Crenolanib Plus Chemotherapy Provides Long-Term Survival Benefit in FLT3-Mutant AML

Eunice Wang, MD

Advancing newer generations of FLT3inhibitors to the front line could improve survival in patients with FLT3-mutant acute myeloid leukemia (AML), according to Eunice Wang, MD. She noted that crenolanib, a newer-generation FLT3inhibitor, in combination with chemotherapy, resulted in long-term survival benefits and minimal residual disease (MRD) negativity in younger, newly diagnosed patients.¹

“Now that we have crenolanib and other newer-generation FLT3 inhibitors [that have demonstrated high overall remission rates], the standard of care may change to these newer inhibitors in the next few years,” Wang said. “We may start to see people using these newer-generation FLT3 inhibitors throughout the treatment continuum, starting with the initial diagnosis of FLT3­-mutant disease, through maintenance and consolidation, and at the time of relapse.”

In an interview with OncLive^®, Wang, chief of the Leukemia Service, medical director of Infusion Services, and professor of oncology at Roswell Park Comprehensive Cancer Center, discussed the long-term results of a phase 2 trial (NCT02283177) investigating crenolanib plus chemotherapy in adult patients with newly diagnosed FLT3-mutant AML. She emphasized the superiority of crenolanib over midostaurin (Rydapt) in this population and highlighted future directions for this regimen and other targeted therapies layered with chemotherapy.

OncLive^®: How did this study seek to expand on the current standard of care in FLT3-mutant AML and potentially resolve an unmet need in this setting?

Wang: About a third of patients who are newly diagnosed with AML will have disease that’s characterized by a particular gene mutation, a FLT3 mutation. Typically, for these individuals, we offer a backbone of intensive chemotherapy plus an FLT3 inhibitor to specifically block that gene mutation and the receptor that drives the disease in this subtype.

Currently, we use the FLT3 inhibitor midostaurin, but this was a drug that was repurposed from use in solid tumors and was not specifically designed to inhibit mutant FLT3. In this study, we’re using crenolanib, which is a second-generation, potent and highly specific FLT3 inhibitor that was specifically selected for its ability to block mutant FLT3 and variant FLT3 mutations that confer resistance to other receptor TKIs, such as midostaurin. Crenolanib also inhibits different types of FLT3 mutations, including internal tandem duplication [ITD], as well as tyrosine kinase domain mutations. Crenolanib has a broad spectrum of activity and higher specificity.

We combined this newer FLT3 inhibitor with the standard backbone of intensive chemotherapy and treated individuals aged 19 to 75 years. We looked at efficacy, tolerability, and adverse effects with this regimen.

What updates in long-term survival data have been reported from this trial?

This study was completed in December 2019. This recent dataset is from 45 months of follow-up for the 44 patients enrolled in this study. Twenty-nine patients were under the age of 60 years, and 15 patients were 60 years or older. We previously reported high overall remission rates of 86% after 1 to 2 cycles of chemotherapy, in combination with crenolanib.

We are now looking at MRD-negative responses. A total of 16 out of 18 patients younger than the age of 60 achieved MRD negativity with this therapy, which is a high rate of deep response with the addition of this new TKI.

More importantly, we looked at long-term outcomes in event-free survival [EFS] and overall survival [OS]. We saw particularly in the younger patients, ages 18 to 60 years, that their median EFS and median OS had not been reached. More than half of these individuals, 57%, were still alive at 45 months of follow up. Older patients didn’t do quite as well. Their median EFS was 7.9 months, and their median OS was 19.7 months. However, these are remarkable data for this subset of patients to whom we have traditionally offered allogeneic stem cell transplantation as the best form of treatment.

One of the most interesting findings was that there was a cumulative risk of relapse in 15% of these younger patients. This risk of relapse seems to be similar in patients who went to transplant, as well as those who received chemotherapy alone. This is intriguing because it brings up the possibility that in the future, we may be able to treat these patients with only chemotherapy. These long-term, durable responses give us confidence that the addition of these newer inhibitors could be a step forward for the treatment of these patients in the future.

What other surprising data from this study would you like to highlight?

We looked at the 15% of patients who relapsed, and interestingly, in almost all those patients who continuously received the protocol-specified therapy with the FLT3inhibitor, none relapsed with FLT3-mutant disease. This suggests that the patients who relapse develop new mutations or new pathways of resistance that make them able to escape the inhibitor. It wasn’t the inhibitor’s failure; it was the selective pressure.

Although AML is a biologically diverse disease with many different tumor clones, these data are intriguing and [make us consider] possibilities for patients when they fail potent FLT3 inhibitors, such as targeting different pathways. In the past, [patients relapsed on these therapies] because the inhibitors weren’t good enough. In our case, it’s possible that [in patients who are] taking the inhibitors as directed and as they’re able to so that they’re effective, there may be novel escape mechanisms that warrant future study.

What are the next steps for this research?

Based on remission rates in the earlier findings, we have already moved forward with a randomized phase 3 trial [NCT03258931], where patients aged 18 to 59 years, that younger population in which we saw such good results in the phase 2 study, will be enrolled up front and randomized either to receive crenolanib plus standard intensive chemotherapy or the older FLT3 inhibitor midostaurin plus cytarabine and daunorubicin, which is the standard of care.

How will newer FLT3 inhibitors fit into the treatment landscape in this patient population?

Currently, the standard of care is to use first-generation midostaurin at diagnosis, and to only use these newer generations of agents at the time of recurrence. But as we know, when we have high efficacy and tolerability with agents in the relapse setting, we want to move them up front, because our best chance to cure, maintain quality of life, and extend survival in our patients is to use these inhibitors as early as possible.

These newer inhibitors may replace the older inhibitors moving forward, and we’re going to see them used throughout the treatment continuum. In addition to chemotherapy replacing or potentially supplementing transplant, we may see chemotherapy added to other targeted therapies, because there are other mechanisms of relapse. We now have drugs that target other gene mutations, such as IDH1 and IDH2. We also hope to have strategies that can help treat p53 mutations in AML. As we move forward, we may see more and more targeted agents layered upon either low- or high-intensity chemotherapy backbones.

What is your main message about the future of AML treatment?

In the future, we’re going to move toward more potent, specific, and targeted therapies for AML. We’re moving away from only using standard chemotherapy and moving toward more personalized medicine for AML that will target many mutations to give the best clinical outcomes for our patients.

As we are starting to develop regimens that are leading to complete remission rates of 80% to 90%, we are now beginning to incorporate MRD data. In the past, when we were only able to cure around 30% of our AML patients, [we didn’t prioritize MRD positivity or negativity], because most patients didn’t respond to treatment.

Now that we have regimens such as crenolanib plus cytarabine and daunorubicin and other doublet and triplet targeted therapies, we’re starting to see higher overall remission rates. In this trial, we had an overall remission rate of 86%. That's when MRD starts to be important. This research may give us tools that we can use to help further refine our treatments for AML going forward.

Reference

Wang ES, Goldberg AD, Walter RB, et al. Long-term results of a phase 2 trial of crenolanib combined with 7+3 chemotherapy in adults with newly diagnosed FLT3 mutant AML. J Clin Oncol. 2022;40(suppl 16):7007. doi:10.1200/JCO.2022.40.16_suppl.7007