Tag Archive for: NPM1 mutation

Emerging AML Treatment Classes Showing Promise

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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.

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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. 

Why Is the Menin Pathway Important in AML?

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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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What Promising AML Treatments Are Available for Newly Diagnosed Patients?

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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.“

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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. 

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