Daniel A. Pollyea, MD, MS

 AML [acute myeloid leukemia] is far from a solved problem. It’s a disease defined by unmet needs. We don’t have good therapies for patients with relapsed/refractory disease. We need to be better at recognizing the patients at diagnosis who will respond well to venetoclax-based regimens and to try to predict who won’t, and give them a therapy that could work better. For younger patients who might be good candidates for intensive induction chemotherapy, we also have to work on better approaches, because their outcomes have historically been quite poor. There’s a lot to work on in every clinical aspect of AML.

The good thing about the AML community is that we have lots of brilliant people who work in the clinical and laboratory spaces, and great partnerships with companies that are making drugs. There’s a lot to be excited and hopeful about in the near future for AML. There are some exciting, targeted therapies, some genomically targeted therapies, others for 

, and some mechanisms that might have the potential to target the leukemia stem cell population, similar to what we discussed for venetoclax, to make a big impact on this disease. I’m very excited about the near future for drug development in AML.

My hat goes off to community oncologists who are seeing patients with AML. To be able to have the fluency in every type of cancer that you see and treat, and to do that well for patients, is really admirable. If it were me dealing with a disease that I might not commonly see, a crucial thing to do would be to try to have some relationship with someone local or near local who sees a lot of this disease. I can’t imagine having to keep up with all these diseases the way you do. The nuances can be really challenging. Having that partnership, and having that person to call, email, or text when a patient comes in to make sure nothing is being missed in the best interest of that patient is extremely important. We need to make sure we’re all doing the best we can for the patients.

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Daniel Pollyea, MD, MS, discusses the unmet needs and future management strategies of acute myeloid leukemia.

Future of AML Management

 Venetoclax plus HMAs [hypomethylating agents] are incredibly effective therapies for newly diagnosed unfit patients with AML [acute myeloid leukemia], but there are important considerations that must be taken for these patients. In particular, in the initiation of the therapy, tumor lysis syndrome can occur. Those of you who treat CLL [chronic lymphocytic leukemia] with venetoclax know about this and take extraordinary precautions to mitigate or prevent this from happening. It doesn’t appear that the incidence is anywhere near the same in AML with venetoclax-based regimens. In fact, it’s probably only around 1%. But you have to remember that those numbers came into existence in the setting of very aggressive mitigation strategies that were done in the clinical trial setting—admission for the patient, interrupt patient dose escalation from 100 to 200 to 400 mg on days 1, 2, and 3 for venetoclax with an HMA, very aggressive fluid management and electrolyte management. With those aggressive mitigation techniques, the incidence of tumor lysis is quite low in AML, but it’s something that folks are aware of.

Another issue with venetoclax-based regimens are cytopenias. Cytopenias occur with almost every treatment we have for patients with AML. An HMA alone has a considerable incidence of cytopenias. Venetoclax is somewhat myelosuppressive and can contribute to or worsen these numbers. But with careful attention, this doesn’t necessarily have to impact a patient’s clinical status in terms of having more bleeding or infectious complications. The main way to mitigate this is to take breaks between treatment cycles.

After the first cycle of therapy with venetoclax plus an HMA, it’s important to check a bone marrow biopsy. This isn’t like just giving an HMA alone, where you can wait 4 to 6 months or 4 to 6 cycles to check a bone marrow biopsy. One must check a bone marrow biopsy after cycle 1 because you would do things differently if the patient is not in a remission and they are cytopenic because of that. You’d have an array of decisions to make. You might want to just go right into a second cycle because the blast percentage has come down considerably but they’re not yet in a remission. Or you might want to move on from this therapy and try something different if it doesn’t seem like it’s working. That would be very different from knowing that after cycle 1 the patient is cytopenic but the blasts are gone. They’re in a morphological remission. If that’s the case, it’s very important not to go right to the next cycle.

It’s very important to take a break and give upward of 2 weeks off therapy to allow blood counts to recover. Sometimes giving growth factor support to hasten that recovery is a fine thing to do. But taking those breaks between cycles is critical to manage the cytopenias. If that isn’t done, the cytopenias will become significant and very difficult to manage. Then you’ll begin to have clinical manifestations with respect to infectious or bleeding complications. In terms of venetoclax plus HMA, those are 2 of the biggest toxicities or considerations that folks need to be aware of. But the message should be that these are manageable complications.

In my practice, this is the treatment of choice for all newly diagnosed patients with AML who were unfit for intensive induction chemotherapy. Even very frail, older patients should be given a chance to see if they can respond to this regimen. With aggressive supportive care, I find that even the most frail or older patients can get through this and have a chance at a remission. You wouldn’t use this combination for patients who can’t absorb an oral medication for whatever reason. With patients who were treated with an HMA for MDS [myelodysplastic syndromes] and then evolved to acute leukemia, you might want to use venetoclax plus low-dose cytarabine instead, because the VIALE-C study, which looked at venetoclax plus low-dose cytarabine vs low-dose cytarabine alone, and also resulted in the approval of that regimen, included those types of patients. Patients with MDS who received an HMA alone and then progressed and had AML were included in VIALE-C, so that might be a consideration in that setting.

Beyond the labeled indication for venetoclax, there are other populations of patients in which venetoclax-based regimens can be promising. In off-label use for patients with relapsed/refractory AML, there appears to be some efficacy that’s exciting. The same goes for patients with myelodysplastic syndromes. Both have ongoing clinical trials. The third population is patients who would be eligible candidates for intensive induction chemotherapy but have disease biology that would suggest a worse response to this type of approach. The patients with adverse disease biology, complex cytogenetics, maybe those with mutations in 

, would be predicted to have poor outcomes to intensive chemotherapy strategies but not necessarily to venetoclax-based strategies. Those are patients in whom you could consider the use of a venetoclax-based regimen, even in a patient who would be eligible for intensive induction chemotherapy. It’s important to say that it would be an off-label treatment for venetoclax.

Unfortunately, the cost of medicine is an issue that impacts our patients all the time. These are expensive medications, and we sometimes struggle getting them approved or getting the co-pays for these expensive oral therapies affordable. There are assistance programs and grants that can help with this. Patient affordability is a potential barrier. This is a problem for all of society to work on. But there are some resources out there that can help with this.

An expert describes the considerations in choosing to treat acute myeloid leukemia patients with venetoclax.

Considerations in Choosing Venetoclax for AML

 The VIALE-A trial was a landmark confirmatory study mandated by the FDA for full approval of venetoclax. It was a randomized study that enrolled newly diagnosed patients with AML [acute myeloid leukemia] who were older or unfit for intensive chemotherapy. It randomly assigned them to receive azacitidine alone, which has been the standard of care in the United States for this population, or venetoclax plus azacitidine. The results were very clear. Based on all the relevant end points, including response rate and survival, the venetoclax arm was really superior. There were much higher response rates and a significant improvement in overall survival. As a result, this has become the standard of care for this population of patients with AML.

There are some really intriguing data around the ability to achieve MRD [minimal residual disease] negativity with a venetoclax-based regimen. This is a less intensive therapy, so it was unclear whether this would allow for a deep response, an MRD-negative response. We had some data from Keith Pratz at the recent ASCO [American Society of Clinical Oncology Annual Meeting] showing that a significant percentage of patients can achieve MRD negativity with a pretty stringent MRD assay, and they appear to have more durable responses and improved overall survival.

First, it’s very exciting to see that a low-intensity regimen can allow these deep types of responses. This goes back to the mechanism that I mentioned before that this can target the leukemia stem cell population. Maybe it’s not surprising that this can allow for these deep types of responses, but it also shows that these are better responses clinically. The next step is going to be figuring out who these patients are that are having deep responses and how that can be replicated in other patients who aren’t responding as well.

It’s very important to look for all the different mutations in patients, as we discussed before. Several have approved targeted therapies. I’m talking about 

, both of which are mostly in the relapsed/refractory setting. But there’s some interest in whether this information in the up-front setting might be helpful and if this should be the preference to target a targetable mutation in the newly diagnosed setting, or to use a venetoclax-based regimen.

It’s my opinion, and the opinion of most of my colleagues, that while that could be a future strategy to target a genomic mutation in the up-front setting, most of us would prefer to continue using a venetoclax-based regimen for a couple of reasons. One is that there do not appear to be worse outcomes with respect to response rates with patients with 

 mutations with venetoclax-based regimens. To the contrary, patients with 

 mutations have unusually good responses to venetoclax-based regimens. The second issue is more of a logistics issue. Starting a venetoclax-based regimen for any patient with any gene mutation allows you to get started with a treatment more quickly than if you had to wait for the results of a gene mutation, like 

. This is also reflected in the NCCN [National Comprehensive Cancer Network] Guidelines that the standard of care, even with patients with known 

 mutations, is still to give venetoclax-based regimens. We’ll see if this changes in the future. There are some emerging data that IDH inhibitors plus azacitidine might also be very effective. We’ll see how that holds up in the near future.

Dr. Pollyea breaks down data from the recent VIALE-A phase III clinical trial.

VIALE-A Trial: Acute Myeloid Leukemia

 At diagnosis, the goals need to be very thoroughly considered. Because for some patients, the goal might be cure. We hope to find that solution for the majority of patients. But that’s not always in the cards because of age or comorbidities at diagnosis. In some cases, the goal is remission and to keep that remission going for as long as possible. If a patient is a transplant candidate, or even a potential transplant candidate, then that’s often the goal that’s moved toward. Because in many cases, except for some select patients with favorable-risk disease, they can be cured only with the transplant. Depending on age and comorbidities, that could be the goal.

What are the different treatment options to address these different goals? The first goal of treatment beyond thinking many moves ahead—how long is the patient going to live and whether you can cure them—is just getting the disease into a remission. At the moment, for younger, fit patients, the recommendation in most cases is to use intensive induction chemotherapy, the so-called 7+3 regimen, to achieve this goal. However, patients with AML [acute myeloid leukemia] have a median age of 68 at diagnosis, and anyone over 60 can have considerable toxicity, morbidity, and mortality with an induction chemotherapy regimen. We now have a variety of other regimens for patients who aren’t candidates for induction chemotherapy at diagnosis. Those would include the venetoclax-based regimens, venetoclax plus an HMA [hypomethylating agent], venetoclax plus low-dose cytarabine, or the Hedgehog inhibitor glasdegib plus low-dose cytarabine. Or if a patient has an 

 mutation in the United States, they could be a candidate for ivosidenib as a single-agent therapy, the IDH1 inhibitor.

Once any strategy is successfully used to get a patient into a remission, whether that’s intensive chemotherapy or any of the less intensive options that I just described, a patient could be considered for a transplant if appropriate or treated with consolidation or a maintenance strategy, hopefully for as long as possible until the disease might return. In a nutshell, that’s the way to think about this. This is the way the NCCN [National Comprehensive Cancer Network] has broken down the thought process for the initial approach to this disease.

The monitoring of a patient with AML varies based on the treatment they’ve had. For instance, in a patient who’s had intensive induction chemotherapy and then gets consolidation chemotherapy, there’s usually some end of consolidation bone marrow biopsy to ensure the patient is still in a remission. Then they’re monitored, usually at 3-month intervals for about a 5-year period until they’re released and told that the thinking is they’re cured. For people who are getting less intensive regimens like venetoclax-based regimens, there’s no end date to those, so the patients typically continue those treatments indefinitely. There are different ways to monitor this. Some people will do a bone marrow biopsy every 6 or 12 months. Some people won’t recommend a bone marrow biopsy unless the blood counts reflect some concern about disease recurrence. I don’t think there’s any right or wrong there to the monitoring of those patients. It’s not well known.

With respect to MRD [minimal residual disease], any patient who’s in a remission should be monitored for residual disease. There are many ways to do this. The most popular is with sophisticated flow cytometry–based assays to tell if there’s evidence of residual disease below the surface despite pathologists saying the patient is in a remission, which means no increased blasts in the bone marrow biopsy under a microscope and good count recovery. It’s tough to utilize this evidence in practice. We know that the presence of MRD predicts relapse, worse survival, and is a cause of concern, but we don’t know how to impact this and whether employing a treatment in the setting of MRD can eradicate MRD and improve outcomes. There’s a lot more to be done here. It’s important to monitor for this so that you can set expectations with your patients, but I don’t think we’re at the point where we would make recommendations based on interventions based on the presence or absence of MRD.

BCL2 is a very important protein in the everyday existence of almost every cell in the body. As we all learned as undergraduates, in medical school, and in professional school, cells have to make decisions as to whether they should survive on a minute-by-minute basis based on the environment, what type of cell they are, what they’re doing, etc. It’s a very complicated dance that they’re always doing to decide, “Should we survive or should we die?”

One way that cells normally die is apoptosis. There are proteins responsible for keeping a cell alive and other proteins that are responsible for triggering apoptosis. These 2 sets of proteins are always in some degree of equilibrium. There are pro-apoptotic proteins that promote the destruction or death of a cell, and there are antiapoptotic proteins that do the opposite. BCL2 is 1 of the main antiapoptotic proteins, so its job is to prevent cell death. In cancer cells, the thinking is that this signal is inappropriately overexpressed and that BCL2 is helping cells survive when they should be dying. Cancer cells have a lot of abnormalities, mutations, and lesions. In a normal system, those would trigger cell death, but the overexpression of BCL2 is keeping that from occurring naturally. The thinking is that if you can target BCL2, then you can allow a cancer cell to appropriately die.

The other intriguing part of the mechanism of BCL2 is that for over 10 years, it has been recognized that it appears to be important in the survival of the leukemia stem cell population, the root cause of the disease. In fact, with the venetoclax-azacitidine regimen, that has been shown to specifically target and eradicate the leukemia stem cell population through a novel mechanism that doesn’t have anything to do with what I described to you before about the canonical function of BCL2 and its role in apoptosis. Nevertheless, it seems to be really intriguing. We think it may be responsible for the deep and durable remissions that we see with venetoclax-based regimens.

A hematologist details the frontline treatment options and goals in acute myeloid leukemia and describes venetoclax.

Frontline Treatment Options in AML

 Acute myeloid leukemia, or AML, is a pretty heterogeneous disease. We’ll get to some of that on the biological front. But with respect to the epidemiology, compared with other types of malignancies, it’s quite rare. There are probably around 30,000 cases a year in the United States. The risk factors for this disease are poorly understood. We think there are some environmental exposures that can cause this to occur, but those are very poorly understood. Lots of exposure to benzene in the setting of an industrial accident and radiation in large amounts are 2 examples. For the most part, we don’t know what causes AML.

There are some other risk factors that are a little more obvious. AML can evolve from an antecedent hematologic condition like MDS, or myelodysplastic syndromes. That’s a common way for AML to evolve, particularly in older patients. There are also some emerging data on some inherited genetic mutations that can prompt this. We only recently started recognizing this in the setting of some families in which this diagnosis clusters. But this is a very uncommon scenario. With respect to the prognosis, it’s very varied. With some of these new therapies that we’re going to discuss, the prognostic abilities of us to make an assessment are less accurate because of a shorter track record with some of these new therapies. The jury is out. Historically, the prognosis has been quite poor for AML, but we hope that’s changing.

At diagnosis, it’s important to collect some information from patients, because if you’re successful in getting patients into a remission, then this information will no longer be available to you. The only time you’ll have access to it is at diagnosis. Because of the importance of this information on the treatment plan on decisions such as whether a patient should get a transplant, it’s critical to get this information.

What information are we talking about? At diagnosis, you need flow cytometry, which can help make a distinction between AML and ALL [acute lymphocytic leukemia]. You need cytogenetic data, so metaphase cytogenetics is really important. There are also FISH [fluorescence in situ hybridization] panels that can be used if cytogenetics fails, or to supplement the cytogenetic data. The last is what we call molecular data, the status of any gene mutations that may be present. There are upward of 50 that are recurrently mutated in AML. There are large panels that include all 50 of these mutations that you need to send for at diagnosis because of the implications of this. This is all recommended by the NCCN [National Comprehensive Cancer Network]. These are the standard recommendations for the care and diagnosis of a patient with AML.

In addition to that broad spectrum genomic panel, if a patient is a potential candidate for intensive induction chemotherapy, one must have access to getting 

 mutation status within a couple of days. Because if you’re giving a patient standard induction chemotherapy, and they have a 

 mutation, it’s necessary to add in midostaurin by day 8. That’s a very important element as well.

It’s important to retest all these at relapse or suspected relapse. There are a couple of reasons for that. One is that the disease can evolve and change. Sometimes a patient who didn’t have a particular gene mutation at diagnosis develops it at relapse. That can be an opportunity for a targeted therapy. That’s one reason, because it can change the therapeutic approach. Another reason is to gain a more sophisticated understanding of how the disease has evolved and what the best course of action might be. In the relapse setting, the only curative strategy would potentially be a transplant. Typically, if a patient is a transplant candidate, regardless of the disease biology, at relapse, that’s the plan. But it’s really important to investigate that gene mutation panel in particular because the disease can evolve and mutations can come and go. That can give you some way to approach the disease that you didn’t before.

Not all patients are getting this recommended testing for a variety of reasons. In some cases, it’s a knowledge issue, knowing and understanding what needs to be collected and when. In other cases, there are reimbursement issues. There are also issues with respect to different institutions doing this differently. At some institutions, it’s the job of the pathologist. At other institutions, it’s the job of the clinician. Sometimes that hasn’t been clearly defined, because this is a rare disease. In a community-based oncology practice, they may be seeing only a few cases of AML a year. All those barriers are at play. But it’s really important to address them, because this is crucial for the effective treatment and best possible outcomes of these patients.

Daniel Pollyea, MD, MS, explains the risk factors for acute myeloid leukemia, the importance of biomarker testing, and the challenges that prevent every patient from being tested.

Biomarker Testing in AML

Daniel A. Pollyea, MD, MS, assistant professor of Medicine at the University of Colorado Cancer Center and clinical director of Leukemia Services at the CU School of Medicine, discusses how far the field of acute myeloid leukemia (AML) has come in the last 1 to 2 years.

For years, this patient population had limited treatment options with poor outcomes, according to Pollyea. Over the last few years, there has been a huge acceleration in terms of options available for these patients.

Daniel A. Pollyea, MD, MS, discusses how far the field of acute myeloid leukemia has come in the last 1 to 2 years.

Daniel A. Pollyea, MD, MS | Authors

Articles

Future of AML Management

Considerations in Choosing Venetoclax for AML

VIALE-A Trial: Acute Myeloid Leukemia

Frontline Treatment Options in AML

Biomarker Testing in AML

Overview of Advances in Recent Years for Patients With AML