Tag Archive for: Magrolimab

Emerging AML Treatment Classes Showing Promise

Emerging AML Treatment Classes Showing Promise from Patient Empowerment Network on Vimeo.

What therapies are in development for acute myeloid leukemia (AML)? Dr. Ann-Kathrin Eisfeld discusses the latest research for AML treatment, including menin inhibitors and CAR T-cell therapy.

Dr. Ann-Kathrin Eisfeld is Director of the Clara D. Bloomfield Center for Leukemia Outcomes Research at The Ohio State University and a member of the Leukemia Research Program at the OSUCCC – James. Learn more about Dr. Eisfeld.

See More From INSIST! AML

Related Resources:

Emerging AML Treatments: What Is Menin Inhibitor Therapy

AML Treatment Approaches | Factors That Impact Options

AML Targeted Therapy: How Molecular Test Results Impact Treatment Options

Transcript:

Katherine Banwell:

Are there therapies in development that are showing promise for patients with AML? 

Dr. Eisfeld:

There are so many of those. It’s hard to count. And this makes me very happy. There are exciting and again, targeted drugs.  

Once drug class is called menin inhibitors, which we – which were just published that show high promise.  

And again, very difficult to treat several groups of patients who harbor chromosome changes in MLL genes in here. So, that is a very exciting option.  

And there’s very exciting treatments with respect to what you call antibodies – monoclonal antibodies that attacks the surface proteins that are being checked regularly. And one of those, for example, is called magrolimab. And that has even promise in these high-risk leukemias or adverse risk leukemias.  

And then we are not there yet, but I’m sure we will be in the not too near future. There are also multiple trials that are looking at what we call CAR-T cells. But patients might have heard about for lymphomas or acute lymphoblastic leukemias. AML is a little more tricky with respect to those. 

But we’ve seen pre-clinical studies that look really exciting. And I think it’s just going to be just a little more fine-tuning to make those easier, available, and more targeted for AML patients. And I’m very much looking forward to seeing those come more onto the market.     

Katherine Banwell:

You mentioned the new menin inhibitors. Who are they right for?  

Dr. Eisfeld:

We try to find out more, but definitely for patients that have been shown to be beneficial for patients who have chromosomal and rearrangements of the MLL gene or KMT2A gene. And there’s also good data on patients who have NPM1 mutations.  

Even though we know – and these are mutations who harbor this kind of genetic change – have now a plethora, which is a great, of treatment options. 

Because we know even conventional chemotherapy has been working decently well in them. We know that venetoclax also is supposed to work very well in them. But again, the data on the menin inhibitor with respect to NPM1 mutations is very exciting. 

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

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.”

Download Resource Guide

Download Resource Guide en español

See More from [ACT]IVATED AML

Related Resources:

What Are the ASH 2022 Takeaways for AML Patients

What Are the ASH 2022 Takeaways for AML Patients

Why Is the Menin Pathway Important in AML

Why Is the Menin Pathway Important in AML?

What Is MRD-Positive Acute Myeloid Leukemia

What Is MRD-Positive Acute Myeloid Leukemia?

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. 

Share Your Feedback About [ACT]IVATED AML

A Look at Ongoing Acute Myeloid Leukemia Phase III Trials

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.”

Download Resource Guide

Download Resource Guide en español

See More from [ACT]IVATED AML

Related Resources:

What Are the ASH 2022 Takeaways for AML Patients

What Are the ASH 2022 Takeaways for AML Patients?

Why Is the Menin Pathway Important in AML

Why Is the Menin Pathway Important in AML?

A Look at Lower Intensity Chemotherapy in Untreated AML

A Look at Lower Intensity Chemotherapy in Untreated AML

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. 

Share Your Feedback About [ACT]IVATED AML

A Look at Treatment Strategies for High-Risk AML Patients

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.” 

Download Resource Guide

Download Resource Guide en español

See More from [ACT]IVATED AML

Related Resources:

What Are Some Clinical Predictors for Relapse in Acute Myeloid Leukemia

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

Assessing Untreated AML Patients Who Are Ineligible for Intensive Chemotherapy

Assessing Untreated AML Patients Who Are Ineligible for Intensive Chemotherapy

What Does Triplet Therapy in AML Mean for the Future (2)

What Does Triplet Therapy in AML Mean for the Future?

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. 

Share Your Feedback About [ACT]IVATED AML

AML Research Updates: News From ASH 2020

AML Research Updates: News from ASH 2020 from Patient Empowerment Network on Vimeo.

AML expert Dr. Jeffrey Lancet shares the latest news from the 2020 American Society of Hematology (ASH) annual meeting. Dr. Lancet sheds light on headlines from the meeting including FLT3 inhibitor research, combination therapies with venetoclax, a promising inhibitor therapy, and shares his optimism about the future of AML treatment.

Dr. Jeffrey Lancet is Chair and Program Lead in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, FL. He is nationally and internationally recognized for his clinical research in the field of acute leukemias. Learn more about Dr. Lancet, here.

Download Program Resource Guide

See More From INSIST! AML

Related Resources:

Navigating AML Treatment Decisions

New AML Therapies vs. Traditional Chemotherapy: What’s the Difference?

Transcript:

Katherine:      

Hello, and welcome. I’m Katherine Banwell. Today we’ll discuss the latest news from ASH 2020 and how AML patients can advocate for personalized care. Joining me is Dr. Jeffrey Lancet. Welcome. Would you please introduce yourself?

Dr. Lancet:                   

Hi, sure. My name is Dr. Jeff Lancet. I’m at the Moffitt Cancer Center in Tampa, Florida, where I am the Chair of the Malignant Hematology Department. We spend a lot of time treating patients and conducting clinical trials of Acute Myelogenous Leukemia.

Katherine:                   

Okay. Thank you. Dr. Lancet, the American Society of Hematology Annual Meeting just closed. What are the AML headlines from this year’s meeting?

Dr. Lancet:                   

Yeah, so as usual, AML was a very busy area for clinical presentations this year at the ASH meeting focusing largely on novel and targeted therapies.

I don’t believe that there were many practice changing developments per se, but rather discussions about many promising therapeutic strategies that are still under development and moving forward rapidly largely in the areas of targeted therapy, low intensity therapy, measurable residual disease and things of that nature.

Katherine:                   

What does this research news mean for patients?

Dr. Lancet:                   

Well, I think that there’s a lot to be encouraged about and maybe I’ll take the time to review some of the highlights in what was presented with respect to some of the novel therapeutic approaches that many of our patients can look forward to receiving in the not too distant future.

So, we often talk about you know, targeted therapies and, of course, one of the major targets over the years has been that of mutated FLT3 which is one of the most common mutations in AML.

And at this meeting we saw several presentations on clinical trials resolved to utilizing inhibitors of FLT3, with some emphasis on the most recently approved second generation drug called gilteritinib.

There were I thought three major presentations focusing on gilteritinib and one was an update on a randomized Phase III trial comparing gilteritinib plus azacitidine versus azacitidine alone in newly diagnosed unfit for induction chemotherapy patients with FLT3 mutations, preliminarily showing good tolerability and high composite complete response rates in the combination on.

There was another trial of gilteritinib plus venetoclax in relapsed and refractory FLT3 mutated AML.

And what was interesting was that a very high percentage of patients achieved response with this combination of gilteritinib plus venetoclax, many of whom were heavily pretreated previously and many of whom had also gotten prior FLT3 inhibitor therapy during an early stage of the disease. So, the combination of gilteritinib and venetoclax and this more refractive study, it was encouraging to see these promising responses.

And then we saw some data reporting the effects of gilteritinib in combination with more traditional chemotherapy induction with a couple of studies demonstrating both a high complete response rates as well as high rates of mutation clearance of the FLT3 mutation.

So, those were very encouraging data that were presented with respect to the FLT3 mutated AML population.      

So, another very important drug that reached the marketplace for AML recently is a drug called venetoclax, which is an inhibitor of a protein called BCL2.

And this drug was recently FDA approved for use in combination with low intensity chemotherapy drugs such as azacitidine or decitabine.

And it seems as though the combination of venetoclax plus one of these hypomethylating agent drugs, azacitidine or decitabine has resulted in very, very strong efficacy signals as recently published in a New England Journal of Medicine paper that reported on the results of the Phase III trial of venetoclax plus azacitidine.

So, that has now become standard of care for older less fit adults with newly diagnosed AML; the combination of venetoclax plus a hypomethylating agent such as azacitidine.

And naturally, there’s been interest in really kind of taking it several steps further to advance the role of these combinations and to also look at additional drugs in combination with venetoclax plus hypomethylating agent therapy.

So, we saw some of that at the ASH meeting this year. One approach would be to take venetoclax and then to combine it with more intensive chemotherapy for perhaps more fit patients or younger patients that could undergo a more intensive program.

So, we saw presentations of venetoclax being combined with a drug called CPX-351, which is a novel liposome formulation of two common chemotherapy drugs that had been approved a few years ago for secondary AML. And we also saw a combination strategy with venetoclax, and a regimen known as FLAG-IDA, which is a commonly used induction regimen in acute myeloid leukemia.

And I think it’s important to recognize that although these trials that combine the venetoclax with more intensive chemotherapy showed signs of good efficacy with good response rates, there were definitely signals of increased toxicity, hematologic toxicity primarily, which is not completely unexpected with venetoclax knowing that it can cause significant lowering of white blood cells and platelets and hemoglobin.

And then finally, there is a lot of interest in, you know, doing these types of combinations with venetoclax in different subsets of AML and one subset of AML that has been very important recently is that of the IDH mutated AML population of patients.

IDH is a fairly common mutation that occurs either in the Isoform of IDH1 or IDH2 and there’s about a 15 to 20 percent incidence of IDH mutations in AML.

Now we do have an inhibitor for both of these types of mutations: ivosidenib for IDH1 and enasidenib for IDH2, but there also appears to be a strong role for venetoclax plus azacitidine in IDH mutated AML.

We saw from a series of patients presented by a physician at MD Anderson looking at outcomes with venetoclax plus azacitidine in IDH mutated AML. And the response rates were very high when you give HMA plus venetoclax to these patients with IDH mutated AML.

But I think more importantly was that there were what we call high intro patient response rates when switching between venetoclax and HMA therapy with an IDH inhibitor containing regimen.

In other words, a patient would have a good chance of responding to the initial therapy and then if or when that therapy stops working, having a good effect from a salvage therapy with the other regimen. So, when you see initially azacitidine plus venetoclax and then had a relapse, the IDH inhibitors worked well and vice versa if you had received an IDH inhibitor and then subsequently received HMA-venetoclax at a later time point that also worked well.

So, it’s encouraging to see that you can potentially sequence these drugs and get continued responses along the way and ultimately we think will help a survivor and keep patients in a better state of health even longer.               

So, I just wanted to take a few minutes also and discuss some of the newer more novel therapies that are really hitting or approaching the landscape right now. One of these is called CC486, also known as oral azacitidine or ONUREG. And this drug was shown in recent literature to prolong overall survival in patients who are in first remission from their AML who had received induction chemotherapy.

So, this drug was used as maintenance therapy after a variable number of consolidation regimens. And people who got this ONUREG or oral azacitidine drug as maintenance therapy, it resulted in longer survival compared to those who had received placebo.

And this was presented at last year’s ASH meeting, but this year’s ASH meeting provided an update, a very important update, showing that the overall survival advantage from this drug, this oral azacitidine drug, when used as maintenance was independent of whether a patient had measurable residual disease at the time that they went onto the maintenance therapy.

In other words, whether you had MRD, measurable residual disease or not at the time of the study entry, your responses were still more favorable, your outcomes were more favorable, if you received this oral azacitidine drug.

So, this was FDA approved earlier this year for patients in the maintenance phase of therapy for AML who had gotten prior reduction chemotherapy.

And importantly, this drug was also shown to be able to convert about 25% of patients who were positive for measurable residual disease; convert them from positive to negative. So, even though they were in remission, they had measurable residual disease and this drug in about 25 percent of the cases converted that from positive to negative. So, that’s a very important finding as well.

Another important drug that I think you should keep your eye on is a drug called magrolimab. This is an antibody against a certain type of protein that is present on the immune system cell called the macrophage, and when this magrolimab drug was combined with azacitidine in a recent clinical trial, it was demonstrated very high response rates of over 65 percent.

And, in particular, in patients with P53 mutations, which is a very bad mutation to have in most cancers, including AML, in patients with this high-risk mutation, the combination of magrolimab with azacitidine appears to be effective based upon the early data that we have with high response rates.

And then finally, I just wanted to make mention of another important area in, not really just AML, but in all cancer and that’s  outcomes disparities between different races and ethnic groups. And we saw a very important presentation at the plenary session this year where the authors reported outcomes amongst younger patients with AML who were African American compared with Caucasian.

And the data clearly indicated a worse overall survival amongst Black patients compared with white patients under age 60. And this included patients who were enrolled in clinical trials. So, that it appeared that African American patients have a worse outcome than Caucasian patients with acute myeloid leukemia highlighting the need to better understand various risk factors and other factors that play into these disparate outcomes between our Black American population and a white American population, which I think could shed light on additional disease characteristics that may help everybody as well.