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FLT3-Mutated AML
Expert Perspectives With FLT3-Mutated AML Testing and Treatment: Challenges and Opportunities

Released: April 30, 2025

Expiration: April 29, 2026

Harry P. Erba
Harry P. Erba, MD, PhD
Eunice S. Wang
Eunice S. Wang, MD
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Key Takeaways
  • NGS testing may miss some FLT3-ITDs especially with longer repeats but could reveal noncanonical FLT3-TKD mutations that may be targets of available FLT3 inhibitors.
  • Currently available FLT3 inhibitors—midostaurin, quizartinib, and gilteritinib—have varying approved indications for patients with AML based on the presence of FLT3-ITD and FLT3-TKD mutations as well as patient treatment history.
  • Novel AML approaches in development include FLT3 inhibitors combined with menin inhibitors or less intensive venetoclax-based triplet regimens.

In this commentary, acute myeloid leukemia (AML) experts Harry P. Erba, MD, PhD, and Eunice S. Wang, MD, discuss a few of today’s key challenges in AML care with an emphasis on FLT3 mutation testing, associated therapeutic implications, and new promising directions in AML treatment combining FLT3 and menin inhibitors.

What do you see as some of the ongoing challenges with FLT3 testing and how can oncology healthcare professionals (HCPs) overcome them?

Eunice S. Wang, MD:
With a new diagnosis of AML, it can be challenging to obtain all the necessary molecular testing results to inform a thorough understanding of the disease molecular profile and consequently select the optimal targeted therapy. However, performing a thorough comprehensive diagnostic workup and in a timely fashion is essential in the current age for selection of therapeutic options. The diagnostic panel should ideally capture the breadth of important myeloid mutations including FLT3, IDH1, NPM1, KMT2A, and TP53 in all patients newly diagnosed with AML.

Harry P. Erba, MD, PhD:
In addition, HCPs should have a thorough understanding of the difference between FLT3 internal tandem duplications (FLT3-ITD) and FLT3 tyrosine kinase domain (FLT3-TKD) mutations in terms of their incidence and prognosis. FLT3-ITD mutation is more common and has been associated with a worse prognosis. FLT3-ITD–positive AML was considered high-risk disease by prior European LeukemiaNet (ELN) risk stratification.  However, FLT3-ITD is now included in the intermediate-risk category in the 2022 ELN criteria because of the survival benefit associated with the addition of FLT3 inhibitors to intensive induction and consolidation chemotherapy and continued as a maintenance. The presence of co-mutations also affects prognosis in both FLT3-TKD–positive and FLT3-ITD–positive AML. HCPs need to understand that the FLT3 mutations have variable sensitivity to the commercially available FLT3 inhibitors. 

HCPs should also have a clear understanding of the advantages and disadvantages between the different testing methods: polymerase chain reaction (PCR) and next-generation sequencing (NGS). PCR typically has a shorter turnaround time (as short as 2 business days for at least one newer PCR test) and is better able to identify longer FLT3-ITD mutations, which are not uncommon. PCR also reports the FLT3-ITD:FLT3 wild-type (normal) allelic ratio, which can be incorporated into clinical decision-making to help determine whether the addition of an FLT3 inhibitor would be beneficial. Although NGS may miss larger FLT3-ITDs, it could reveal noncanonical FLT3-TKD mutations that are targets of FLT3 inhibitors.

Eunice S. Wang, MD:
I agree with Dr Erba that the correct identification of FLT3-ITD mutations is important for these patients. On occasion, FLT3-ITD testing is missed on NGS panels. At my practice, we aim to start an appropriate FLT3 inhibitor for all fit, younger patients with FLT3-mutated AML following intensive chemotherapy on Day 8. In some practices where it may take 1-2 weeks to obtain mutational profile results, the opportunity to add an approved FLT3 inhibitor to intensive chemotherapy on Day 8 may be missed. In this clinical setting, there currently are 2 approved FLT3-targeted inhibitors for combination with intensive chemotherapy: midostaurin, which is approved for FLT3-ITD and FLT-TKD mutations, and quizartinib, which is approved for FLT3-ITD mutations. Both are associated with significantly improved overall outcomes in combination with intensive chemotherapy and represent the standard-of-care approaches for these patients.

Harry P. Erba, MD, PhD:
Another point to remember is that it is very important to retest for a FLT3 mutation when a patient with AML has resistant disease or experiences progression or relapse. The FLT3 mutation may have been present at diagnosis and lost at the time of relapse or, conversely, a FLT3 mutation may appear at the time of relapse. Testing at the time of relapse is critically important.

What are some of the important factors that HCPs should consider when thinking about FLT3 therapy for their patients?

Eunice S. Wang, MD:
It is important to recognize the differences among the commercially available FLT3 inhibitors. For instance, compared with the first-generation agent midostaurin, the newer generation inhibitor quizartinib is a much more potent, targeted FLT3 inhibitor with fewer off-target interactions and gastrointestinal toxicities. For younger patients with FLT3-ITD, quizartinib is my preferred agent for these reasons.

However, HCPs should keep in mind some specific adverse effects associated with quizartinib, primarily the potential for cardiac toxicity. Patients with underlying cardiac issues who are receiving baseline QTc prolonging agents that cannot be discontinued or patients with a significant history of underlying arrhythmias or cardiac problems might not be the best candidates for quizartinib, given its known potential for QTc prolongation.

Overall, in my experience, quizartinib is very well-tolerated in my patients. By contrast, midostaurin does have significant gastrointestinal toxicity including nausea and vomiting. For instance, when you open the package of midostaurin, there is a strong odor that is associated with it. A trial in Europe demonstrated that a substantial proportion of older patients discontinue the use of midostaurin long term largely because of these adverse effects; I have not seen as many discontinuations for these reasons with quizartinib. Because of this, quizartinib is my preferred FLT3-targeted agent if patients have no significant contraindications such as a prolonged QTc interval or the presence of required QTc prolonging agents.

Harry P. Erba, MD, PhD:
Gilteritinib is another second-generation, more potent FLT3 inhibitor. It is a type 1 inhibitor with activity against both FLT3-TKD and FLT-ITD. It is currently approved only for patients with relapsed/refractory AML with FLT3-ITD or FLT3-TKD mutation. Gilteritinib can be used to bridge patients to allogeneic transplant in the relapsed/refractory AML setting.

What are you excited about as the next steps in the treatment of patients with AML?

Harry P. Erba, MD, PhD:
We need to consider the biology of the disease that we are trying to treat. FLT3 mutations occur as later events during leukemogenesis. It is amazing that we see the clinical activity of FLT3 inhibitors as single agents. However, the benefit is typically short lived without subsequent allogeneic stem cell transplant.

We now know that there are other founder mutations such as the NPM1 mutation, which is now considered a defining mutation of AML regardless of the blast percentage by WHO criteria.

Eunice S. Wang, MD:
Considering this, there are new and promising agents, specifically, the menin inhibitors, which disrupt the menin–KMT2A master transcriptome complex. This complex is found primarily in patients with rearrangements in the KMT2A or MLL gene, as well as in patients with mutations in the NPM1 gene.

Of interest, both NPM1 and KMT2A are frequently co-mutated in the presence of FLT3 mutations. NPM1 mutations have been seen in patients with FLT3-ITD and/or FLT3-TKD whereas KMT2A mutations are seen in patients with FLT3-ITD and FLT3-activating mutations.

One potential future avenue of therapeutic intervention under clinical trial investigation is combining FLT3 inhibitors, such as quizartinib, gilteritinib, and midostaurin, with menin inhibitors to target 2 different signaling pathways that promote leukemogenesis in patients with AML. The FLT3 mutation tends to be a secondary mutation that drives an extremely high white blood cell count and increased cell proliferation and growth. Leukemias harboring NPM1 and KMT2A rearrangements are characterized by transcriptomic and epigenetic changes that lead to a differentiation block. Targeting both menin and FLT3, therefore, may not only release the differentiation block but also dampen the proliferation signal. Combinations of these 2 targeted approaches are currently in clinical trials and have shown promising efficacy and potential for use as targeted therapies with or without additional cytotoxic agents.

Your Thoughts
What are your challenges regarding molecular testing and the treatment of AML? Share a comment below and continue to check the CCO website as we post new certified activities that focus on FLT3 testing, therapeutic advances in FLT3 inhibitor therapy, and mitigating FLT3 inhibitor–related adverse events in the care of patients with AML.

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What type of molecular testing do you routinely obtain for evaluating FLT3-ITD and FLT3-TKD mutations in your patients with newly diagnosed AML?

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