New Era Begins of Molecular Monitoring and Targeted Therapy in AML

Eric S. Winer, MD, highlights the targeted therapies that have made the biggest clinical impact for patients with acute myeloid leukemia.

Eric S. Winer, MD

Eric S. Winer, MD

Eric S. Winer, MD

In the current era of acute myeloid leukemia (AML), treatment plans can be tailored based on each patient’s molecular profile, which is far more than what cytogenetics allowed for, explained Eric S. Winer, MD.

“With the advent of molecularly targeted agents, we're able to target these areas a little bit better, [which is resulting in] higher remission rates,” said Winer, a physician at Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School.

Thus far, a myriad of targeted therapies for patients with FLT3 mutations and IDH mutations have received regulatory approval and have become accessible in the clinic. In 2017, midostaurin (Rydapt) was approved by the FDA for use in combination with chemotherapy for newly diagnosed patients with FLT3-positive AML. This was followed by the November 2018 approval of gilteritinib (Xospata) for the treatment of adult patients with relapsed/refractory AML who harbor a FLT3 mutation.

Within the same month, the FDA granted a priority review designation to a new drug application (NDA) for quizartinib for patients with relapsed/refractory FLT3-ITD—positive AML, with an original action date of May 25, 2019. However, in April 2019, 3 months were added to the review period for the application, allowing the FDA to review additional data. Since then, the FDA has scheduled an Oncologic Drugs Advisory Committee hearing for May 14, 2019 for the NDA for quizartinib. The anticipated action date for this agent is August 25, 2019.

Furthermore, enasidenib (Idhifa) received approval for the treatment of patients with IDH1/2-mutant disease, and ivosidenib (Tibsovo) is approved for use as monotherapy in those with relapsed/refractory IDH1-mutant AML. Ivosidenib is now under FDA review for use in combination with azacitidine for patients with newly diagnosed IDH1-mutant AML ≥75 years old or those who are unfit for intensive induction chemotherapy.

“Right now, molecular testing is the most important aspect of AML,” said Winer. “Ten to 15 years ago, we stressed cytogenetics; that was the benchmark for how we thought about prognosis. Now, with molecular testing we’re able to identify these targets somewhat prognostically and pair them with targeted therapy.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Winer highlighted the targeted therapies that have made the biggest clinical impact for patients with AML.

OncLive: What are some of the historical challenges in developing new targeted agents in this space?

Winer: If you go back 10 or 15 years, we treated all of AML as one disease. Over time, we were able to delve into the cytogenetics and use risk factors to determine who needed transplant and who didn't. However, we weren't really able to determine how to best put people in remission because everyone received the same chemotherapy.

Could you speak to the advances that have been made with FLT3 inhibitors?

We know FLT3 mutations carry a poor prognosis. FLT3 inhibitors have allowed us to target these mutations. There are 2 main FLT3 mutations; one is an ITD, and the other is a TKD mutation. These inhibitors target those mutations and mitigate some of their punitive factors.

There are a few different trials that have revolutionized how we treat these patients. One is the RATIFY trial, which was mainly constructed by the Alliance group. The trial showed a marked difference in overall survival of 74 months versus 26 months with the addition of a FLT3 inhibitor to standard induction therapy versus induction therapy alone, respectively. Now that midostaurin is approved, other FLT3 inhibitors are moving into the space, some of which are more specific [than midostaurin]. However, it's unclear whether more specificity is going to better.

In terms of relapsed/refractory disease, we've seen the importance of drugs such as quizartinib. A presentation from the 2018 ASH Annual Meeting showed an improvement in [response rates versus salvage chemotherapy in patients with relapsed/refractory FLT3-ITD-mutated AML].

Gilteritinib is approved in the relapsed/refractory setting and is another FLT3 inhibitor [that is available for use]. [Data from the] trial hasn’t been published yet, but it led to the agent’s approval.

The next step is determining whether we can use these drugs in the maintenance setting. Sorafenib (Nexavar) is the one drug that has demonstrated efficacy as maintenance therapy, but there are other drugs being studied right now. Those studies are ongoing, but we're hopeful that they'll give us good results.

What can you share about the development of IDH inhibitors?

IDH mutations are seen in about 15% to 20% of patients [as a result of the] isocitrate dehydrogenase enzyme; it's what everybody remembers from the Krebs cycle from high school biology. When those genes are mutated, you get a product called alpha-Ketoglutaric, which stops cell differentiation. Two drugs, ivosidenib and enasidenib, have been used to block that. A few studies have come out, 2 which have already been published, which talk about the efficacy of these agents in relapsed disease. At the 2018 ASH Annual Meeting, there was a presentation regarding the potential benefit of using these agents in the frontline setting in patients with de novo AML.

Beyond these inhibitors, what other novel approaches under investigation?

The more we look at different mutations, the more we're trying to find targets for those mutations. There are several mutations [for which we’re seeing more agents in development]. For example, we’re seeing the value of p53 refolding agents in clinical trials for patients with p53-mutated AML.

We haven’t seen a tremendous boom with antibodies as we have in the lymphoma or the acute lymphoblastic leukemia world. The targets may not be as good. However, there are a couple of agents coming down the line that look like they're going to be somewhat promising. This is specific to CAR T cells, monoclonal antibodies, or bispecific antibodies, particularly against CD33 or CD123.

Are there specific trials that you’re excited about?

All of the CD123 antibodies are very interesting. There was a recent publication with a CD123 bispecific antibody that lends towards [the use of] more of a blinatumomab (Blincyto) type of a process. That may be exciting down the road. We all need to be very temperate with our antibody expectations because it will not result in the same “home run” as [was witnessed] in the lymphoma world.

What is the importance of molecular testing and monitoring in this space?

Molecular testing allows us to see how these different mutations interact and provides us with an understanding of how the disease develops. As we learn more about how the disease develops, we are able to determine how to halt the disease at an earlier state and better treat the disease.

What would you like to emphasize for your colleagues working in the space?

There have been many advances made over the past 5 years. In the AML world, we went decades using the same therapy [for every patient]. The advent of molecular agents is really changing the way we treat this disease, making [our efforts] more successful and less toxic.

Editor's Note: Overall survival results for gilteritinib were presented at the 2019 AACR Annual Meeting. Click here for more information.

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