Published on September 1, 2021
What Are the Most Common AML Mutations?
What are the most common AML mutations, and how do they factor in prognosis? Follow along as Eunice Wang, MD, Chief of Leukemia at Roswell Park Comprehensive Cancer Center, explains when AML patients should be tested and re-tested for mutations and how the mutational status impacts treatment choice.
Transcript | Blood Cancer Awareness Month: AML Mutations
What Are the Most Common AML Mutations and How Do They Factor into Prognosis?
Dr. Wang: So, the most common mutation found in newly diagnosed patients with acute myeloid leukemia remains the FLT3 gene. The FLT3 gene mutations can occur in up to 25-37% of new cases of AML. Typically, those mutations fall into one of two categories, FLT3-ITD, or internal tandem duplication mutations, are the majority of the FLT3 mutations, and a smaller subset are mutations found in the tyrosine kinase domain, or the TKD domain, of that receptor.
FLT3 mutations carry a worse prognosis if they are the ITD mutation type. Prior studies have shown patients with FLT3-ITD mutations respond less well to chemotherapy and have shorter intervals of remission without proceeding onto recurrence. The presence of the FLT3 mutation now is considered a targetable mutation. And to combat or reverse or mitigate the adverse prognostic impact of that mutation, we are now utilizing FLT3 inhibitors in combination with chemotherapy backbones, both in the upfront and the relapsed and refractory setting. It's important to note that about 20-22% of patients who don't have FLT3 mutations at diagnosis may have the mutations appear at the time of recurrence.
The second most common mutations involve a mutation NPM1, or nucleophosmin-1 mutation, as well as less commonly a mutation in DMNT3A. Currently neither one of those mutations are considered prognostically negative. In fact, in the absence of FLT3 mutations, either of those mutations may be considered prognostically neutral or even favorable in some circumstances. NPM1 mutation is a mutation which can persist throughout the disease course of patients with AML. Novel therapies, specifically Menin inhibitors, have been designed that may be able to target the underlying biological underpinnings of NPM1 mutant disease and are in clinical trial development at this time.
How Are Patients Tested for Mutations, and When Should a Patient Be Retested? How Does the Mutational Status Impact Treatment Decisions?
Dr. Wang: It's important to recognize that acute myeloid leukemia is an incredibly complicated and heterogeneous disease. It is many, many, many different types of disease rolled under one diagnosis. So, with the exception of FLT3 mutations, every other mutation that is found in acute myeloid leukemia occurs in less than 20% of patients. The majority of mutations that we identify are, in fact, found in less than five or 10 percent. In addition, those mutations can occur singly or together. And it's not just the specific mutations, but sometimes the co-mutations which can confer not only prognostic, but therapeutic challenges.
Therefore, it is incredibly important, given the fact that we now have targeted therapies, for specific mutations, i.e., FLT3, IDH1 and IDH2, to perform molecular mutational testing at diagnosis. Many studies have suggested that that mutational information can potentially be obtained within a short interval of time, in some centers in less than three to five days or definitely in less than a week. Because those mutations can have impact in the choice of therapy and the inclusion of targeted therapy, it is highly encouraged that practitioners await the results of specific mutational testing before proceeding with and selecting an upfront regimen.
It's equally important to recognize that given the complexities of the disease at the time of diagnosis that there can be even further complexities which occur over the treatment course. Single cell sequencing studies have subsequently demonstrated that not only is AML complicated overall, but there can be many different mutations or different disease clones that are present at the time of diagnosis, and those can evolve over the treatment course. Therefore, it is equally important, if not more so, at the time of disease recurrence to repeat that mutational testing, again, looking for FLT3 and IDH1, IDH2 mutations which can be targeted with specific agents, but also to look for additional mutations which may make patients eligible for additional experimental therapies including p53, MPM1, and KMT2A mutations.
Therefore, what I would recommend, and what I personally do, is to perform mutational testing throughout the continuum of the disease process to allow myself to have the most accurate and appropriate information on the biology of the disease in the patient as we move forward with selecting the optimal treatment regimen for individual patients.
Are There Any New FLT3 Inhibitors on the Horizon?
Dr. Wang: At ASCO 2021, we saw data presented by Mark Levis and colleagues, and I'm happy to include that we were additionally one of the treatment sites, of a novel FLT3 inhibitor by FUJIFILMs. This novel inhibitor differs from prior FLT3 inhibitors in that it not only binds the mutant FLT3, but it does so in what we feel is an irreversible way, and that the binding and potency of this inhibitor allows it to be highly effective against FLT3 mutant cells that may have been exposed to the prior tyrosine kinase inhibitors. In this early phase study, the dose and regiment and the frequency of this [FUJIFILM] FLT3 inhibitor were determined with tolerable side effects. And a proportion of patients, most of which had been previously treated with other tyrosine kinases, including gilteritinib (Xospata), did show evidence of clinical response.
Moving forward, the development of FLT3 inhibitors, as well as combinations of FLT3 inhibitors with other agents, are going to be needed to further enhance the benefit that we see with FLT3 inhibitor monotherapy, particularly in the relapsed/refractory setting. This agent, as well as other agents in development, pave the way forward to providing long-term cure or control for patients with this very aggressive and poor prognostic AML subtype.