Crenolanib Shows Promise in AML Patients With Variant FLT3 Mutations

Angelica Welch
Published Online: Monday, Aug 21, 2017

Eunice Wang, MD
Eunice Wang, MD
At the 2017 European Hematology Association (EHA) Congress, Eunice Wang, MD, presented an abstract examining the biology of newly diagnosed patients with FLT3-positive acute myeloid leukemia (AML) who achieved a response to the FLT3 tyrosine kinase inhibitor (TKI) crenolanib combined with chemotherapy.

Wang et al reported that complete remission (CR) with full count recovery was achieved by all 4 patients discovered to have novel variant FLT3 mutations.

In an interview with OncLive at EHA, Wang, chief, Leukemia Service, professor of Oncology, Departments of Medicine and Immunology, Roswell Park Cancer Institute, discussed her research and the next steps for crenolanib and other emerging FLT3 inhibitors in AML.

OncLive: Please provide an overview of the study.

Wang: This is actually a follow-up of a phase II clinical trial that was presented at the ASH 2016 Annual Meeting. In this trial, we combined crenolanib, which is a novel potent type 1 receptor TKI FLT3 with standard chemotherapy for the treatment of newly-diagnosed FLT3 mutant patients with AML.

On this trial, we saw initially very high response rates overall—CR/CR with incomplete hematologic recovery rates of over 80%. And the drug was generally very well tolerated with very few dose reductions required, at least during induction chemotherapy.

This particular abstract is just following up on some of the patients that achieved complete remission and achieved responses on that trial to say, what was the biology of the patients that were treated? We know that there is a lot of heterogeneity in the FLT3 mutations that our AML patients can present with, and there is increasing data that some of these mutations can predict resistance to other TKIs in development for the treatment of this disease.

What are the findings so far?

This is just our analyses of deep sequencing of the FLT3 mutation, which was performed in about 24 patients in the trial…It was really looking at these specific mutations that were found in these patients. What we did find was that a number of our patients had unique, or not standard, FLT3 mutations when we did this deep sequencing to look at these abnormalities. We actually identified 4 patients that had variant FLT3 mutations, which have not been well described but could be predictive of resistance to standard TKI therapies. We describe the specific abnormalities in these 4 unique patients, some of whom had variant allele frequencies of up to 29%, which implies that they were really potentially driving the leukemia at the time of presentation.

We then go on to show that treatment with crenolanib was very successful in eradicating these abnormalities. All 4 patients had subsequently showed an eradication of these specific mutants. Even if there is a broad spectrum or abnormal FLT3 mutations, molecular aberrations, driving this disease we feel that this is very potent data to say that the use of a very very potent targeted, specific, type I FLT3 TKI could overcome these, in conjunction with chemotherapy.

The best chance that we have to eradicate this disease is diagnosis. Whether that is to cure the patient, allow them to get into a remission, or receive a potentially curative transplant. So, the ability to knock out all of these disease variants at the time of diagnosis and achieve that response is clinically meaningful.

Your EHA abstract conclusion states that "a potent pan-FLT3 inhibitor with the ability to inhibit [internal tandem duplication (ITD)], D835, as well as other activating mutations may be beneficial."

There are a number of FLT3 inhibitors that are in clinical development, most of them are type II inhibitors, meaning that they bind the FLT3 receptor only in its inactive conformation. Crenolanib is a type I FLT3 inhibitor, so it binds both the inactive and the active conformations. Because it has that ability to bind both, it inhibits both FLT3 TKD and ITD mutations.




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