Influx of Targeted Therapies Prompts Several Questions in AML Paradigm

Mary-Beth Percival, MD

There is no question that the availability of targeted agents, such as FLT3 inhibitors and IDH1/2 inhibitors, has led to survival gains for patients with acute myeloid leukemia (AML). Despite progress, concerns over the timing and potential toxicities of treatment remain, said Mary-Elizabeth Percival, MD.

“There's still a lot of room to grow. We know that there are a lot of mutations, but finding appropriate inhibitors can be challenging,” said Percival, an assistant professor, Division of Hematology, University of Washington School of Medicine. “Figuring out which inhibitor to use when somebody has multiple mutations is a really challenging area that we haven't crossed the threshold of.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Percival, who is also assistant member in the Clinical Research Division with Fred Hutchinson Cancer Research Center, and an attending physician with the Seattle Cancer Care Alliance, discussed advances and challenges with targeted agents in AML and remaining questions in the field.

OncLive: How has the ability to target FLT3 and IDH1/2 mutations impacted the outlook of those with AML?

Percival: With midostaurin (Rydapt), for example, we’ve definitely seen an overall survival (OS) benefit in the frontline treatment of patients with FLT3-mutated AML; that's very positive. Some of the gains seen with IDH inhibitors have been more modest, but maybe that's to be expected because they've been used in the relapsed/refractory setting.

What are some of the advances that have been made with FLT3 inhibitors?

There are 2 FDA-approved FLT3 inhibitors right now. One is midostaurin, which is approved for newly diagnosed patients. We have not had a lot of experience in the relapsed/refractory setting because once that agent came out, there was so much interest and many trials focused on that particular drug. The following drugs, the second-generation FLT3 inhibitors, have really focused on relapsed/refractory patients. The second drug that is approved for the treatment of patients with FLT3-mutated AML is gilteritinib (Xospata). That agent is only approved for patients who have relapsed/refractory FLT3-mutated AML. There is a study that will open soon that is going to compare gilteritinib with midostaurin in the frontline setting of FLT3-mutated AML. Right now, these agents are pretty separate in terms of the populations that you would think about using them in, based on the populations they've been studied in.

What drugs are available for patients with IDH1/2 mutations?

There are 2 IDH inhibitors that are FDA approved right now. Ivosidenib (Tibsovo) is approved for newly diagnosed and relapsed/refractory patients with IDH1-mutated AML. Enasidenib (Idhifa) is approved for IDH2-mutated AML. There is talk that there is a pan-IDH inhibitor being studied right now, but it's still in preclinical phases. I don't know whether it's going to be used in AML or other tumors that also have IDH1/2 mutations, such as glioblastoma.

Given the number of available therapies, what challenges does that create?

It creates many challenges in terms of [determining] how to [best] treat patients. When you see a newly diagnosed patient, should you wait for their FLT3 status to come back before you assign a treatment? You want to make sure you're including something that has a FLT3 inhibitor, such as midostaurin.

It also makes it challenging for physicians in the community who see a newly diagnosed patient and want to start treatment right away, or for [a patient] who has a high white blood cell count. The timing is an issue. Insurance approval can also be an issue because some of the drugs are very expensive. That makes it very challenging, prompting a back-and-forth between the physician and their staff [in our attempt] to advocate on behalf of the patient.

It's also challenging because some of the new drugs have a lot of adverse events (AEs) and we're only starting to become familiar with some of them. I mentioned differentiation syndrome with the IDH inhibitors; that may be occurring a lot more often than we expected. Frankly, it's kind of surprising when you consider the function of the IDH protein in the cell to [figure out] exactly what's going on that would lead to differentiation syndrome. It's also not as classic as the differentiation syndrome seen in another blood cancer like acute promyelocytic leukemia, where we have a well-stratified time of when it occurs and how to treat it. That’s not really the case for patients [with AML who are] on IDH inhibitors, as it can occur up to 3 months after they start the drug. We don't know the best way to treat [this AE]; it will probably include steroids, but we don't know for sure.

Could CAR T-cell therapy have a role in AML?

Right now, there's a lot of hope [for this approach] but there are not a lot of data beyond that. Some of the earlier CAR T-cell therapy studies for AML have had to close accrual for a variety of reasons. Accrual was very slow to start off with because we have to make sure that the toxicity concerns in a phase I cellular therapy—based trial were not too great. There is a lot of interest and there are many ongoing trials in which investigators are trying to figure out where CAR T-cell therapy is going to fit into AML, but it is definitely not ready for primetime.

What is the biggest population with unmet needs to address?

I'm not sure there's one patient population, but I would say that patients with relapsed/refractory disease are our greatest unmet need right now; that extends to patients before they have a full-on relapse. These patients have minimal residual disease (MRD) where we know their outcomes are going to be worse with any of the treatments we have to offer them, whether that's a bone marrow transplant or more chemotherapy. We don't really have something we can offer them that's necessarily targeted at their MRD. Another major problem has been that many patients, even after they achieve an initial complete remission, still relapse. Figuring out how to deal with patients who relapse and offering them the best chance of cure when we're able to is really important.