domain]; and the type 2, which maintains the inactive confirmation of FLT3, will only be active against ITD since many of the tyrosine kinase domain mutations force the protein into an active confirmation, which the type 2 inhibitor will not find.

In terms of responses to these different classes of agents, for the first-generation drugs, which were less specific for FLT3, the response rates were very low. Midostaurin and sorafenib as single agents, for example, have very low response rates. Now, in the evaluation of the second-generation drugs—the type 1 inhibitors, gilteritinib and crenolanib, and the type 2 inhibitor, quizartinib—the overall response rate or CR [complete response] rate is about 40% to 50%. Those are complete remissions and complete remissions with incomplete count recovery. If you also include morphologic leukemia-free states and partial remissions, the response rates can be as high as 50% to 60% with each of the 3.

Now, of course, for the patients who have an FLT3 tyrosine kinase domain mutation, a type 2 inhibitor, such as quizartinib, may not be as active. In the phase II analysis of single-agent quizartinib, there was a group of patients who tested negative for the FLT3 internal tandem duplication, having an allelic ratio of less than 10%. Some of these patients were truly negative: The response rates were lower than what was seen for patients with the FLT3 ITD mutation. However, some of these patients did respond, questioning whether there may be benefit even in wild-type FLT3 or specific instances of a TKD mutation as well.

Richard F. Schlenk, MD: Single-agent treatment with FLT3 inhibitors can induce complete remission, but we have to distinguish the first and second-generation variants. The first-generation inhibitors, these broad multikinase inhibitors, are not able to induce a complete remission. In contrast, patients who receive a second-generation inhibitor with active disease are given crizotinib, gilteritinib, and crenolanib, all of which are able to induce complete remissions. However, these complete remissions are sometimes not durable. In some patients, they are prolonged, but it’s not a permanent solution. We have to include other treatment strategies following treatment with the FLT3 inhibitors to prolong a disease-free state and overall survival. A possible solution is a bridge to transplant. This is always an essential step, post-complete remission, after treatment with an FLT3 inhibitor.

Transcript Edited for Clarity