Tag Archive for: Quizartinib

FLT3 Inhibitors for AML Update

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Introduction

Mutations in the FLT3 (fms-like tyrosine kinase 3) gene are the most common mutations seen in Acute Myeloid Leukemia (AML) patients. FLT3 mutations are seen in about 30% of AML patients. There are 2 different FLT3 mutations, FLT3-ITD (internal tandem duplication) mutation and tyrosine kinase domain mutations (TKD) mutation. Here I report some newer results of treatments with FLT3 inhibitors, that I have come across in the last several months.

There are quite a few drugs that target the FLT3 gene, including:

First generation drugs:

  • Sorafenib (Nexavar)
  • Midostaurin (Rydapt)
  • Lestaurtinib clinical development of lestaurtinib has been discontinued as it did not provide significant clinical benefit.

Second generation drugs, which tend to have fewer and less severe side effects and are more effective include:

  • Gilteritinib (Xospata)
  • Quizartinib (Vanflyta) – Only for ITD mutations.
  • Crenolanib – Not FDA approved.

FLT3 inhibitors are effective treatments for AML with a FLT3 mutation. However, there are still a number of open questions. How should FLT3 inhibitors be used, with induction chemo, with consolidation chemo and/or for maintenance after a stem cell transplant (SCT) or chemo? Can they be used as a single agent for treating patients who are not good candidates for chemotherapy? Do they work well with newer treatments, specifically with azacitidine and ventoclax regimens? There have not been a lot of comparison between the different drugs. Finally, there is the question of why all these drugs have names that are barely pronounceable!

Gilterinib

There is a new study looking at the use of gilterinib as maintenance after SCT. This was a multi-national randomized study, comparing maintenance with gIlterinib against placebo. The result was overall the patients who received gilterinib had better relapse-free survival (RFS) compared to patients who received placebo. However, this difference was not considered statically significant.  However, the trial had a pre-specified secondary objective to look at the subgroup of patients who had measurable residual disease (MRD), that is they were MRD+.

About half of the patients were MRD+ either before SCT or after (or both). In this group, the RFS survival in the patients receiving gilterinib was significantly greater than the placebo group. Unfortunately, there were more side effects in the gilterinib group. It is likely that, because of this study, patients who are FLT3+ and undergoing a transplant will get gilterinib as maintenance if they are MRD+ and not if they are MRD-. The use of gilterinib or other FLT3 inhibitors as maintenance therapy will continue to be a subject of active research.

Quizartinib

I wrote a post on quizartiinb: Quizartinib in FLT3-ITD-Positive AML that was an overview of a trial of this drug along with induction and consolidation chemo and as maintenance after chemotherapy. In July, 2023, Quizartinib was approved for treatment of FLT3-ITD AML in the United States by the FDA.

Crenolanib

Crenolanib is a second-generation FLT3 agent that works for both FLT3-ITD and FLT3-TKD mutations. In Crenolanib and Intensive Chemotherapy for Adults With Newly Diagnosed FLT3-Mutated AML, crenolanib was given with “7+3:” induction and then with consolidation chemotherapy and as maintenance therapy after consolidation chemo and after a SCT. About 2/3 of patients were younger than 60, but patients as old as 75 were included. Although this was not a randomized trial and was fairly small (44 patients), it seemed that Crenolanib added to chemotherapy and as maintenance improved survival compared to midostaurin (the first drug approved for FLT3 AML) and quizartiinb (described above).

Sorafenib

While sorafenib is an FLT3 inhibitor, this first study is on its use in AML patients even if they did have a FLT3 mutation. Previous studies had shown sorafenib improved survival when given with standard “7+3” induction for AML. This study (Sorafenib Plus Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone for Untreated AML) looked at sorafenib with cladribine, high-dose cytarabine, granulocyte colony–stimulating factor, and mitoxantrone (CLAG-M). The first part of the study (Phase I) tried increasing doses of sorafenib and mitoxantrone. The Phase II part of the study used the recommended phase 2 dose (RP2D) to treat more patients. When compared with historical controls who received CLAG-M without sorafenib, the patients who received the RP2D had improved survival.

Finally, there is a report on the long term follow-up of a trial looking at using sorafenib as maintenance therapy after a transplant (Sorafenib Maintenance After Allogeneic HSCT in Patients With AML With FLT3 Internal Tandem Duplications). The use of sorafenib as maintenance reduced relapse which improved survival in patients with FLT3-ITD AML. The non-relapse mortality and the incidence of chronic Graft-Versus-Host Disease (GVHD) in those who had a transplant was similar in patients who received sorafenib and those who did not. This result was sustained long-term (with a median follow-up of about 5 years).

Conclusion

The best way to use FLT3 inhibitors in patients with FLT3 mutation is still an area of active research. Newer agents promise better results – fewer side effects and better survival.

Further Reading

FLT3 Tyrosine Kinase Inhibitors for the Treatment of Fit and Unfit Patients with FLT3-Mutated AML: A Systematic Review, Int J Mol Sci. 2021 Jun; 22(11): 5873.

Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments, Cells 2020, 9(11), 2493.

Gilteritinib as Posttransplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3, Practice Update (registration required, free), March 26, 2024.

Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3, Medscape, June 21, 2023.

Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3, Journal of Cinical Oncology. March 12, 2024..

Quizartinib Approval Adds New Treatment Option for AML, Including in Older Patients , National Cancer Institute, Cancer Currents Blog , August 15, 2023.

Crenolanib and Intensive Chemotherapy for Adults With Newly Diagnosed FLT3-Mutated AML, Practice Update (registration required, free), March 4, 2024.

Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML (JCO article) Journal of Clinical Oncology February 07, 2024.

Sorafenib Plus Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone for Untreated AML Practice Update (registration required, free), July 25, 2023.

Phase 1/2 study of sorafenib added to cladribine, high-dose cytarabine, G-CSF, and mitoxantrone in untreated AML, Blood Adv (2023) 7 (17): 4950–4961.

Sorafenib Maintenance After Allogeneic HSCT in Patients With AML With FLT3 Internal Tandem Duplications, Practice Update (registration required, free), July 25, 2023.

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial, The Lancet, Volume 10, ISSUE 8, e600-e611, August 2023

Phases of AML Therapy | Understanding Treatment Options

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Phases of AML Therapy | Understanding Treatment Options from Patient Empowerment Network on Vimeo.

What are the types and phases of acute myeloid leukemia (AML) treatment? Dr. Alice Mims, an AML specialist, defines induction, consolidation, and maintenance therapy for patients. Dr. Mims also explains the role of stem cell transplant and discusses promising new AML therapies.

Dr. Alice Mims is a hematologist specializing in acute and chronic myeloid conditions. Dr. Mims serves as the Acute Leukemia Clinical Research Director at The Ohio State University Comprehensive Cancer Center – James. Learn more about Dr. Mims. 

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Transcript:

Katherine Banwell:

I’d like to move on to treatment now, Dr. Mims. And, of course, treatment takes place in phases for AML. The first is induction therapy. Can you start by defining induction therapy for our audience?  

Dr. Alice Mims:

Sure. So, induction therapy is really terminology that we use to talk about initial therapy for someone with a new diagnosis. So, we can have intensive induction therapies and non-intensive induction therapies. But the goal for either of those types of treatment is to get the leukemia into remission.  

Katherine Banwell:

And what are the available treatment options for induction therapy?  

Dr. Alice Mims:

So, to talk about that in a little bit more detail, for intensive induction regimens, those typically involve cytotoxic chemotherapy. So, you may hear terminology like, “7 + 3 induction,” or “high-dose cytarabine regimens,” but those are typically more intensive regimens that we use that can have increased side effects but may be very important based off the type of acute leukemia. 

And then for non-intensive based regimens, one of the standards has really evolved to be venetoclax (Venclexta) and azacitidine (Vidaza) as a non-intensive regimen that can work very well for a majority of patients. And there are some off shoots of that as well. 

Katherine Banwell:

Okay. And when does stem cell transplant come into play? 

Dr. Alice Mims:

Sure. So, stem cell transplant is something that we all think about at the beginning for anyone with a new diagnosis of acute myeloid leukemia where as we’re working to get back genomic information about the individual’s acute leukemia, we may go ahead and start looking for different donors, doing typing, just in case that’s something that we need as far as someone’s therapy.  

But typically we reserve stem cell transplant for patients who have either intermediate or high-risk features of their AML. Or who may have even favorable respite are not responding as well as we would like when looking at the depth of remission. And so, we always want  to be prepared in case that’s something we need to move forward with as part of their care, if the goal of their treatment is for curative intent. 

Katherine Banwell:

Let’s talk about what happens after the initial phase of treatment. What’s the purpose of consolidation therapy? 

Dr. Alice Mims:

Sure. So, there are a few different purposes we can use consolidation therapy for. So, for patients – consolidation therapy is used for patients who have achieved remission. And then it’s either to try to hopefully get them cure of their AML. The patients have more favorable risk features of their AML and cure is an option through just chemotherapy alone.  

Or it can be used to try to keep people in remission while we’re working to get towards stem cell transplant as that can sometimes take a few months to get a donor ready, have things ready to move forward with transplant. 

Katherine Banwell:

And what are the options for consolidation therapy?  

Dr. Alice Mims:

Sure. So, options for consolidated chemotherapy are typically based off of what you had initially for induction chemotherapy. So, if it’s more intensive-based regimens, it typically is consolidation with intensive consolidation, cytarabine-based (Cytosar-U) regimens.  

For lower intensity regimens, typically consolidation is more continuing therapy on what you started but may have adjustments of the treatment based off of trying to decrease the toxicity now that the patients are in remission. 

Katherine Banwell:

And how are patients monitored in consolidation therapy? 

Dr. Alice Mims:

Sure. So, it definitely is based off of the individual’s type of consolidation chemotherapy or treatment. But most patients, if we feel like the treatment is going to lower blood counts, they have bloodwork twice a week, and we’re watching for things, for side effects for treatment, looking out for risk of infection, giving transfusion support, and then if something happens that we feel like we can’t support patients in an outpatient setting, then we’ll get them back into the hospital if they need to for care. 

Katherine Banwell:

What side effects are you looking for? 

Dr. Alice Mims:

So, most of the side effects with any of the treatments that we give are what we call myelosuppressives. So, it lowers the different types of blood counts.  

So, white blood cell count which increases risk of infection, red blood cells, so, side effects or symptoms from anemia. And then risk of bleeding from low platelet counts.  

Katherine Banwell:

Okay. Maintenance therapy has become more common in other blood cancers particularly in multiple myeloma. Is there a role for maintenance therapy in AML? 

Dr. Alice Mims:

There actually is now, which is something that’s newer that has evolved for acute myeloma leukemia. So, in the context of intensive therapy, we now have oral azacitidine (Onureg), which is a little bit different than some of the IV formulations that we give.  

But for patients who receive intensive induction therapy, get into remission and may receive consolidation but are not able to go onto transplant if they have that immediate or higher risk features, there’s FDA approval for oral azacytidine, which has been shown to improve overall survival and keep people in those remissions for longer. 

More recently, specifically for patients who have a particular type of mutation called FLT3, if they also receive intensive induction therapy with a FLT3 inhibitor added onto that, then their quizartinib (Vanflyta) was just recently approved as a maintenance therapy for patients with that particular type of AML. 

Katherine Banwell:

Are there emerging AML therapies that patients should know about other than what you just mentioned? 

Dr. Alice Mims:

Sure. So, I think there are a lot of exciting treatments that are up and coming based off of many small molecule inhibitors that are being studied.  

One in particular I would mention that everyone’s very excited about is a class of agents called menin inhibitors.  

And so that’s an oral agent that has been shown to have responses for patients with relapsed or refractory AML who have NMP-1 mutations or have something called KNT2A rearrangements. And seeing responses with just a single agent in the relapsed/refractory setting, it’s been really exciting. And so, I think we’re hopeful that that may become FDA-approved in the near future. And it’s also now being explored in combination with intensive chemotherapies as well as less intensive induction regimens. And so, maybe we can do a better job with upfront treatment by adding these therapies on.  

The Importance of the FLT3 Mutation in AML

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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.“ 

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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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Quizartinib in FLT3-ITD-Positive AML

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Introduction 

I generally think of treatments for AML as old, meaning they were around when I was diagnosed in 1992, or new ones that were developed after that. In the first 25 or so years since I was diagnosed, there were very few new treatments. In the last 5-7 years, however, there have been several new treatments. There are targeted treatments like, Ivosidenib (which I wrote about in November: Ivosidenib and Azacitidine for IDH1-Mutated AML) as well as Ventoclax which is used with a number of different drugs (Azacitidine, Decitibine and low dose Ara C). This post is about a new (to the U.S. anyway) drug, Quizartinib, which is used in AML patients who have a specific mutation FLT3 (fms-like tyrosine kinase 3), specifically a FLT3-ITD (internal tandem duplication) mutation. 

Overview of FLT-3 

There are two different mutations in the FLT3 gene, ITD and tyrosine kinase domain mutations (TKD). The most common mutation in AML is in the FLT3 gene. About 30% of AML patients have an FlT3 mutation, with FLT3-ITD mutations more common than FLT3-TKD ones. Some of the existing drugs for FLT3 mutations treat both. Midostaurin (Rydapt) and Gilteritinib (Xospata) are used in patients with either FLT3 mutation. Quizartinib is only used to treat patients with a FLT3-ITD mutation. 

Current Study of Quizartinib 

The current study, the results of which were presented at the 2022 European Hematology Association (EHA) Annual Meeting in Vienna, tested standard chemotherapy with Quizartinib or with a placebo, followed by maintenance with Quizartinib or placebo for 3 years. More than 500 patients with a FLT3-ITD mutation were treated in the trial. Quizartinib or a placebo were added to the “7+3” standard induction therapy, which consists of 7 days of cytarabine (Ara-C) plus 3 days of daunorubicin or idarubicin. Patients who were in remission after induction either went on to up to 4 rounds of high dose cytarabine consolidation with Quizartinib or placebo and/or an allogeneic (donor) stem cell transplant, followed by up to 3 years of maintenance therapy with Quizartinib or placebo. 

The patients who received Quizartinib had a median overall survival of more than double the patients who received the placebo. Almost all patients in both arms experienced side effects of the treatment (emergent adverse events or AEs). This is not a surprise, most patients treated for AML have significant side effects. Patients who received Quizartinib had more side effects, in particular there was a higher incidence of significant neutropenia (low white counts) and more patients who received Quizartinib discontinued treatment because of adverse events. There were 56 treatment related deaths in the trial, somewhat more in those who received Quizartinib. 

Quizartinib looks like a promising treatment for FLT3-ITD AML patients. I believe that this is the only randomized (Phase III) trial that has been completed of a drug that treats mutations in the FLT-3 gene along with standard chemotherapy. It will be interesting to see how it compares to other drugs for patients with FLT-3 mutations. On the downside, it is only used for FLT3-ITD mutations, unlike Midostaurin and Gilteritinib. 

Further Reading 

Quizartinib Doubles Overall Survival in FLT3-ITD-Positive AML, article from Medscape on the trial of Quizartinib and Chemotherapy, June 13, 2022. 

Quizartinib Prolonged Survival VS Placebo Plus Intensive Induction and Consolidation Therapy Followed by Single-Agent Continuation in Patients Aged 18-75 Years With Newly Diagnosed FLT3-ITD+ AML, from 2022 European Hematology Association (EHA) Annual Meeting in Vienna. 

Daiichi Sankyo’s survival data mean it may finally be ready to compete with Novartis’, Astellas’ marketed AML meds, an article from Fierce Biotech, which covers the biotechnology industry. 

Xospata FDA Approval History, from Drugs.com, gives a history of the FDA approval of Xospata (gilteritinib). 

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure, Capelli, D.; Menotti, D.; Fiorentini, A.; Saraceni, F.; Olivieri, A. Cancers 2022, 14, 4315. A long journal article on treating FLT-3 AML (I have not read all of it). 

FLT3 Inhibitor Quizartinib Improves Survival in AML reports on an older study showing patients with relapsed/refractory FLT3-ITD-positive AML have improved survival with Quizartinib, given as a single agent compared with standard-of-care chemotherapy. Medscape, July 02, 2018.