Pathobiology of Acute Myeloid Leukemias (AML)

Transcript:Ruben A. Mesa, MD, FACP: Hello, and thank you for joining this OncLive TV Peer Exchange. Genomic and epigenetic studies have led to novel insights into the biology of acute myeloid leukemia. These insights provide important information pertaining to dysregulated pathways involved in leukemic transformation, potential new therapeutic targets and risk-adjusted approaches to treatment.

In today's panel discussion, my colleagues and I will discuss the latest advances in treatment and supportive care for patients with acute myeloid leukemia. I, myself, am Dr. Ruben Mesa. I'm the chair of the division of Hematology and Medical Oncology, a professor of Medicine, and the deputy director of the Mayo Clinic Cancer Center.

Joining me today are Dr. Rafael Bejar, an assistant professor in the Division of Hematology and Oncology at the UCSD Moores Cancer Center. Dr. Elias Jabbour, an associate professor in the Leukemia Department at the MD Anderson Cancer Center. And Dr. Rami Komrokji, clinical director, senior member and professor of Oncologic Sciences in the Malignant Hematology Department at the Moffitt Cancer Center. Thank you each for your joining us today. Why don't we go ahead and get started?

So first, we're going to be focusing on the biology of acute myeloid leukemia. And Rami, perhaps I'll reach out to you with having this discussion. First, what do we know about the pathobiology of leukemia in this day and age in terms of the hematopoietic stem cell alterations, microenvironment, aberrant signal transduction? We're learning a lot here at this American Society of Hematology meeting. Give me a flavor of what we're learning at this meeting.

Rami Komrokji, MD: I think we have learned in the past several years much more than we've known in the past, and obviously with the newer technologies that have to do with next-generation sequencing on patients, we've been learning a lot. I think we know about the somatic mutations in those patients. We've learned about their role in terms of what are some of the founder mutations, what are some of the driver mutations in the disease.

Obviously, there are things we already have been using, and in practice, even sometimes risk stratifying patients. So, for example, based on the FLT3 status of the NPM1, we know that those are important factors. We know that leukemias are probably oligoclonal disease. There are few clones that compete; there are several changes at different levels.

We learned from MDSM that those diseases are mostly diseases that have epigenetic alterations. We learned about the spliceosome machinery changes in those diseases. So I think there is a lot of information that's been coming that will be helping us in understanding the disease, and obviously the more we understand about that, the more we'll be able to see if we can target some of those pathways in terms of translating that into therapy.

Ruben A. Mesa, MD, FACP: I would agree with you entirely. It's really been, even during my relatively brief career, quite an evolution from where we really started, that it was all about histology. Which of those FAB subclassifications? Is it a 4; is it a 5? There was a lot of handwringing over those sort of histologic features that, largely, we didn't find had, with the exception of APL and a couple of others, a big impact on how we chose therapy.

I think clearly it was cytogenetics. A bit more crude, but very helpful approach to learning about the genetic environment. And now, it's just at such a different level between the mutations, the epigenetic mutations. Rafael, this has been an area of great interest for you. As we think, particularly, around epigenetic mutations, and trying to think about these different sort of categories, how do you view our understanding?

Rafael Bejar MD, PhD: I think the more that we've actually delved into the biology of AML, the more we learn that this really isn't one disease, and we got a sense of that already just by looking at the cytogenetics. There were certainly chromosomal translocations that identified subtypes of disease that we've known about for some time.

But even when we focus on those patients that have normal cytogenetics, we know that at the genetic level there probably are a variety of different disorders. And some of them are defined by those mutations you discussed, the epigenetic regulators. And genes with names like TET2 and DNA methyltransferase 3A. And at the moment, while we don't have therapies that are directly targeted to them, understanding these molecular subgroups of AML will help us develop those treatments in the future, and some of them are actually quite close on the horizon.

Ruben A. Mesa, MD, FACP: Very good. Now we're learning more about the microenvironment in stem cells that is part of this niche, as well. Elias, you've clearly had a very strong career focusing on new drug development in the myeloid space overall. How do you think, as we're looking at, not only the genetics, but also the microenvironment, the stem cells, they're playing a role?

Elias Jabbour, MD: At least there were plenty of drugs being assessed. Some of them are being presented at the ASH meeting, the year before at ASCO, and hopefully moving forward, there will be more drugs. Rafael mentioned some mutations, we're going after them from the IDH2 inhibitors and others.

We know that the cancer cells survive by inhibiting the apoptosis and then death of the cells. We have new compounds, ABT-199, anti-BCL2, MDM2 inhibitors, trying to focus on multiple facets of this cancer life and trying to control cancer. Obviously, these are not enough.

We don't think with one pill or one drug we're going to cure cancer. But learning more from the biology and trying to implement some strategy, we can get therapy of combination, with ultimately dissecting the disease, and implement the best strategy to control cancer and hopefully get to the cure one day.

Ruben A. Mesa, MD, FACP: Absolutely. I heard you mention in the individual. You know, in all of cancer we're really focusing on this concept of individualized medicine or precision medicine, or there's a variety of synonyms for it. But really seeing what a broad spectrum these patients really have, in terms of their disease, not only clinically, but all the different pathways that they can take from the truly de novo to the secondary AML.

Many of us have a strong hand in other chronic myeloid disorders as well, whether they be myeloproliferative or myelodysplastic, including though there's a variety of paths that one can follow into that.

Rami Komrokji, MD: Right. I think going to the microenvironment point, a couple of things. I think first, as you were mentioning in diseases like even myelodysplastic syndrome, we are learning a lot about the role of the inflammation that's happening, and that can actually be a triggering factor for some of the mutations that happen. And in acute myeloid leukemia, even clinically, our observation is, it's always very easy to clear the blasts from the peripheral blood, or if you do test tubing, you kill the blasts.

But when you do the treatment for patients, there's some protection from the microenvironment for the myeloblasts in the bone marrow that doesn't allow the same phenomena to be observed. For example, from my clinical experience with FLT3 inhibitors, alone, single agent, you could clear the peripheral blasts very easily. But when you repeat the bone marrow, it seems that those are protected by the niche or the microenvironment it’s supporting those.

So some of the targeted therapy or some of the methods had been as old as priming of the cells with growth factors to more like inhibitors of this interaction or the protection from the microenvironment for the cells. So I think definitely there is a role for a microenvironment in those diseases.

Elias Jabbour, MD: Practically, we have, to add to what Rami is mentioning, the stem cell mobilizer, used in autotransplantation in myeloma and lymphomas. There are trials assessing CXCR4 inhibitors, moving the leukemic cells to the blood flow, and trying to kill them, with other agents, like sorafenib, for example.

We did a study at Anderson where we combined a CXCR4 inhibitor plus sorafenib, with the aim to get the cells out of the natural stem cell environment, and then give them sorafenib to kill the cells.

Transcript Edited for Clarity