Targeting AML: The Latest Advances

Sangeetha Venugopal, MD, MS

Patients with acute myeloid leukemia (AML) have benefited from recent advancements in treatment. The advent of drugs targeting specific genetic mutations, such as FLT3, IDH1, IDH2, NPM1, and KMT2A, as well as improved methods for genetic testing have changed the landscape for physicians and the patients they treat. Still, questions remain on how to best optimize treatment protocols.

In an interview with Targeted Oncology^TM for Leukemia and Lymphoma Awareness Month, Sangeetha Venugopal, MD, MS, assistant professor of medicine in the leukemia program, the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, discussed the evolving landscape of AML treatment as well as unmet needs among these patients.

Targeted Oncology: What are some of the unmet needs among patients with AML?

Microscopic examination revealing red blood cells, white blood cells, neutrophils, eosinophils: ©AkuAku - stock.adobe.com

Venugopal: AML [is mainly] an older age group [of] patients. The median age of diagnosis is 69 years, but that does not mean that it does not occur in younger patients. The treatment that revolutionized the survival outcomes in older patients is hypomethylating agents in combination with venetoclax [Venclexta]. We can give this treatment indefinitely, meaning there is no stopping point. What I would like to know, and most of the patients would like to know, is if there is a stopping point for this treatment? And if that is the case, what are the subgroups where we can stop treatment? I am sure it is a selected subgroup of patients who with whom we can stop treatment.

How has the treatment of AML evolved in the last 10 or so years?

I started my fellowship in 2017, and 2017 was the first year that saw the approval of midostaurin [Rydapt], which targets FLT3 mutations. Since then, we have had several drugs approved for special molecular subsets, and that has changed the treatment landscape of AML immeasurably.

Especially for FLT3, we now have now 3 drugs that target the mutation because it is one of the most common molecular subgroups. Those are midostaurin, which targets both FLT3 [internal tandem duplication (ITD)] and [tyrosine kinase domain (TKD)], gilteritinib [Xospata], which targets the FLT3 ITD and TKD, and quizartinib [Vanflyta], which targets FLT3 ITD.

We have a couple of other [targets], including IDH1, and we have 2 medications to that target the IDH1 mutation. One is ivosidenib [Tibsovo], and the other is olutasidenib [Rezlidhia], which was approved recently. For IDH2, we have enasidenib [Idhifa].

The other exciting aspect that I am looking forward is that we have a new kid in the block, which is a Menin inhibitor, and that targets against NPM1 mutation and KMT2A rearrangements. I am looking forward to how this is going to play out for Menin inhibitors.

How do you go about assessing the best course of treatment for a patient? At what point does molecular testing come into the process?

The molecular landscape of AML is dynamic, so we do genetic testing at diagnosis, because we incorporate FLT3 inhibitors on day 8. We need to know the genetic makeup of the AML before we decide on whether we are going to add a FLT3 inhibitor or not, and FLT3 inhibitors are added in frontline treatments. We [do molecular testing] at diagnosis to incorporate the molecularly targeted treatment, and we do it at remission, which is treatment assessment of the bone marrow at the end of the first cycle of treatment, to know if the molecular aberration is still present or absent. That would help us decide how the how the prognosis is going to be, because some of these patients may be going to transplant. In those patients, we want to make sure that they do not have any of these molecular aberrations left to give a best possible outcome for transplant. After that, we do molecular testing at any time the AML relapses in a patient, mainly because we need to know the dominant clone that is driving this leukemia. Was this the same molecular aberration that was present at diagnosis, or is this something new that will affect the management?

What role does measurable residual disease [MRD] play in determining treatment?

We measure the residual disease by 2 ways. One is through flow cytometry, and the other is specific testing for molecular subgroups. Looking at the measurable residual disease, we want to look at a deeper level than the morphology and the pulse sequencing. The measurable residual disease needs a depth of at least 10^-5.

The reason why we are looking at measurable residual disease is because it predicts the outcomes in long-term outcomes. For example, in a patient with core binding factor leukemia, if we track the measurable residual disease by, especially for the [inversion 16] and RUNX1-RUNX1T1 translocation, and when we track it, we can find if, at some point, they lose that response. For example, all along it is negative, and suddenly we see something like popping up which is positive, even though it is low-level positive. Then we increase the frequency to see if we can intervene before there is a frank morphological relapse. Right now, we do not intervene if it is just molecular relapse; however, we monitor the MRD more frequently than usual if we see that the level of MRD is rising.

Who do you consider referring for transplant with AML?

All patients must be referred for evaluation for hematopoietic cell transplant, regardless of the age, because sometimes the biological age may not matter. Sometimes, the biological age may be lesser than the chronological age. I do think that all patients would benefit from referral for hematopoietic cell transplant.

REFERENCE:

Venugopal S, Sekeres MA. Contemporary management of acute myeloid leukemia: a review. JAMA Oncol. Published online August 8, 2024. doi:10.1001/jamaoncol.2024.2662