Advances in AML Treatment and Research Archives

Why Is Post-Access Enrollment Vital in AML Clinical Trial Participation?

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Why Is Shared Decision-Making Important for AML Patients?

Transcript:

Lisa Hatfield:

Dr. Hantel, can you elaborate on the significance of oncologists believing that AI-based clinical decision models need to be explainable? And how might this impact AML patient care and decision-making processes?

Dr. Andrew Hantel:

Sure. So I think just taking a step back and saying you know what is AI, and what does explainability of AI even mean? So AI or artificial intelligence is essentially computer algorithms that learn to some extent like us, but in other ways differently, kind of how to process information and make decisions based on that information or make recommendations, at least.

And to some extent, like you or I, we can’t really explain “Why did I decide to have Cheerios this morning versus having like whole wheat toast or something?” It’s kind of difficult for me to say, “Oh, I just felt like I wanted to do that instead of that.” To some extent, AI also does that. It can kind of arrive at a decision after digesting a lot of different data over its lifetime to say that it prefers Cheerios versus whole wheat toast.

But it can’t necessarily tell you why it wanted one versus the other. And in medical decisions, to some extent, the same things can happen. It can’t really adequately explain to some extent why it might recommend one treatment versus another. And we like to think that in medicine, we’re making evidence-based recommendations that we choose treatment one or treatment two over treatment three, because the evidence for one and two is better for the person in front of us.

And AI can also kind of explain things some ways to that extent, but in other ways it might not know all of the other characteristics of the person that aren’t in that computer that make us think treatment one or two is better than three. And so our ability to actuallyd say, “Is the AI making this decision appropriately and able to explain why it came to decision one and two?”

If it can’t do that, we can’t actually understand whether or not it’s gone wrong and whether or not we should trust what it’s recommending. And so for that, we kind of have to create artificial intelligence models that are explainable by saying, “I’m telling you, you should choose this option versus that option because of reasons A, B, and C as they apply to this patient who is being taken care of.” And the hope is that there are ways computer scientists are using to try and get AI towards that.

But we really need to make sure that we create an AI that’s trustworthy in order for us to make you know AML patient care decisions that do better for our patients, because we know that AI is powerful, and it can bring in a lot of different data sources that are difficult for any human to make in any kind of scenario. But to be able to do that in a way that doesn’t put patients at risk and that really improves their care and improves our ability to maintain and optimize people’s health is essential. And so while AI is not kind of right now being used to make decisions in AML patient care, it’s going to be tested probably in the near future to help out with that in clinical trials and controlled settings.

And so you as a patient or somebody who is very interested in the power of AI, I would say once we start to hear about those things, it might be something that you’re interested in participating in a trial, or you’re interested in kind of learning more about that. We could come back and talk about that more. For the moment though, I think it’s just more of a risk that we’re trying to avoid of making AI that’s not explainable and potentially harms patients rather than helps them.

Lisa Hatfield:

Okay, thank you. One of the things I know in some cancer research is they are using artificial intelligence and machine learning models to help predict outcomes based on certain therapies. And I wonder if you have any comments on, because the data used is historical and real time coming in all the time, but we know there are inherent biases based on disparities in healthcare anyway from underrepresented communities. Do you think that those biases can be overcome in future models that are used to predict outcomes to treatment for different types of cancers?

Dr. Andrew Hantel:

Yes. So I think there’s a number of different biases that can come into artificial intelligence models. And it’s the same, a lot of the same biases that we have in our current clinical trials, and that historically marginalized groups have not been well-represented, either in participating in trials or in their data that’s input into these AI models. And for kind of the same reason, we don’t really know how generalizable the data that we have from the trials or from the AI really apply to those populations.

We assume because they have a lot of the other same characteristics as the people who are in the trials or kind of in these models that we can apply those data to them. But I think the push is to use both data sets and to encourage participation in trials for those communities, such that we know that these drugs and that AI are safe and effective for them.

And so there are both efforts to do that in leukemia and cancer broadly, and across healthcare even more broadly. And that can be either by working together with kind of multinational consortia of physicians and researchers to kind of pool data that includes patient populations from around the world. And the same thing is being done for trials as well as to kind of help make sure that the people who are underserved also kind of within our own communities are included in both of these processes.

Lisa Hatfield:

If a patient were to come on to you and said, “Dr. Hantel, I looked up on ChatGPT, what is the best treatment for me given these mutations or this characteristic of my disease?” What might you say to them? Would you involve that in your decision-making? Would you discuss that with them a little bit more? How would you handle that?

Dr. Andrew Hantel:

I think I would just generally be curious about you know what the actual transcript of the conversation was like. I think right now one of the major concerns for a lot of AI is that it can hallucinate things. And so there are some famous examples of lawyers putting in you know kind of briefs that they wanted to file and the AI coming up with like court cases that never existed to justify things. And so the last thing that we want is in medical decisions for people to rely on kind of made-up facts to make treatment choices.

And so, I’d be interested in kind of its medical decision-making process and kind of the data that it was able to rely on to make the decision. More from the standpoint of curiosity and education for myself to understand how patients are interacting with these things, as well as to make sure that the patient was also understanding kind of the information that was being put out and wasn’t having any misconceptions.

I think that the potential for these AI to help patients is vast in terms of their ability to understand a lot of the medical jargon and a lot of the information that’s coming at patients through portals and everything else, that could be very scary. But I also want to make sure that we’re not kind of overloading patients with what we think is an answer, but actually can come with a lot of falsehoods and harm.

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Advancements in AML Treatment | Tailoring Therapies to Individual Patients

March 24, 2024/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

Advancements in AML Treatment | Tailoring Therapies to Individual Patients from Patient Empowerment Network on Vimeo.

What are the latest AML treatment advancements? Expert Dr. Sara Taveras Alam from UTHealth Houston discusses how treatments have advanced over recent years with personalized therapies beyond a one-size-fits-all approach.

[ACT]IVATION Tip

“…patients to be really informed about all of the details of their AML and ask questions about the genetic drivers of their disease and whether or not there are medications that can target those drivers. Similarly, the decision to do a stem cell transplant or not will be driven by this, so it’s very important for the patient to be informed about all of the details of their AML, not just the fact that they have acute myeloid leukemia diagnosis.”

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AML Diagnosis | Exploring Bone Marrow Biopsy and Alternatives

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Transcript:

Lisa Hatfield:

Dr. Taveras, what are the latest advancements and treatment modalities for AML?

Dr. Sara Taveras Alam:

Well, over the last decade, there have been many new medications approved for the treatment of AML, and this has really allowed for the treatment of acute myeloid leukemia to be individualized rather than using a one-size-fits-all approach, so typically for us to decide the treatment that best suits the patient, we take into consideration patient characteristics and into consideration, their age and their fitness level, other medical problems that they may have, and we also take into consideration characteristics of the leukemia itself, so not all acute myeloid leukemia are the same, and we try to get as much information as we can about what is driving the acute myeloid leukemia to see how we can best attack it.

One of the medication groups that we have available to us over the last decade are FLT3 inhibitors, and that is a class of medication that directly targets FLT3 mutations that may be present in patients with AML, and if the patient does have a FLT3 mutation and they’re able to be started on this class of medication, they do a lot better than they would have done, say, 20 years ago without those medications being available. Similarly, we have medications that target IDH mutations, IDH1 or 2 that are options for our patients. We have less intensive chemotherapy that is more appropriate for older patients with comorbidities, perhaps maybe more tolerable than the traditional IV intensive chemotherapy.

So my activation tip for this question is for patients to be really informed about all of the details of their AML and ask questions about the genetic drivers of their disease and whether or not there are medications that can target those drivers. Similarly, the decision to do a stem cell transplant or not will be driven by this, so it’s very important for the patient to be informed about all of the details of their AML, not just the fact that they have acute myeloid leukemia diagnosis.

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Challenges in Treating TP53-Mutated AML, Hope on the Horizon

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

Challenges in Treating TP53-Mutated AML, Hope on the Horizon from Patient Empowerment Network on Vimeo.

TP53-mutated acute myeloid leukemia (AML) treatment has some challenges. Dr. Naval Daver from the University of Texas MD Anderson Cancer Center shares his perspective. Learn about promising treatments on the horizon for this AML subgroup.

[ACT]IVATION TIP from Dr. Daver: “The TP53 mutation remains the most difficult subset of acute myeloid leukemia, there is hope on the horizon with new treatments such as CD47 antibodies and targeted therapies like APR that are being looked at, and also a strong consideration for allogeneic transplant in TP53, because this seems to be the only modality associated with a good chance of cure after achieving remission with one of the frontline therapies.”

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Transcript:

Art:

Dr. Daver, what have we learned about TP53-mutated AML? And what is the takeaway for these patients?

Dr. Naval Daver:

TP53-mutated AML remains the most difficult molecular subset of all acute myeloid leukemia. Patients who have this mutation, unfortunately, do not respond well to any of the established standard care therapies, including intensive chemotherapy, the HMA alone, such as azacitidine (Onureg or Vidaza), decitabine (Dacogen) alone, or even HMA venetoclax (Venclexta) with all of these, we do see responses, especially with HMA venetoclax or intensive chemotherapy, we can see 15 to 55 percent remission rate, but the remission, very short lived, early relapses and the median overall survival across all of these currently available standards of cares are between six to 10 months.

So there has been an intense effort in the last six, seven years to develop TP53-directed therapies or therapies that will work regardless of TP53 mutation, and there are two drugs this time that are very promising and being evaluated as ongoing Phase II and Phase III studies.

One of them is an immunotherapy drug called magrolimab which seems to have very similar activity and probability with good response rates in TP53-mutated AML. This has been completed in a single arm phase 1B study in front line TP53-mutated AML where we saw close to 50 percent CR, CRI complete permission rates. And median survival was above 11 months in older unfit TP53, which is better than any survival we have seen in the past in this population.

The other study was with the oral care targeted therapy towards TP53, called APR, and this therapy was specifically designed to target the TP53 mutation, and this is being evaluated in the frontline setting in combination with a society in venetoclax. We hope that these regimens are these novel therapies, one or both of them will be able to at least incrementally improve their current outcomes in TP53.

The other area where we have really been doing a lot of research, and I think the data is suggesting, is that allogeneic transplant may work for separate, and we are routinely considering transplant in these patients in the frontline setting, once they are able to achieve remission.

My activation tip is the TP53 mutation remains the most difficult subset of acute myeloid leukemia, there is hope on the horizon with new treatments such as CD47 antibodies and targeted therapies like APR that are being looked at, and also a strong consideration for allogeneic transplant in TP53, because this seems to be the only modality associated with a good chance of cure after achieving remission with one of the frontline therapies.

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A Look at Ongoing Acute Myeloid Leukemia Phase III Trials

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Clinical Trials, Access, and Health Disparities, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

A Look at Ongoing Acute Myeloid Leukemia Phase III Trials from Patient Empowerment Network on Vimeo.

What are the acute myeloid leukemia (AML) Phase III clinical trials that are ongoing? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center shares his perspective about encouraging trials. Learn about the MORPHO Study and others.

[ACT]IVATION TIP from Dr. Daver: “The maintenance with gilteritinib and the MORPHO Study, as well as the relapsed refractory study as well as the use of a e-selectin inhibitor called uproleselan, and hopefully this will lead to approval of the next batch of three or four drugs, which will further improve outcomes for frontline as well as relapsed AML.”

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Transcript:

Art:

Dr. Daver, can you speak to some of the ongoing Phase III trials in AML, what are you most excited about?

Dr. Naval Daver:

This time there are numerous ongoing phase three in acute myeloid leukemia, some in the frontline, some in the relapse setting. In the frontline setting, the ones that I’m most excited about are trials incorporating a novel immunotherapeutic pathway called the CD47 antibody that works to activation of macrophages, these are looking at a very high-risk molecular group of acute myeloid leukemia, the TP53 in adverse cytogenetics, and there are two randomized phase threes with this agent, one focused on TP53 mutated AML looking at the azacitidine and magrolimab versus the current standard of care FDA-approved azacitidine-venetoclax (Onureg or Vidaza-Venclexta) in TP53 mutated.

The other is actually looking at all older unfit AML so trying to improve on azacitidine venetoclax doublet with a triplet, so this is looking at azacitidine venetoclax magrolimab versus azacitidine-venetoclax placebo so if both of these trials are positive, then this will lead to incorporation of immunotherapy in the frontline setting in AML, which is exciting and something we’ve been working towards for the last 10, 15 years.

The other Phase III trials in the frontline setting or in the maintenance setting really that I’m excited about is called the MORPHO Study…this is using a FLT3 inhibitor gilteritinib (Xospata) as a maintenance post-transplant, so we know FLT3-mutated patients respond well, when they receive intensive induction FLT3 inhibitor, we still need to take them to transplant because even though the initial response is good, many can relapse.

So we actually try to give to the cycles of intensive induction for the move to transplant, and then if we start there, we still see at about 40 percent of these patients can relapse in the next three years, so this has led to efforts to add a maintenance FLT3 inhibitor gilteritinib single agent post-transplant as a maintenance for one to two years versus placebo observation, which has historically been a standard of care, and so this is being looked at a large multi-center called the MORPHO Study that we hope to get data from in the near future.

Another study in the similar design that’s being done by the UK cooperative group is looking at maintenance with the oral azacitidine, post-transplant for non-FLT3, so similarly, can we overall improved outcomes not just for FLT3, but the general patient population is going to transplant by using the maintenance oral azacitidine post-transplant versus placebo.

And in the relapse setting, there is a very novel unique oral therapy drug called uproleselan, which is an e-selectin inhibitor, and this agent is now being combined with traditional salvaged chemotherapy such as FLAG-Ida mec versus the placebo mec plus FLAG-Ida or mec in the relapse setting.

And that’s what he’s actually been completed to enrollment, and we’re hoping to hear data from that in the near future. So these are the major randomized studies focusing on TP53, FLT3, and relapsed refractory AML that we’re looking for in the near future and hopefully could lead to two or three more new approvals in the AML space.

My activation tip for this question is that there are ongoing numerous frontline Phase III as well as relapsed refractory Phase III, targeted immunotherapy approaches, specifically among these we’re excited about the CD47 antibodies. The maintenance with gilteritinib and the MORPHO Study, as well as the relapsed refractory study as well as the use of a e-selectin inhibitor called uproleselan, and hopefully this will lead to approval of the next batch of three or four drugs, which will further improve outcomes for frontline as well as relapsed AML.

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What Does Triplet Therapy in AML Mean for the Future?

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

What Does Triplet Therapy in AML Mean for the Future? from Patient Empowerment Network on Vimeo.

What do acute myeloid leukemia (AML) patients need to know about triplet therapy? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center shares his perspective. Learn about the meaning, progress, and outlook for triplet therapy.

[ACT]IVATION TIP from Dr. Daver: “Some of the early data with the FLT3 inhibitor as well as the CD47 antibody triplets are showing very, very promising activity and are now moving into larger multi-center and randomized studies.”

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Transcript:

Art:

Dr. Daver, what does triplet therapy in AML mean for the future?

Dr. Naval Daver:

So when we say triplet therapy, what we’re really thinking about is building on the existing FDA-approved combination of HMA venetoclax (Venclexta), so as a background venetoclax, showed a CR, CRI which is a complete remission rate of about 70 to 75 percent with the median survival in 15 months.

This was in older patients, about 75 years in age, those who were not considered fit for intensive chemotherapy, although this was a major step forward in comparison to what we have seen with traditional low intensities with azacitidine (Onureg or Vidaza), decitabine (Dacogen) alone, we do see the three-year survival is about 25 to 30 percent.

So this is progress compared to 10 percent long-term survival, we used to get a decade ago, but, of course, we want to improve on that. Also, a molecular analysis of data has shown that there are certain molecular subsets that don’t respond as well to azacitidine, venetoclax or if they respond they relapse quickly these include FLT3 mutated and the TP53 mutated as well as potentially MLL rearranged.

And so here we have started incorporating the targeted therapies like inhibitors like the menin inhibitors like CD47 antibodies to target those specific high-risk or bad molecular cytogenetic groups, and we are seeing that with the combinations of these three drugs, especially for those particular molecular subsets.

So azacitidine and venetoclax for FLT3 inhibitor for FLT3 mutator, azacitidine, and venetoclax, magrolimab for TP53 mutated, the response rates that we’re getting, as well as the depth of response and the early trends towards survival are looking very, very promising compared to what we have seen with azacitidine venetoclax alone.

So we believe, and I personally believe that these three drug combinations, the so-called triplets will actually be eventually the way to go forward now, that means that one has to realize that when you add a third drug, there is a cumulative myelosuppression, azacitidine-venetoclax is already a myelosuppressive regimen.

Yes, it’s manageable, but it is myelosuppressive. And the third drug, this can become more cumulative, so we have been working for the last three, four years and continue to work on those optimization because since we are seeing true synergy but pre-clinically and what we think in the clinic, we are not needing to give full doses and we’re doing reduced durations of venetoclax and those with FLT3 inhibitor, and now we feel that some of those triplets are actually giving very, very, very good efficacy.

There’s a lot of discussion in the community of whether we need to combine all two drugs up front or can be sequence these drugs or can we introduce a targeted therapy based on a molecular escape, and I think a lot of these will have to be evaluated and many of these are being looked at in various trials, but I do think the bottom line is that bringing in your targeted therapy or immunotherapies early on in the frontline setting and some way or the other is probably where you’re going to get the most bang for the buck and the most benefit in curing patients long-term rather than trying to reserve them for the salvage, because in salvage AML historically, nothing has really been able to improve the long-term cure rate significantly.

So the activation tip for this question is that now with the identification of certain molecular subsets that have poorer outcomes with the HMA venetoclax, we have started incorporating targeted and immunotherapies in the earlier settings, either up front in the three drug combination or an early sequential approach.

And we believe that with such combinations, we may be able to achieve deeper remission and longer responses. Some of the early data with the FLT3 inhibitor as well as the CD47 antibody triplets are showing very, very promising activity and are now moving into larger multi-center and randomized studies.

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A Look at Lower Intensity Chemotherapy in Untreated AML

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

A Look at Lower Intensity Chemotherapy in Untreated AML from Patient Empowerment Network on Vimeo.

Dr. Naval Daver from the University of Texas MD Anderson Cancer Center discusses whether untreated acute myeloid leukemia (AML) can be treated with lower intensity chemotherapy.

[ACT]IVATION TIP from Dr. Daver: “Ask your physician and your oncologist when you’re talking with them about what all the newest therapies are and what would be specifically the best treatment for their specific leukemia with respect to the different mutations.”

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Transcript:

Art:

Dr. Daver, what are we learning about patients with untreated AML who are ineligible for intensive chemotherapy? Will intensive chemotherapy, a thing of the past, in the near future?

Dr. Naval Daver:

There has been a major shift over the last four or five years towards using lower intensity combinations, such as azacitidine (Onureg or Vidaza) and venetoclax (Venclexta) and patients who are definitely about 75 and not fit for intensive induction. I don’t think anybody debates in that population, but even in patients 60 to 75 years away, you are borderline, and maybe we could give intensive induction chemotherapy and get patients to through it with support of care, antifungals, antibiotics by close monitoring, but we’re seeing similar remission rates with azacitidine (Vidaza), venetoclax (Venclexta), much less toxicity, less mortality, and especially the goal is to get a number of these patients to allogeneic stem cell transplant, which it is.

Then we feel that the lower intensity, better tolerated, smoother remission getting patients in a good condition an allogeneic transplant may be the way to go now, of course, to really make the standard of care, we have to look at this in a randomized fashion to make sure that what we believe is actually what the data is going to confirm, so there is an ongoing randomized study looking at the azacitidine and venetoclax intensity versus the traditional intensive chemotherapy called three plus seven in patients 18 to 65 years of age, and that…then you will, I think, give us a lot of information and data as for whether we can start for placing intensive chemotherapy for a large proportion or majority of AML patients, even those who are younger.

Today, I don’t think that in terms of chemotherapies are a thing of the past, I think those patients who are below 60 or even those who are 60 to 65, who are routinely doing intensive induction chemotherapy, one has to realize that the five-year survival for many molecular subsets are close to 50 to 60 percent with intensive induction chemotherapy, whereas with HMA venetoclax in the older unit, we’re looking at three to five-year survival rates of about 30 percent, so we have still not seen data and younger patients with Hamas to be convinced that this will replace intensive chemotherapy altogether, I think the signal suggests that there is a potential for it to do so, especially with the use of allergenic tensor as plan, which we’re using quite frequently and…or maintenance.

But that has not yet been established. So I would still say we do use intensive chemo in those who are young and fit, so my activation tip for this is that there has been a lot of progress in the lower intensity therapies over the last six or seven years.

A decade ago would not even be asking whether there’s anything that can replace intensive chemo today we do have data with HMA venetoclax that suggest that it may be as good as intensive chemo looking at the response rates MRD negativity, and especially with three drug combinations where adding targeted therapies to HMA venetoclax, those response rates and depth of response looking as good, if not better, than intensive chemo there are randomized studies ongoing that are going to be looking at intensive chemotherapy versus HMA venetoclax and if those show equivalents or superiority for HMA venetoclax, I think in the next five, six years there will be a huge shift towards less use of intense and chemotherapy in the frontline setting, but we’re not there yet.

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A Look at Treatment Strategies for High-Risk AML Patients

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

A Look at Treatment Strategies for High-Risk AML Patients from Patient Empowerment Network on Vimeo.

What acute myeloid leukemia (AML) treatments are available for high-risk patients? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center discusses various mutations, potential for cure, and clinical trials. Learn about the outlook for high-risk AML treatments.

[ACT]IVATION TIP from Dr. Daver: “The best way to get up to these agents is to go on clinical trials and incorporate these therapies, both in the frontline setting as well as in the relapsed refractory setting.”

What Are Some Clinical Predictors for Relapse in Acute Myeloid Leukemia?

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Transcript:

Art:

Dr. Daver, what treatment strategies are available for high-risk AML patients?

Dr. Naval Daver:

High-risk AML patients includes a group of a number of different mutations, and cytogenetic abnormalities, this includes TP53 mutation, as well as adverse cytogenetics, which includes chromosome 17, deletion 5, deletion 7, as well as complex carrier type. This entire group historically had a poor outcome and has had limited responses to traditional intensive chemo, even if we achieve responses there, usually short-lived.

We do have some patients where we are able to achieve remission with intensive chemo or with azacitidine-venetoclax (Vidaza-Venclexta) and transition and transmission them transplant with about 25 to 30 percent potentially achieving a long-term remission and possible cure.

But aside from that, there is very little potential to cure these patients with just traditional intensive chemo, venetoclax in this area, there has been developments with the emergence new class of immunotherapy drugs, called CD47 antibodies, the one that’s most advanced in this field is a drug called magrolimab, and we are evaluating the drugs such as magrolimab in combination with azacitidine as well as in combination with azacitidine-venetoclax and are seeing high remission rates, both in TP53 mutated and TP53 wild type.

So this pathway that works by activating a macrophages or the immune system to attack the tumor cells, seems to be in some way mutation agnostic with response rates being maintained even in the traditional high-risk subsets, especially such as TP53 and complex cytogenetics for some of the other high-risk groups such as MLL, we’re using targeted therapies like menin inhibitors, and these seem to work well in those patients who have these adverse cytogenetic molecular abnormalities, so there is progress, and we think that the CD47 antibody field and hopefully the main inhibitor feed will be able to improve outcomes in these traditionally molecular cytogenetic subsets.

My activation point related to this question is for high-risk mutations and cytogenetic commonalities such as TP53 complex carrier chromosome 17 MLL, best hope at this time is in clinical trials evaluating novel therapies such as CD47 antibodies and menin inhibitors. These are not yet FDA-approved, but based on emerging data from the ongoing Phase I, II studies, we think that there is a good chance they will be approved in the future.

However, this time, the best way to get up to these agents is to go on clinical trials and incorporate these therapies, both in the frontline setting as well as in the relapsed refractory setting.

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Why Is the Menin Pathway Important in AML?

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

Why Is the Menin Pathway Important in AML? from Patient Empowerment Network on Vimeo.

What should acute myeloid leukemia (AML) patients know about the menin pathway? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center shares information from ASH 2022. .Learn research updates about the menin pathway and ongoing clinical trials on the pathway.

[ACT]IVATION TIP from Dr. Daver: “Patients should be checked for arrangements like MLL rearrangement NPM1 mutation, new fusions as these may be amenable to therapy with the menin inhibitors, there are multiple trials with five different menin inhibitors, single agent trials and also combination trials now ongoing across multiple centers both in the U.S. and ex-U.S.“

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Transcript:

Art:

Dr. Daver, what is a menin pathway in AML? And why is it significant?

Dr. Naval Daver:

The menin pathway is very recently discussed that way, the pathway, of course, itself has been known for almost a decade, this is an epigenetic pathway, and in certain subsets of AML such as MLL rearranged NPM1 mutated as well as other fusions, we find that there is an up regulation of the menin impact rearrangement, and this actually results in increased production of two enzymes called meis-1 and hox-DNA) these enzymes actually result in a differentiation blockade. So normally, in the bone marrow we have the early progenitor cells, this then leads to be a report cell and leads to mature neutrophils and monocytes and blood cells, but in a differentiation blockade, we would see that those cells over time would start generating mutations and become leukemic cells.

So one of the most physiological ways to treat AML is to actually remove the differentiation blockade, so the normal process of differentiation with progress, and so these menin inhibitors are able to reduce the levels of MEIS1 and HOXA by doing this, they allow the normal differentiation cascade to progress, and they’re not cytotoxic targeted chemo, they’re not directly killing leukemia, but they’re actually allowing the leukemia itself to then mature to no monocytes and neutrophils.

And so now there are five different menin inhibitors in ongoing clinical trials, but two of these are more advanced and have shown data recently in the ASH 2022 meeting the newer drugs, and are showing close to 40 to 50 percent single agent efficacy, and we believe that after the FLT3, IDH1, IDH2 inhibitors, which have been approved in the last five years, the menin inhibitors are probably the next other targeted therapies that will hopefully get approval and they eventually be used in the frontline setting in combination approaches.

The activation tip related to this question is that patients should be checked for arrangements like MLL rearrangement NPM1 mutation, new fusions as these may be amenable to therapy with the menin inhibitors, there are multiple trials with five different menin inhibitors, single agent trials and also combination trials now ongoing across multiple centers both in the U.S. and ex-U.S., and if one does have an aberration that will be sensitive to such menin inhibitor-based therapy, I would strongly recommend considering trying to get on one of those trials because we believe that these will be the best outcomes with such standard therapies rather than using the standard or traditional chemotherapies.

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The Importance of the FLT3 Mutation in AML

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

The Importance of the FLT3 Mutation In AML from Patient Empowerment Network on Vimeo.

What do acute myeloid leukemia (AML) patients need to know about FLT3 mutation? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center discusses considerations about the mutation. Learn about the incidence of the FLT3 mutation, risk of relapse, and treatment options.

[ACT]IVATION TIP from Dr. Daver: “ it is very important to know the status of the FLT3 the mutation, both in diagnosis to see if one would benefit by the addition of the FLT3 inhibitor to the frontline induction chemo as well as in relapse because this would open up the option for FLT3 inhibitor targeted therapies, which would probably have the best chance of response and long-term outcomes.“

What Is FLT3-Mutated Acute Myeloid Leukemia?

Related Resources:

A Look at Treatment Strategies for High-Risk AML Patients

Challenges in Treating TP53-Mutated AML, Hope on the Horizon

Transcript:

Art:

Dr. Daver, for AML with a FLT3 mutation, what have we learned, and what is currently being investigated?

Dr. Naval Daver:

AML with the FLT3 mutation is very important from both prognostic and from therapy perspective, prognostically, this is considered to be one of the high-risk mutations, it’s also one of the most frequent mutations in AML in, seen in about 30 to 35 percent of younger and about 15 to 20 percent of older patients with AML, and these patients often have very prolific disease, elevated white count leukocytosis. And without the addition of FLT3 inhibitors, there is a high risk of relapse and a short overall survival.

Over the last 15 years, a number of targeted therapies called the FLT3 inhibitors have emerged, these started with the first-generation FLT3 inhibitors drugs, such as lestaurtinib and sorafenib (Nexavar), now we have the second-generation FLT3 inhibitors, this includes drugs like gilteritinib (Xospata), quizartinib, and crenolanib which are more potent, specific, and better tolerated.

The first study that showed that the incorporation of FLT3 inhibitors improves outcome was a study called RATIFY Study, this is a frontline study looking at newly diagnosed FLT3 mutated younger patients where we added the FLT3 inhibitor midostaurin (Rydapt or Tauritmo), which is the first-generation FLT3 inhibitor to the standard induction chemo versus a placebo, added to standard induction chemo, induction chemo being standard of care to that time and this showed that in the addition of FLT3 inhibitor to induction chemo did improve remission rates and overall survival as compared to induction, and led to the approval of the FLT3 inhibitor midostaurin in the frontline setting.

Since then, two other FLT3 inhibitors, second-generation potent FLT3 inhibitors drugs called gilteritinib, and lestaurtinib have also been evaluated. Gilteritinib, in a relapsed setting where single-agent gilteritinib, has given 50 to 60 percent response rates and has been extremely well-tolerated and much better than any other salvage treatment in the FLT3 space that we have ever seen, and in the frontline setting quizartinib and second-generation inhibitor also very recently, just a few months ago, there was data showing the combination of his art with intensive chemotherapy improved survival as compared to intensive chemotherapy alone.

And so we think we are…they will be a third for the inhibitor to get approved, so there’s been a lot of progress overall in the three space, and there are other newer FLT3 inhibitors also in early clinical investigation that we think could eventually be as part or even better, the activation point related to this question is that, for the inhibitors have dramatically improved outcomes, both in the frontline setting when added to traditional backbone intensive chemotherapy as well as potentially lower intensity therapy, as well as in the relapsed refractory setting, and it is very important to know the status of the FLT3 the mutation, both in diagnosis to see if one would benefit by the addition of the FLT3 inhibitor to the frontline induction chemo as well as in relapse because this would open up the option for FLT3 inhibitor targeted therapies, which would probably have the best chance of response and long-term outcomes.

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AML Treatment Approaches Expand for Older and High-Risk Patients

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

AML Treatment Approaches Expand for Older and High-Risk Patients from Patient Empowerment Network on Vimeo.

How have acute myeloid leukemia (AML) treatment approaches expanded for older and high-risk patients? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center shares insight about additional treatment options. Learn about the potential for long-term cures for these patient groups.

[ACT]IVATION TIP from Dr. Daver: “There is a dramatic progress, especially in the treatment of older unfit AML with the approval of the azacitidine-venetoclax combination.”

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Transcript:

Art:

Dr. Daver, for older and high-risk AML patients, how are the treatment approaches expanding?

Dr. Naval Daver:

In older and high-risk AML, the major approval has been the combination of azacitidine (Onureg or Vidaza) and venetoclax (Venclexta), which is a BCL-2 inhibitor, the regimen was evaluated in a large Phase III study called the VIALE study, where we looked at the standard of care for the last two decades for older unfit AML, which azacitidine alone versus the combination of azacitidine and venetoclax and this combination showed a three times higher remission rate, 75 versus 28 percent overall remission rate as well as an improvement in overall survival and long-term survivors.

So this has led to great progress with now remission rates of 75 percent achievable in older unfit AML and many of them being durable at three years with ongoing follow-up, so this has really opened the door for us to be able to treat patients up to 75, 80, 85 years of age with effective therapy given the three parts of these to achieve remission, which is usually associated with freedom from transfusion improvement, quality of life, improved energy, less time in the hospital, less infections.

The other progress now is coming from the use of targeted therapies as well in these populations, and even though the HMA venetoclax or azacitidine combination is doing very well.

We now have data, in fact, from the ASH 2022 December meeting that at three years, about 25 percent or so I would still remain alive with azacitidine was even or 8 percent, now it’s 25 percent. But, of course, we want to do much better than that, and so this is where we are incorporating the targeted therapies, the FLT3 inhibitors, the IDH1, IDH2 inhibitors, menin inhibitors, and immunotherapies onto the backbone of azacitidine-venetoclax, which we hope will further improve that long-term survival cure from 25 to hopefully 50 to 60 percent and beyond.

So a lot of progress, you know, going from less than 10 percent, a 30 percent survival, long-term, and I think in the next few years, even up to 50 percent with some of these new combinations. The activation tip related to this question is that there is a dramatic progress, especially in the treatment of older unfit AML with the approval of the azacitidine-venetoclax combination.

This regimen is now giving high remission rates, which approximate remission rates that are seen with traditional intensive chemotherapy without the mucositis and toxicities and better volatility, and we are now working to further improve the remission and the durability of this dominant of initial.

…potentially adding targeted therapy such as FLT3 inhibitors, IDH1, IDH2 menin inhibitors, and we think that potentially in the next decade, we could be achieving long-term cures in a large proportion of older unfit AML, which was something one could just dream of a decade ago.

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What Promising AML Treatments Are Available for Newly Diagnosed Patients?

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

What Promising AML Treatments Are Available for Newly Diagnosed Patients? from Patient Empowerment Network on Vimeo.

What do newly diagnosed acute myeloid leukemia (AML) patients have for promising treatment options? Dr. Naval Daver from the University of Texas MD Anderson Cancer Center discusses progress in available treatments. Learn about therapies determined by key factors.

[ACT]IVATION TIP from Dr. Daver: “It’s very important to really consider all the available treatment options and if needed to seek consultation with an expert or academic center to get the most up-to-date treatments available for AML.“

What AML Treatment Options Are Available for MRD-Positive Patients?

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A Look at Ongoing Acute Myeloid Leukemia Phase III Trials

Transcript:

Art:

Dr. Daver, for newly diagnosed AML patients, what are the latest and most promising available therapies?

Dr. Daver:

For newly diagnosed AML at this time, the most promising agents include targeted therapies and BCL-2 inhibitor treatments, these are non-chemotherapeutic drugs, and we’ve seen great progress in the application of these as well as recent FDA approvals.

So one of these is an agent called venetoclax (Venclexta), which is a BCL-2 inhibitor and venetoclax in combination with hypomethylating agents such as azacitidine (Onureg or Vidaza) has shown a response to close to 75 percent.

And the nice thing is that this regimen can be given and patients who are older than 70, 75 years of age, and even those who are having comorbidities are not fit for traditional intensive chemotherapy with similar response rates, so this has been approved in the last couple of years for the frontline treatment of AML, and we’ve been using this combination of venetoclax and azacitidine quite frequently with high efficacy in this patient population, the other new agents that have shown breakthroughs in AML are the targeted therapies, these include FLT3 inhibitors that target the FLT3 mutation and these have shown good activity, but the single agents with gilteritinib (Xospata) being approved in the relapsed refractory setting as a single agent where gilteritinib showed a response rate of about 50 percent as a single oral targeted therapy in relapsed FLT3-mutated AML, which is actually better than the response rate with high-dose combination more where the response rate is only about 25 to 30 percent.

So, gilteritinib is now approved, and it’s now moving and being evaluated in frontline setting other FLT3 inhibitors like lestaurtinib (CEP-701), actually just recently completed frontline studies showing improved outcome when lestaurtinib added to intensive chemo versus just intensive chemo in FLT3 in AML. And we hope and think there’s a good chance lestaurtinib will be approved in the near future.

And also IDH inhibitors have been approved both in the relapsed setting, frontline setting, and now we even have a third group of targeted therapy is called the menin inhibitors, they target MLL rearrangement and NPM1 mutations, which are seen in about 15 percent to 20 percent of the AML, so there’s been a lot of progress.

All of this in the last seven years, six, seven years with multiple targeted therapies, with multiple inhibitor-based treatments, showing progress in AML and then also recently, the concept of maintenance therapy, this is something we used for the last couple of decades in a acute lymphoblastic leukemia and multiple myeloma and in lymphoma.

But we had not had clear data in AML, but the recent study using oral formulation of a azacitidine in CC486 has shown the maintenance in patients who complete an induction consolidation and could not go to allogeneic stem cell transplant for one reason or the other was important and improve both overall survival and relapse-free survival, and so this is the first time now we have an FDA-approved and standard use of maintenance therapy after the traditional induction consolidation, so even changing the general paradigm of AML therapy.

So a lot has changed in the last seven to eight years in the treatment of acute myeloid leukemia, and this is very exciting.

And the activation tip related, this question is that there are multiple new targeted and low intensity therapeutic options available for patients with acute myeloid leukemia, and in our institution, in my opinion, even older patients are eligible for some form of therapy or the other…very few patients, if any, today, are being sent to hospitals or palliative care without treatment.

So it’s very important to really consider all the available treatment options and if needed to seek consultation with an expert or academic center to get the most up-to-date treatments available for AML.

Share Your Feedback About [ACT]IVATED AML

What Is FLT3-Mutated Acute Myeloid Leukemia?

February 1, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

What Is FLT3-Mutated Acute Myeloid Leukemia? from Patient Empowerment Network on Vimeo.

Some acute myeloid leukemia (AML) patients may have an FLT3 mutation. Dr. Catherine Lai from Penn Medicine shares insight about the two types of FLT3 mutation, treatment options for FLT3-mutated AML, and progress in research

[ACT]IVATION TIP from Dr. Lai: “Ask your oncologist, if your FLT3 mutation testing was done, ask which type of mutation they have, if it’s the ITD or TKD, if they are FLT3-positive and what the drug options are available for them.”

The Importance of the FLT3 Mutation In AML

Related Resources:

Challenges in Treating TP53-Mutated AML, Hope on the Horizon

BIPOC Patients Living with AML | Mortality Rate and Favorable Genetics

Transcript:

Art:

Dr. Lai, what is FLT3 mutated AML and what treatment options do patients with FLT3 AML have?

Dr. Catherine Lai:

Yeah, so FLT3, FLT3 mutations occur in about 25 percent to 30 percent of patients. There are two different types of FLT3 mutations. There’s a FLT3, the ITD mutation and the FLT3, the TKD mutation. They just are there, different parts of the mutation on different parts of the cell, and so how I think about that is, if you think of a leukemia cell and each leukemias has a different color-coded flag, and so the FLT3 mutation I think of is just having a specific color coding, and while a FLT3 mutation in general does predict for a worse prognosis for patients, we do have targeted treatments. In a newly diagnosed setting, we have midostaurin (Rydapt), which is added to intensive chemotherapy for those fit enough to tolerate it.

And in the relapsed refractory setting, we have a medication called gilteritinib (Xospata), which is given as a single agent, so a chemo pill, and that was compared to all types of chemotherapy, both intensive and low intensive chemotherapy, and that pill alone and the refractory and relapsed setting was better than either of the chemotherapies alone, so we’ve made a lot of progress for the FLT3-mutated patients to the majority of those patients end up going to transplant if possible, and so there are studies that are looking at FLT3 inhibitors in the post-transplant setting to also help improve long-term survival and overall survival. So the activation tip from that standpoint, that is to ask your oncologist, if your FLT3 mutation testing was done, ask which type of mutation they have, if it’s the ITD or TKD, if they are FLT3-positive and what the drug options are available for them.

Share Your Feedback About [ACT]IVATED AML

What Are the Latest Acute Myeloid Leukemia Therapies?

January 31, 2023/in [ACT]IVATED AML, Acute Myeloid Leukemia, Advances in AML Treatment and Research, AML Activated, AML Activated Experts, AML Newly Diagnosed, AML Programs, AML Programs New, AML Treatments and Clinical Trials, AML Video ND, AML Video TC /by Kara Rayburn

What Are the Latest Acute Myeloid Leukemia Therapies? from Patient Empowerment Network on Vimeo.

What are the latest treatments in acute myeloid leukemia (AML)? Dr. Catherine Lai from Penn Medicine discusses the increase in available AML treatments. Learn about combination therapies and treatment options for patients with IDH1, IDH2, and FLT3 mutations.

[ACT]IVATION TIP from Dr. Lai: “Ask your physician and your oncologist when you’re talking with them about what all the newest therapies are and what would be specifically the best treatment for their specific leukemia with respect to the different mutations.”