Hetty E. Carraway, MD, MBA
The shift toward more individualized, molecularly informed approaches to treatment in acute myeloid leukemia (AML) is essential to optimize outcomes, as demonstrated by growing evidence that minimal residual disease (MRD) status can accurately inform transplant decisions, and the reliance on molecular phenotype to determine potential benefit with emerging agents, such as menin inhibitors, according to Hetty E. Carraway, MD, MBA.
At the inaugural Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Meeting, expert oncologists delved into ongoing innovations as well as critical diagnostic and therapeutic gaps in the management of AML and myelodysplastic syndromes (MDS), among other hematologic malignancies. Following the meeting, a consensus manuscript outlining key advances, expert treatment recommendations, and other emerging considerations for disease management, was published.
In an interview with OncLive®, Carraway expanded on these topics and provided additional insights on the necessity of molecular profiling at diagnosis for identifying optimal first-line therapies in AML; factors for consideration when selecting a first-line treatment approach for older or molecularly-defined AML subgroups; and the potential for MRD-guided therapy, particularly in FLT3-ITD–mutated AML.
“There are gaps not just in the treatment of patients [with AML and MDS], but [there are] also [gaps] in the classification of their diagnosis, as well as identifying and using tools to better help us with prognosis and making shared decisions about treatment,” explained Carraway, who is a staff associate professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Ohio. “This [manuscript] is a fantastic culmination of work, year after year, to see where the gaps are.”
Carraway also serves as vice chair of Strategy and Enterprise Development at the Taussig Cancer Institute in the Division of Hematologic Oncology and Blood Disorders at the Cleveland Clinic and is a member of the Immune Oncology Program at Case Comprehensive Cancer Center.
OncLive: What is the importance of publishing this manuscript from the Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Meeting?
Carraway: This has been a fantastic effort to highlight where the gaps are in our space as we understand the kinds of treatments for patients with MDS and acute leukemias. [It is important to] come together and understand the current [treatment] landscape, where the needs are, and then the real application of all of that [data]. There can be these gray zones, and [we need to figure out how] to handle them.
[This manuscript also] highlights where our future goals should be focused, [so we can] hone in on what we need to prioritize for patients and the community.
What is the ideal management strategy for patients with AML between 65 and 70 years of age?
This one is more challenging. There are a number of studies that we’re waiting to read out. Currently, we know that the FDA has approved the combination of azacitidine [Vidaza] and venetoclax [Venclexta] for patients over the age of 75. In our younger patients, we typically use standard cytoreductive therapy, including 7+3.
In this [65 to 70] age range specifically mentioned, which [regimen] should we use, and is there evidence that we should use one or the other? We are using some of our molecular phenotype [data] to help us sway in one direction or the other, particularly with regard to mutations that may indicate this is more an MDS [to] AML diagnosis rather than de novo AML.
Certainly, in our patients with core binding factor leukemias, we know those types of leukemias tend to do well with high-dose cytarabine in consolidation and intensive chemotherapy. There are certain phenotypes, depending on the molecular profile, that may push us in one direction or the other.For patients with FLT3-mutated AML, we’re leaning more toward 7+3 and a TKI, and then use that approach to try to get a patient to transplant.
Again, some of this is nuanced; it depends on the molecular phenotype and/or particular agents that are now out and being used. Some [ongoing developments] we’re excited about now is the use of menin inhibition in patients with NPM1-mutated AML, as well as KMT2A-rearranged AML. It’s important to be aware of these ongoing clinical trials, and the landscape is going to be changing for these patients. We’ll have yet more questions that emerge, hopefully, as more of these agents get FDA approved.
What is one key action item to identify the most optimal first-line treatment regimen for fit patients with newly diagnosed AML?
I would again turn to the molecular phenotype. Specifically, knowing whether they harbor a FLT3 mutation, whether there is an NPM1 mutation, and whether there is a clinical trial that allows us to incorporate a menin inhibitor—these are essential in really understanding the type of leukemia you’re working with and better refining and choosing the best therapy in the up–front and first-line setting.
What is the current role of MRD-guided therapy in FLT3-ITD–mutant AML?
We now have fantastic tools to measure MRD, and because of this particular high-sensitivity test, we’re able to determine whether FLT3 inhibitors are helping the disease reach a deep molecular remission.
What we’ve learned from some of these studies is that in the post-transplant setting, for patients who have MRD testing that is negative prior to transplant, we’re not quite sure they need to proceed to transplant. In contrast, patients with MRD-positive disease before transplant are the ones who really benefit from transplant and having access to FLT3 inhibition post-transplant.
There are still some remaining questions to be answered, but this represents exciting progress for patients. If we can identify those who do not require transplant, that would be a major advance. We need to double down and figure this out for our patients. The current state is that we are very excited about the available FLT3 inhibitors, which appear to be highly potent, and we are also grateful for the tools we now have to evaluate MRD and make critical treatment decisions.