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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

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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