AML Landscape Rapidly Changing as New Treatment Options Become Available

November 21, 2018
Danielle Ternyila

Patients with acute myeloid leukemia now have more treatment options available than ever, due to some major changes to the field over the last year. With 2 drugs already approved for patients with <em>IDH</em> mutations and 4 new drugs expected to receive approval in the next year, it is a more hopeful time than ever for this patient population.

Alexander Perl, MD

Patients with acute myeloid leukemia (AML) now have more treatment options available than ever, due to some major changes to the field over the last year. With 2 drugs already approved for patients withIDHmutations and 4 new drugs expected to receive approval in the next year, it is a more hopeful time than ever for this patient population.

“This is an exciting time in the acute myeloid leukemia world,” said Alexander Perl, MD. “We’re seeing, finally, drug approvals happening with a rapid pace.”

Targeted agents have been significantly impacting the treatment landscape. Perl’s own research in AML has been focused on targetingFLT3mutations.

“We expect there will be at least 1 FLT3 inhibitor [approval this year] and hopefully 2 FLT3 inhibitors approved in the next year [based] on randomized studies, some of which are now public and presented, and others [that] will be presented soon,” Perl said. “There are very exciting data in this area changing paradigms, and it’s really neat to watch this in front of our own eyes.”

In a presentation withTargeted Oncology,Perl, associate professor of medicine at the University of Pennsylvania, discussed some of these targeted agents, including the FLT3 inhibitors, and how these are expected to change the treatment landscape for AML. He also highlights other approaches that are advancing the field as well, such as antibody-drug conjugates (ADC), combination therapy, and minimal residual disease (MRD).

TARGETED ONCOLOGY:What are some of the key points to understand about targeted therapies in AML?

Perl:The big point to make in AML is that everything is just different. Everything you already knew about how to treat AML is changing and changing rapidly. It used to be that we had “1 size fits all” treatments for AML. We would give intensive chemotherapy for younger and/or fitter patients, and we would give low-intensity chemotherapy for older, less fit patients. Patients fit for intense chemotherapy received 7 + 3, or something similar to it. Patients who weren’t would receive low-dose, low-intensity chemotherapy to avoid toxicity.

Now we have ways to treat patients with greater efficacy. If they have certain genetic or historic factors in their leukemia and [even] certain carrier types, in particular, [they] respond to targeted agents. We also know that certain mutations respond to targeted agents, such asFLT3mutations, and there are not 1 but 2 approved drugs that are mutation-targeted in the relapsed [setting] for [patients with]IDHmutations.

All of this has happened just in the past year, with potentially 4 new drugs approved in the coming year, so this is very exciting and a real time of influx in terms of the current standard of care. Things are really changing rapidly in a good way, finally, in a disease [where] we have known a lot on the biology of the disease but really have not had a lot to do in terms of taking that knowledge and turning it into therapies that really impact outcomes for patients. The really gratifying thing is some of these therapies have reduced reliance on really intensive approaches that now, in head-to-head trials, are less effective than targeted agents.

It’s interesting. I just saw a patient yesterday that said, “Is this as strong or stronger than the therapy I just got?” And I said, “Thankfully, it’s less strong and yet it works better.” That’s exciting to have options like that for patients.

TARGETED ONCOLOGY:Does that bring upon a new challenge, though, in deciding which patient should receive which treatment?

Perl:In a good way, but yes. We do need to figure out important questions like sequencing and to my line of thinking, I think combinations are the next important frontier. We do need to figure out, does it matter [if we] treat patients earlier with targeted therapy? Do we wait until standard therapies aren’t working and add them in? The impression is that targeted agents will likely need to go earlier in the disease course to get the best impact on relapse, protection, and survival, which is ultimately the name of the game. For patients who are less fit for intensive approaches, the key thing is just making sure we aren’t adding drug on drug on drug and increasing the toxicity, because that’s something we should avoid, if at all possible.

That being said, as we get more effective low-intensity therapies, and there are a few really exciting combinations such as venetoclax (Venclexta) combinations, then the more we can use this. For more patients we could really impact their lives, and AML is a much less frightening disorder if you say we have a few effective therapies for this.

I think it’s a really exciting time in the field, and everybody is really excited and revved up to see what drugs will finally come to our pharmacopeia in the near future in terms of standard therapies, not just experimental therapies, or difficult to acquire therapies. This is really a great time in AML therapy right now.

TARGETED ONCOLOGY:What kind of role do you think ADC&rsquo;s will have in AML?

Perl:There’s already one drug that’s approved, which is gemtuzumab ozogamicin (Mylotarg). That’s a drug that we’ve known about for a while and was previously approved for relapsed disease. Then, because of toxicity concerns when it was added into combination regimens, the approval was actually withdrawn for single-agent use of the drug because unfortunately in that setting, we had plenty of experience with the drug, and we weren’t quite seeing the toxicity that was really feared. Nonetheless, the drug was not available until the randomized data came out to show that it had a role. It does have a role. It’s important to look at who benefits from that drug and primarily patients with relatively favorable chemo-sensitive genotypes. Core-binding factor AMLs in particular are very sensitive to the effects of gemtuzumab ozogamicin. That’s a very good therapy for them. I’ve certainly incorporated it into my standard therapy for patients with CBF-positive AMLs.

Now are there other drugs coming down the pike for this population? Sure. The real question is what targets, what payloads, what combinations do we want to use, and do we want to deliver chemotherapy or do we want to deliver an immune attack? With what we know on how to treat acute lymphoblastic leukemia (ALL), we are trying to incorporate those lessons into new approaches for AML. There’s a lot of really exciting immunotherapeutics coming forward which Naval G. Daver, MD, is going to talk about. I’ll leave that area of his expertise, but I think everyone in the field is excited to see can we do this same thing in AML that we are doing in ALL? If you look at how we can change the field and really move therapies forward, that’s a really untapped resource at present in terms of approved therapeutics.

TARGETED ONCOLOGY:Do you think CAR T-cell therapy will impact the landscape at all?

Perl:I hope so. They’ve had a great impact in ALL, primarily in childhood ALL. We’ve done a lot of development at my own institution for adult ALL, and they have significant activity as well as significant toxicity that has to be mitigated, but the lesson learned from that is have a plan for how to deal with the side effects which took us a while to figure out. [However], now that we have that approach in ALL, we are certainly using that approach in lymphoma patients who are getting CAR T cells and leukemia patients who are getting CAR T cells.

Can we get that kind of response for patients who have AML? We hope so. There’s been very exciting data that were presented last year and we are looking at updates at ASH as to the CAR T cell approaches in a lot of different settings. I think the field wants to see that we can do this in AML the same way that we have in ALL. This being said, it’s harder to design a good CAR T cell against AML, knowing how similar AML blasts are to normal elements in the bone marrow that are critical for hematopoiesis, so avoiding toxicity, again, is a major challenge with that approach.

TARGETED ONCOLOGY:Can you talk about the role of MRD in this space?

Perl:I think MRD is a very important new measure of whether your current therapy is working. If you’re looking at, is this patient in remission, it’s really not going to be good enough going forward to say we don’t see leukemia under the microscope. It’s like saying the surgeon saying we got it all, yet we know there is going to be some disease there after an operation. That’s where the question is. Now that we know something is there, what’s the best approach? We’re getting better at figuring out should we keep doing what we are doing, more chemotherapy, or should switch to a transplant approach? Is this patient likely to relapse or not? That’s really what MRD tells us. It largely tells us what is the tumor burden at the time of sampling and also if the therapy you’re giving is effective in eradicating that clone.

There’s challenges in AML in terms of how we measure MRD, whether we use flow-based assays [or] whether we use molecular detection, and there is disagreement on what the best approach is for patients. It would be nice if we had 1 measure that worked for everybody, but there really isn’t that ability. For patients who have gene fusions like core-binding leukemia, we can look at those transcripts and quantify them. For patients with nucleophosmin, we can use highly sensitive NPM1 assays. Even for patients with FLT3/ITD, we can do the same. That’s true for a number of mutations, but what is less clear is that if you find a low level of MRD at the end of a course or 2 of induction chemotherapy, should you change therapy then to dose-escalated or otherwise add in additional agents? Is that going to change the natural history?

We know from ALL that this is extremely powerful in terms of predicting relapse. It’s a little less clear in AML if you change therapy at that point, if it is going to change the natural history. You may just be at largely identifying patients at very high risk of relapse. That’s really the value.