Better Patient Selection Needed for AML Therapies

Alexander E Perl, MD

Alexander E Perl, MD

While there are many remaining therapeutic challenges for patients with acute myeloid leukemia (AML), recent advances with drug approvals and an improved understanding of how to treat patients with the disease are steps in the right direction, according to Alexander E. Perl, MD.

“The big difference this year, and I’ve been giving updates in AML talks for some time, is that we have new drug approvals in AML, which is exciting because the therapy for AML has really lagged behind the understanding of the disease at a biologic level,” Perl said.

OncLive: What did you discuss in your presentation?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Perl, an associate professor of medicine at Perelman School of Medicine at the University of Pennsylvania, discussed the future of FLT3 inhibitors, current obstacles with treating patients with AML, and what pivotal trial results the community can expect to hear in the coming months.Perl: We are getting better at defining which patients respond to which therapies in terms of targeted therapies—which is not a new idea, but a new option in the clinic. We have never had that before like we have now. Even with certain subsets, whether they are patients who respond to CPX-351 (Vyxeos), which is a different formulation of older chemotherapy, this seems to work better than the traditional way that we treated AML. That's an exciting advance, as well.

The drug gemtuzumab ozogamicin (Mylotarg) was removed from the market a bunch of years ago. It has now reentered the market, so we now have that as an option. There is an IDH2-targeted drug called enasidenib (Idhifa) that was just approved, as well as the drug midostaurin (Rydapt) for FLT3-mutated AML. There are a lot more IDH1/2 inhibitors and FLT3 inhibitors coming down the pike that are currently in development, so it's a start. It's not the last word and this is not going to be the only year where there are drug approvals.

The hard thing about this is, with so many to choose from, working up AML has actually changed because now we need to know more about our patients before we start on therapy—and that's new. We used to quickly get our patients treated and now we should slow down and say, "What's the best therapy for the patient based on information that’s coming out?”

Can you discuss other inhibitors moving through the pipeline?

Similarly, pathologists need to keep up to speed with the clinicians in terms of providing genetic data, flow cytometry data, and other information to us at a pace that matches our need to treat patients, but it will all work out. It's just going to be a little bit of initial growing pains. I can speak mostly about FLT3 inhibitors, which are drugs that I’ve been helping to develop. Midostaurin is actually a pretty old FLT3 inhibitor. It’s one of the first drugs to ever be tested as a FLT3 inhibitor in the clinic and the first clinical trials of midostaurin were done in 2002; that tells you how long it has taken to get from early-phase studies to be an FDA-approved drug.

If we looked at that drug, it was relatively weak in terms of its potency against FLT3 and hit a lot of other targets. What has developed since that time are much more potent drugs and much more selective drugs, so now they are just FLT3 inhibitors and not multikinase inhibitors—which is a better description of what midostaurin is doing.

The 3 drugs that just jumped to mind are quizartinib, which is the first of the selective inhibitors, and then the drugs crenolanib and gilteritinib, which are drugs that can work to similarly do what quizartinib is doing. However, it also attacks some of its weaknesses in terms of resistance mutations that we had seen with that drug.

If we continue to explore FLT3 inhibitors and more get approved, will we run into sequencing issues in determining which one to give and when in these FLT3-mutated patients?

The future is bright for patients who have FLT3 mutations. There are phase III studies that have completed accrual or will soon complete accrual in relapsed/refractory patients with FLT3 mutations, and frontline phase III studies have just started this year to get underway—both for newly diagnosed patients and also for those undergoing transplant, so that's an exciting advance.Well, that's kind of the $64,000 question. If we know that midostaurin works in frontline therapy, do we need a new frontline drug? Or, do we just need to get patients the best response to frontline therapy and then figure out what drug we can give as maintenance therapy for long periods of time? At present, we are steering a lot of patients to bone marrow transplants because we think that, at least for FLT3-internal tandem duplication (ITD) mutations, that’s the best therapy to protect patients against relapse.

What are some additional remaining challenges the community needs to tackle over the next couple of years?

Two questions have come up. If we use FLT3 inhibitors in the post-remission setting, or as maintenance therapy after that, would that decrease the need for transplant? We don’t know the answer. Also, even when we do allogeneic transplant for patients with FLT3 mutations, there are still relapses. What can we do to decrease the likelihood of that happening? There are phase III studies looking to answer that question by giving gilteritinib as post-consolidation maintenance or post-transplant maintenance. There are 2 phase III studies; one is looking at the drug in each of those contexts.The hardest thing is that we know a lot about the genetics of AML, but we don’t have a targeted therapy for every patient. We are still learning whether there are patients in whom we acan add certain therapies to their treatment and if that will improve outcomes. Do we need more targeted drugs, or just smarter drugs that are out there? Who are the patients that should get more-intensive therapies versus less-intensive therapies?

Actually, there is a very interesting development, which is that the addition of venetoclax (Venclexta) to a hypomethylating agent or low-dose cytarabine has had rather dramatic effects in patients who are considered unfit for intensive approaches. Many people have posed the question that, if this works in patients who might be less fit for intensive therapy, how well does it work relative to intensive therapy? If we look at younger patients or even those with less comorbidities, could these lower-toxicity approaches be just as good as very intensive therapies that have a lot of side effects to them?

Nobody knows the answer until we do that study, but we are excited based on the data coming out in venetoclax combinations. The other thing I'm uncertain about is why that seems to work so well in frontline therapy and, yet, venetoclax as a single agent in the relapsed/refractory setting has very limited activity. There's certainly something different there that we don’t quite understand yet, but we are finding that is a very exciting combination.

There are 2 early-phase studies that have been moving along of the combination of venetoclax with either low-dose cytarabine or a different study looking at venetoclax combined with either decitabine or with azacitidine and different dosing schedules.

What trials could we potentially hear about at the 2017 ASH Annual Meeting?

Realistically, the differences between those approaches are quite small. The response rates are very high and appear to be much more durable than chemotherapy response rates—using either azacitidine alone, decitabine alone, or low-dose cytarabine alone. Now, researchers are starting to get some real follow-up where they can say this is not just a quick response and then it’s lost over a short period of time. These look to be true treatment responses that are more durable than just a quick response and, “Oops, it's gone.” I'm excited about the 2017 ASH Annual Meeting. We have a lot to look forward to in terms of questions for the field. [There were] many questions that were posed after the recent approval of drugs, including midostaurin. Are there going to be subsets of patients who benefited? We didn’t get any data on molecular subgroups in response and maybe that's something we are going to see.

There are data emerging on the role of minimal residual disease and how that should shape therapy. I don’t think we know the answer well enough in our hands to use that today. [We don’t know yet] how it's best to use that and whether it should be molecular testing or flow cytometry testing. Everybody wants to do it, but it has been awfully hard thus far. Emerging data say that could shape treatment options. That’s something we're looking forward to—more mature data [moving forward].

In terms of novel agents, there are a lot of trials out there that we're waiting on. There are many phase III studies that are ongoing that we need to keep in our minds. As I mentioned before, there are phase III studies of FLT3 inhibitors that are ongoing. I don’t know if those data will be mature enough for the 2017 ASH Annual Meeting, but that might be there 1 year from now.

There are also data with the combinations of hypomethylating agents and venetoclax or low-dose cytarabine and venetoclax. We can look for that and see whether there are updates this year. Ivosidenib is an IDH1 inhibitor that was very near to finishing its clinical development last year and we didn’t get any data on that. Perhaps this year we'll see updates. There are a bunch of interesting agents out there. I’m looking forward to the meeting.