Examining Treatment With Existing Drugs and More on the Horizon in AML

Siddhartha Mukherjee, MD

Acute myeloid leukemia (AML) is a heterogenous disease that requires oncologists to think outside of the box when treating their patients, explained Siddhartha Mukherjee, MD.

“There's not 1 AML, there are many AMLs,” explained Mukherjee, assistant professor of medicine at Columbia University Medical Center.

In recent years, risk stratification practices have made it clearer which treatment-naïve patients are candidates for chemotherapy or transplantation. For patients in the relapsed/refractory setting, oncologists have a better understanding of allogeneic transplantation with post-transplant therapy. Moreover, targeted therapies have made it possible to address the unique genetic makeup in some patients with AML.

Clinical trials in AML continue to evaluate chimeric antigen receptor (CAR) T-cell therapy approaches for the treatment of the disease, and agents that have demonstrated positive results in other hematologic malignancies are making an appearance in AML studies as well.

In an interview with Targeted Oncology™, Mukherjee, examined the current treatment landscape for AML and therapies on the horizon.

TARGETED ONCOLOGY: What is the golden standard for frontline treatment of AML?

Mukherjee: First, the thing to know about AML is that it's a very heterogeneous disease. … The first thing we try to do is to subdivide patient populations based on their risk. So, if they're low risk, intermediate risk, or high risk, and these are defined by gene sequencing, patients who are low risk generally tend to respond better to chemotherapy. Patients who are intermediate/high risk generally tend to respond poorly to chemotherapy, and of course, those with high-risk disease respond extremely poorly to chemotherapy. Therefore, those low-risk patients are usually treated with chemotherapy upfront. High-risk patients are generally treated with a directionality towards allogeneic transplantation, and with intermediate-risk patients it's at the physician’s discretion.

There are 2 or 3 targeted therapies that are available for genetic mutations One of them would be for patients who are positive for FLT3 mutations, and midostaurin [Rydapt] is 1 therapy available for them. Then, some patients have mutations in the IDH gene, and again, there are some IDH inhibitors available for them. That's been the standard of therapy for the frontline.

What is the standard-of-care treatment in the relapsed/refractory setting?

For relapsed/refractory AML, aside from enrollment in a clinical trial, allogeneic transplantation remains the core of treatment. There are probably 100 trials that combine allogeneic transplantation with post-transplant therapy or different regimens to enable allogeneic transplantation. But I repeat that the core therapy remains allogeneic transplantation.

Which clinical trials can you pinpoint that are illustrating the promise of CAR T cells for the treatment of AML?

There are very few CAR T-cell trials in AML that have shown a lot of promise. One trial I will point to is a trial in which WT1 was used as a target for CAR Ts. This work was done in Seattle, Boston, and several other places.

Also, I am involved with a trial in which we delete an antigen from the donor cells and then use that. The fact that now these normal cells don't have that antigen, while the AML cells have that antigen, we can now direct CAR T cells against AML cells. CD33 is 1 of them. There are a few other entities that we're working on. And all of a sudden now we’ve bioengineered a unique tumor cell antigen. That trial is also recruiting, and we're very excited about it. We, of course, don't have any data about it yet, but I'm optimistic about it.

What are some potential challenges with bringing CAR T cells to the AML space?

The biggest challenge is that although we've looked for almost a decade, we haven't found antigens that are unique to AML cells but are not present in normal hematopoietic myeloid or common myeloid progenitor cells. If CAR T cells eat your AML, it will also eat the rest of your bone marrow. And that's a big problem because you can't live without your bone marrow. And you can't live without your normal hematopoietic apparatus. And so, chronic irreversible myeloid toxicity is a huge challenge.

What FDA approved therapies are there in other hematologic malignancies that you think may be translatable in AML?

I think there are several. A combination of venetoclax [Venclexta] and a methylation inhibitor is a potential option. It is being used a lot and has really changed the direction of how we treat patients with AML. So, these are FDA-approved drugs that were not initially approved for AML but have now been more used in the context of AML. I already talked about the FLT3 inhibitor, and there are many more that are coming along that are more specific with less toxic profiles.

Also, I think there is a possibility of repurposing some of the FDA-approved drugs for AML therapy, particularly in the context of conditioning before transplantation. And that's an area that is very rich. Another area that's very rich is what I call post-transplant therapy. In our CAR T trial, we are first going to use the FDA-approved drug gemtuzumab ozogamicin [Myloetarg] for deleting CD33 in the normal cells.

From this conversation, what is key for oncologists to take away?

The idea is that AML is a disease understood at a genetic level, almost better than virtually any other malignancy. And to solve this disease, which has really haunted us for human history, we need to think outside