Therapeutic Breakthroughs in AML Lead to Improvements in OS Outcomes

Naval Daver, MD

A wealth of new drugs and novel combinations has significantly improved 5-year overall survival (OS) rates for elderly patients with acute myeloid leukemia (AML); however, the remaining challenge for research involves determining where these emerging strategies best fit in with traditional therapies, according to Naval G. Daver, MD.

In addition to standard chemotherapy options, IDH1/2 inhibitors, such as ivosidenib (Tibsovo); FLT3 inhibitors, such as quizartinib; antibody—drug conjugates, such as gemtuzumab ozogamicin (Mylotarg); and more have emerged in the space.

“We are seeing the field heading toward a nonchemotherapy or low-chemotherapy backbone,” said Daver, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “For the first time now, there is a lot of excitement about developing low-intensity regimens with targeted therapy, immunotherapy, and venetoclax [Venclexta].”

OncLive^®: What are the current treatment options for patients with AML?

In an interview with OncLive^® during the 23rd Annual International Congress on Hematologic Malignancies,^® Daver discussed the recent advances made in AML, stressed the importance of minimal residual disease (MRD) testing, and highlighted where research in the field is heading in order to achieve a higher cure rate.Daver: There are now many treatment options for patients with AML. It has been a fantastic last 2 years, with 8 drugs approved and a couple of drugs also under FDA review. [These developments have] dramatically shifted the landscape of AML. Historically, we selected treatment based on the fitness and age of the patient. Therefore, if patients were considered fit enough to receive high-dose chemotherapy, they were given induction with the 7 + 3 regimen or the 7 + 3 “light” regimen. Those who were not considered fit enough because of their age or performance status were given low-intensity therapy. Although we were able to cure about 50% of younger patients, only about 15% to 20% of older patients were cured.

Now, with the advent of several targeted therapies, such as IDH inhibitors, we are seeing response rates of 30% to 40% as single agents. We do not think their ideal use is in the relapsed setting, because we are seeing that the use of combinations in the frontline setting with chemotherapy is leading to higher responses. The survival seems to be better [with that approach], as well.

Similarly, with other targeted agents, such as quizartinib and gilteritinib (Xospata)—both of which are very active—we see that these drugs give us about a 50% response rate in patients with FLT3 mutations who fail frontline chemotherapy. A recent randomized study showed that the use of quizartinib as a single-agent oral therapy gave us double the response rates seen with triplet chemotherapy. We also saw an improvement in OS. Even though these are pills and intuitively, we may think they will not be that powerful, we essentially doubled responses. That is where the field is moving—so that we can use these agents not in the salvage setting but incorporate them [up front], where the curative potential is greater. We have studies now combining [FLT3 inhibitors] with induction chemotherapy.

Another agent that is probably the most important breakthrough we have had in AML is a drug called venetoclax, which is a BCL-2 inhibitor. The study that was done in elderly patients with AML combined standard treatment with azacitidine alone versus azacitidine with venetoclax. That study, at this time, is ongoing in a phase III format. What we are seeing is that the combination of azacitidine and venetoclax gave us a response rate of 72%, which is 3 times higher than what has been seen with azacitidine alone. The median OS was 17 months—double that of standard therapy.

We are very excited about this because for the first time in our elderly patients with AML, we are now looking at 5-year predictive survivals of about 40%; historically, this was about 15%. This is just the beginning, because once we establish azacitidine plus venetoclax as the standard of care, the next step is going to be figuring out how to improve on that further. Can you add the FLT3 inhibitors if the patient has FLT3 mutations? Could you add IDH1/2 inhibitors? Can we add immunotherapies? We are starting several trials looking at this at The University of Texas MD Anderson Cancer Center.

What are some other agents or approaches that are emerging in the AML space? Where do you see future research headed?

In the next couple of years, we think there will be a switch toward us being more comfortable treating patients with azacitidine plus venetoclax, with the addition of either targeted therapy or immunotherapy. We will be using less and less chemotherapy.A couple of other drugs emerging in AML are immunotherapies. There is an antibody—drug conjugate called gemtuzumab ozogamicin, which has been FDA approved in the frontline setting. This drug seems to show the best activity when it is combined with chemotherapy in a specific group of patients with AML. We specifically use gemtuzumab ozogamicin with induction in our patients with what is called core binding factor. The phase III data show anywhere between 15% and 20% absolute survival improvement in these patients. We think this is where gemtuzumab ozagamicin should be used.

Midostaurin (Rydapt) is another drug being used; this was the first FLT3 inhibitor to receive FDA approval. All in all, we have a very wide variety of choices compared with 5 years ago, when we just had 7 + 3 versus azacitidine for elderly patients. We now have multiple targeted therapies, monoclonal antibodies, and venetoclax.

What are the biggest unmet needs in AML that still need to be addressed?

What is the role of MRD assessment in hematologic malignancies?

The next 4 to 5 years of research will look at how we optimally combine them and sequence them and how to incorporate MRD assessment. Most importantly, what is the role of stem cell transplant? Are we still going to require transplant in the majority of our intermediate- and high-risk patients? Instead, can we bring in maintenance strategies with our newer agents?Even though we have many new drugs in AML, we are still not curing more than 70% of the younger patients. That is probably the highest estimate we can give for a patient younger than 60 years of age. We need to identify the patients who will relapse and give them maintenance or transplant. The second big area is that now that we have a regimen that works with venetoclax and azacitidine, we are starting more major research. If you look at survival with this regimen, our follow-up data are still short; it is about 45% at 3 years. Although this is definitely better than 15%, it is not 90%. We still have a long way to go to get there.MRD has become a very important parameter for both assessing response and gauging prognosis. In some cases, MRD can determine transplant or posttransplant maintenance. MRD is analyzed using 1 of 2 major techniques. One of them is called multiparametric flow cytometry, which looks at particular antigens and uses high sensitivity flow with 15 to 17 colors. We are usually able to get down to a level of 100 times more sensitivity than what a pathologist would do on morphology.

The other way to look at MRD is by next-generation sequencing (NGS). If we know a patient has a particular mutation or fusion, we are able to track that over time by doing polymerase chain reaction or NGS approach. If that mutation is completely eradicated, then we know there is no MRD. This MRD approach has emerged as a very important outcome for patients, and what we see is that there are several patients who are considered to be in morphological remission by bone marrow criteria. This has been the gold standard that we have used for many decades, but, in fact, when you look at MRD, many of these [patients] could be MRD positive, and the prognosis of these patients who are MRD positive is actually almost as bad as those who do not achieve remission.

What is your key takeaway on MRD?

Therefore, the thought process is evolving more [toward considering] MRD as a [potential] true indicator or a best clinical surrogate for OS and long-term outcome—much better than the historical complete remission and other endpoints. The problem is that very few trials are using MRD as a prospectively evaluating marker. Even though it will not be used as a primary endpoint, because it has not been FDA approved, it can at least be used as a secondary endpoint. This will make a strong case for it to be considered as a [regulatory] endpoint. Historically, many companies have not been willing to do that, but going forward, we are seeing that a large number of phase III trials are incorporating this. In the next 5 years, we are going to see a lot of prospective, randomized frontline trials using MRD.We have to assess MRD in any prospective clinical trial we are doing. We are not completely ready to make decisions on it, but we do need to do it so that, as we gather more and more data, we can make an informed decision in the next few years as to how to use MRD.

There is a lot of debate on the best technique to use for MRD and how best to define MRD. There is no real consensus. There are 2 major techniques, and both seem to be quite sensitive. On their own, they are predictive in that about 80% of patients who are MRD negative will have long-term survival.

In those who are MRD positive, only about 20% to 25% will have long-term survival. This applies regardless of which of the 2 techniques you decide to use. What is emerging is that when you use both of these techniques together, and you are able to show that the patient is MRD negative, you get the highest predictive value. In fact, when patients are deemed MRD negative from both modalities, 95% of them are alive at 5 years. In this instance, you are getting a really nice differentiation.