A New Drug Is in the Pipeline for AML

Eunice Wang, MD

In a recent study conducted by Eunice Wang, M.D., newly diagnosed patients with FLT3-positive acute myeloid leukemia (AML) 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 four patients discovered to have novel variant FLT3 mutations.

Can you provide an overview of the study?

In an interview with CURE at the European Hematology Association (EHA) Congress where her abstract was presented, 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.This is actually a follow-up of a phase 2 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 percent. And the drug was generally very well tolerated with very few dose reductions required, at least during induction chemotherapy.

What are the findings so far?

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.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 four 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 four unique patients, some of whom had variant allele frequencies of up to 29 percent, 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 four 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 1 FLT3 TKI could overcome these, in conjunction with chemotherapy.

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."

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.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.

What are the next steps with crenolanib?

What is the biggest challenge in treating patients with variant FLT3 mutations?

Some other TKIs, for example, Nexavar (sorafenib) or quizartinib, miss out on the activity on the TKDs. One of the issues that we have seen with the prolonged use of these TKIs in long-term disease control or postmaintenance settings, is the development of resistant mutations. Having a broader agent provides the ability to overcome therapy resistance, but also to prevent the development of therapy resistant clones, of which could potentially result in clinical disease relapse. Based on the results of this phase 2 trial of crenolanib plus standard induction chemotherapy, there are plans in the works for there to be launching of a phase III trial that will directly compare crenolanib [with] 7+3 versus midostaurin (Rydapt) [with] 7+3 to see if in this particular clinical disease setting, do we need a more potent selective FLT3 inhibitor like crenolanib, or would it be better to have a broader spectrum multikinase inhibitor like midostaurin, which really also inhibits FLT3. I think that trial is very intriguing and would be the first to use midostaurin/7+3 as its control arm. I think it is just following the disease. Typically, we do FLT3testing at diagnosis, but I think as we bring on more and more relevant FLT3 inhibitors, it is going to be more important to test for FLT3 abnormalities at different time points. At relapse, currently, we would do that, but it may be useful to do them throughout the treatment course with some of these inhibitors because you might begin the development of some of these variant clones.

What other emerging FLT3 inhibitors are showing promise in this space?

It may also be good to do some of this deep sequencing for these abnormal aberrations at the time of diagnosis. That would really require next-generation sequencing or whole-genome sequencing FLT3 analysis, and not just a simple pCR for the most common variants. I think that knowing that you have these aberrant variants that are not typical could guide your choice of a TKI therapy. Or, if it didn’t, it could allow you to at least be suspicious if they were to recur.The other FLT3 inhibitor that looks very promising in addition to crenolanib would be gilteritinib, which was in a recently published article in Lancet Oncology. It was evaluated in the relapsed/refractory setting, resulting in overall response rates of about 50 percent and extension of overall survival for several months. I think that drug is also highly potent and hits both the FLT3 TKD and ITD mutations.

Quizartinib is a very potent FLT3 inhibitor that is in development, but may miss out on some of the TKD [mutations]. I am sure we are going to see other novel FLT3 inhibitors coming down the pike. But I think right now, with the approval of midostaurin as the first FLT3 inhibitor for the treatment of AML, there is a lot more attention being paid to these sort of new generation TKIs.