Tag Archive for: IDH1 Mutation

AML Gene Mutations | Emerging Targeted Therapies in Development

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What are emerging targeted therapies for AML? Dr. Daniel Pollyea discusses the current landscape of targeted treatments for AML gene mutations, while emphasizing ongoing research efforts surrounding less common mutations.

Dr. Daniel Pollyea is Clinical Director of Leukemia Services in the Division of Medical Oncology, Hematologic Malignancies and Blood and Marrow Transplant at University of Colorado Cancer Center. Learn more about Dr. Pollyea.
 
 
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AML Therapy | Emerging Treatments and Clinical Trials

AML Therapy | Emerging Treatments and Clinical Trials

An Overview of Current AML Treatment Types

An Overview of Current AML Treatment Types

 AML Treatment Planning | Key Questions to Ask You Doctor

AML Treatment Planning | Key Questions to Ask You Doctor

Transcript: 

Katherine Banwell:

Chris sent in this question: I would like to hear more about mutations found during molecular testing. Are there new AML drugs in trials for other less common mutations? 

Dr. Daniel Pollyea:

Great question. So, at the moment, what we have clinically available are targeted therapies for patients with FLT3 mutations, IDH1, and IDH2 mutations.  

And there are about 50 different genes that can be mutated in AML, and so that’s a small slice of the pie. Those are relatively common mutations, but still, small slice of the pie. A lot of the very uncommon or less common gene mutations we don’t have great paths to targeted therapies for them.  

And is that just we never will? I don’t think necessarily, but I think those can be really challenging. Not every mutation is amenable to a targeted therapy, at least as far as we know now. The one that’s coming, that we’re hopeful about is NPM1, which may be able to be targeted with one of those menin inhibitors that we talked about. So, that’s the next big one up.  

And that will probably constitute 40 percent of patients that have one of those mutations that I listed. But research is ongoing to kind of try and dig into this more. What I will say is that the AML research community is so fantastic that every lead is being pursued, and there is a lab somewhere in the world whose focus is on whatever small, even the most least common AML mutation; that’s somebody’s focus. 

And so, if there were to be promising therapies developed for even rare mutations, I assure you, the field would take those forward and figure out a way to do those clinical trials and to get to approval if it’s appropriate. So, but I think that’s where the landscape is right now.   

An Overview of Current AML Treatment Types

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Dr. Daniel Pollyea provides an overview of AML treatment options, explaining the choices between intensive chemotherapy and targeted therapies, while also discussing when stem cell transplants are considered.
 
Dr. Daniel Pollyea is Clinical Director of Leukemia Services in the Division of Medical Oncology, Hematologic Malignancies and Blood and Marrow Transplant at University of Colorado Cancer Center. Learn more about Dr. Pollyea.
 

 

Related Resources:

AML Therapy | Emerging Treatments and Clinical Trials

AML Therapy | Emerging Treatments and Clinical Trials

AML Gene Mutations | Emerging Targeted Therapies in Development

AML Gene Mutations | Emerging Targeted Therapies in Development

 AML Treatment Planning | Key Questions to Ask You Doctor

AML Treatment Planning | Key Questions to Ask You Doctor

Transcript: 

Katherine Banwell:

Would you share an overview of the types of therapy for AML, and how do you decide which patient gets what? 

Dr. Daniel Pollyea:

Yeah. Because things are very different at relapse too, but at diagnosis, the options still are intensive chemotherapy, which is a regimen that hasn’t changed much in several decades really, 50 years.  

And then, there are other treatments. There’s a treatment called venetoclax (Venclexta) that we pair with a low-intensity chemotherapy treatment, either azacitidine (Vidaza), decitabine (Dacogen), or something called low-dose cytarabine (Cytosar U). Those are the three sort of partners for venetoclax.  

And then, there’s a targeted therapy against leukemia cells that have an IDH1 mutation that’s called ivosidenib (Tibsovo) that we also give with low-dose chemotherapy. So, in most cases those are the sort of three general options. That last treatment that’s targeted against IDH1, we typically preserve that for older patients or those that really are not good candidates for intensive chemotherapy but who have that IDH1 mutation, which is only somewhere around 10  percent of AML patients.

And then, so then the main decision then is “Do we give intensive chemotherapy, or do we give the venetoclax regimen?” And our policy is sort of, if we think we can cure you within intensive chemotherapy, and there’s certain disease biology subtypes that can be cured potentially with intensive chemotherapy, then that would be our first choice for you.  

If we don’t think we can cure you with intensive chemotherapy, if you don’t have that disease biology or if you do but you’re just not a candidate for that type of an approach, that’s when we give the venetoclax regimen. 

Katherine Banwell:

Are there other targeted therapies that you use?  

Dr. Daniel Pollyea:

Yes. So, venetoclax is a targeted therapy against Bcl-2. Unlike some of these other gene mutations, you don’t have to have something; there’s no mutation in Bcl-2 that you need to be a candidate for venetoclax. We give venetoclax pretty much to any potential AML patients. Genomically-targeted therapies:  you mentioned FLT3. Before I mentioned IDH1. There’s also one for IDH2. We hope there’s a couple more of these coming. Where these are approved, for the most part, at the moment, are in the relapse setting.  

So, a patient who receives a treatment, and then either doesn’t respond or responds and then relapses, that’s typically where we bring in these genomically-targeted therapies. There’s an exception for IDH1 that, like I said, can be used now in the upfront treatment setting. But for the most part, these genomically-targeted therapies are relevant in relapse disease. 

Katherine Banwell:

When would you use stem cell transplant?  

Dr. Daniel Pollyea:

So, stem cell transplant for the majority of AML patients is still the only potential way to cure this disease. And so, a stem cell transplant is something that we give for that purpose. It’s something that we really reserve for people whose disease is in a remission. So, nobody comes in at diagnosis and goes right into a stem cell transplant; that wouldn’t work. So, you first have to achieve a remission with any number of one of the combinations of things that we’ve already discussed.  

But once the patient is in a remission and doesn’t have a curative strategy with, like, intensive chemotherapy or some other approach and is a good candidate for a transplant, which is a whole other sort of set of circumstances that has to be considered, that’s patients who we offer a transplant for. 

Olutasidenib for Relapsed or Refractory Acute Myeloid Leukemia with IDH1 Mutation

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Introduction 

Once again a new drug that was recently FDA approved for some Acute Myeloid Leukemia (AML) patients. Olutasidenib (brand name: Rezlidhia) was approved in December 2022 for AML patients who have relapsed or are refractory to treatment (R/R) with a mutation in the Isocitrate Dehydrogenase 1 (IDH1) gene. There is a different gene called IDH2, which can also be mutated in patients with AML, but different medications are used for IDH2 mutations. 

An existing drug, called ivosidenib (brand name: Tibsovo) was already approved for patients with AML and a mutation in IDH1. It was initially approved in July 2018 as a single agent for patients with R? AML with a IDH1 mutation. Later it was approved for use in combination with azacytidine for newly diagnosed AML patients with an IDH1 mutation. There was also a specific test (the Abbott RealTime IDH1 Assay) approved along with the initial approval of ivosidenib. This test was also approved to select patients to be treated with olutasicdenib.

Results of the Current Study 

The study used to support the approval was a non-randomized trial (all patients received olutasidenib). The study included patients with AML and ones with Myelodysplastic Syndrome (MDS) who had a mutation in the IDH1 gene. Patients were treated with olutasidenib as a single agent (monotherapy) as well as combined with azacytidine. The approval was based on the results of the 147 patients who received olutasidenib monotherapy (the results are described in detail here). 

In the study, about 35% of patients achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) – the latter means that they appear to be in remission, but their blood counts are not normal. In addition, about one third of patients who were platelet and/or red blood transfusion dependent at the start of the trial eventually did not require transfusions for 8 or more consecutive weeks (transfusion independent). All patients experienced 1 or more adverse events (AEs) and almost all experience a serious (Grade III or IV) AE. These AEs are expected in patients with AML, particularly older patients, as most of the patients were. 

Comparison with Ivosidenib 

Now that there are 2 drugs approved for AML patients with an IDH1 mutation, the question becomes which drug should be used and in which circumstances. There have been no studies (at least ones that are published) that directly compare the drugs. According to the paper from Bload Advances on the responses to olutasidenib and ivosidenib as single agents was about the same, however the length of remission in the patients receiving olutasidenib (a median of 25.9 months) compared to ivosidenib (8.2 months0. The big caveat is that, since the comparison was not randomized, it is difficult to determine if there were differences in risks in each group. My guess is that there will not be a randomized comparison of these two groups.

It will be more interesting to look at these drugs in combination with azacytadine and also as a 3 drug combination of azacytidine and venetoclax. In addition, these drugs could be combined with existing intensive chemotherapy regimens (for instance, so-called 7+3 induction with cytarabine and daunorubicin). Likely the combinations would produce more remissions but might have significantly more side effects. 

In summary, the good news is that there is another drug that can help some patients with AML, the bad news is that the determination of the best therapy is yet more complicated. 

Further reading 

Olutasidenib: 

Ivosidenib: 

What Is the AGILE Study? Research for AML Patients With the IDH1 Mutation

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What Is the AGILE Study? Research for AML Patients With the IDH1 Mutation from Patient Empowerment Network on Vimeo.

AML expert Dr. Omer Jamy reviews the results of the AGILE study, a clinical trial evaluating the efficacy and safety of ivosidenib + azacitidine vs placebo + azacitidine in patients with previously untreated AML with an IDH1 mutation.

Dr. Omer Jamy is a Leukemia and Bone Marrow Transplant Physician and Assistant Professor at the University of Alabama at Birmingham. Learn more about Dr. Omer Jamy.

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Transcript:

Katherine Banwell:

Dr. Jamy, data was presented at ASCO from the agile study. What is the study and what does the news mean for AML patients? 

Dr. Omer Jamy:

Yes, thank you. So, the AGILE study is basically a randomized Phase III study. It is specifically for patients with AML who harbor an IDH1 or isocitrate dehydrogenase 1 mutation. Now IDH1 mutation is thought to be rare.   

It occurs in around six to 12 percent of patients with acute myeloid leukemia. So, a few years ago there was a drug approved by the FDA to treat patients in the relapsed or refractory setting with an IDH1 mutation. And that drug is called ivosidenib (Tibsovo). And this drug is also approved for elderly patients ineligible for intensive chemotherapy but it was mainly initially approved for the relapsed/refractory setting.  

So, all of these drugs when they initially get approved – so this is targeted therapy. It’s targeting IDH1 mutant AMLs, so patients with AML without an IDH mutation will not benefit from such a drug. So, when you find targeted therapy, the general workflow is it gets tested in the later settings. If it looks promising, then people try to bring it in the upfront settings. So, this was a Phase III study of newly diagnosed acute myeloid leukemia patients harboring an IDH mutation.  

And it randomized them to a combination of azacitidine plus ivosidenib versus azacitidine plus placebo.  

When the study was started, the standard of care for patients ineligible to receive intensive chemotherapy was azacitidine (Vidaza). So, this study again, just to highlight, focused on patients who were not ineligible for intensive chemotherapy. So, these may be patients who were either above the age of 75 or below the age of 75 but had comorbidities which would have prevented them from receiving intensive chemotherapy. These comorbidities could be any organ dysfunction such as the heart, kidneys, liver, lung, or poor performance status. So, the primary endpoint of the study was event free survival. And the primary endpoint of the study was met with a hazard ratio of .33 in favor of the combination of azacitidine  and ivosidenib. The study also showed that overall survival was improved in patients getting the combination compared to patients just getting azacitidine and placebo.  

Which was roughly around 20 to 24 months versus eight months for the placebo and azacitidine arm. And then obviously when you combine drugs you want to make sure that by adding two drugs, you’re not causing more toxicity. So, the toxicity profile between the two arms was similar actually. They saw less infections and neutropenia in the ivosidenib and azacitidine arm compared to azacitidine alone. So, that was basically the AGILE study where they looked at patients with IDH mutant acute myeloid leukemia.  

Updates from ASH: How Biomarker Testing Has Changed MPN Care

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Updates from ASH: How Biomarker Testing Has Changed MPN Care from Patient Empowerment Network on Vimeo.

MPN specialist, Dr. Andrew Kuykendall, discusses how the identification of specific biomarkers in myeloproliferative neoplasms (MPNs), such as the JAK2 mutation, have moved research forward. Dr. Kuykendall shares promising findings that were released at the 2021 American Society of Hematology (ASH) annual meeting and how this may impact MPN care in the future.

Dr. Andrew Kuykendall is an Assistant Member at Moffitt Cancer Center in the Department of Malignant Hematology. Dr. Kuykendall’s clinical and research efforts focus on myeloproliferative neoplasms (MPNs), MDS/MPN overlap syndromes and systemic mastocytosis (SM). Learn more about Dr. Kuykendall, here.

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Transcript

Katherine:

How has molecular or biomarker testing changed the field of MPN care and treatment?

Dr. Kuykendall:

Well, I think, first and foremost just understanding – going back to 2005 and knowing that we have JAK2 mutations. I think that gave really a lot of clarity to the diagnosis and really understanding the biology of how the disease acted through the JAK-STAT pathway. And certainly, that led to the understanding of MPL mutations and then calreticulin mutations.

We’re still figuring out exactly how calreticulin mutations work. There was a great abstract, a preclinical abstract, this year talking about the impact of interferon on calreticulin mutations and how that may differ from what we see in the impact of interferon on diseases that are driven by JAK2 mutations.

Clinically, we see a little bit of difference in how those diseases respond and we may understand a little bit better about why that happens. Additionally, that’s kind of gone down to looking at these big next generation sequencing panels where we identify high-risk mutations and that can certainly change our understanding of the prognosis of these diseases.

We’re starting to get, at least in the AML world, we’re getting targeted agents that can potentially target some of these mutations such as IDH1 and IDH2 mutations that have specific inhibitors.

Those are mutations that occur in myeloproliferative neoplasm patients and convey a worse prognosis, so there are ongoing trials looking to see if we can use those IDH inhibitors in myeloproliferative neoplasms either in the chronic phase or maybe in the more accelerated advanced phase.

You know the big thing, this meeting, was actually looking at polycythemia vera patients and what’s the relevance of the JAK2 mutant allele burden. I think this is something we’ve talked about a lot as far as how significant this is. We know in chronic phase myeloproliferative neoplasms that that JAK2 mutation tends to be associated with more thrombotic complications.

There are more blood clots in the veins and the arteries. There were a couple great abstracts that looked at the really the implications of the JAK2 mutation and the fact that it is associated with more thrombosis, but maybe more venous thrombosis. That might be a big risk factor for venous thrombosis and it may be that cardiovascular risk factors, such as diabetes, hyperlipidemia that’s really what’s driving the arteriole thrombosis. It also looked at the variant allele fraction, the number of cells that have that JAK2 mutation.

One abstract showed that if you have over a 50 percent allele fraction, if more than 50 percent of the alleles have the mutation – a higher burden of that mutation that’s associated with an increased thrombotic risk even in low-risk polycythemia vera patients. Whether or not that’s enough evidence to really change the paradigm of how we treat low-risk patients is to be determined, but I think very interesting and provocative work.