Genetic Mutations in MPNs: Learning About Prognosis and Progression

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Topics include: Treatment and Understanding

Are there other genetic mutations myeloproliferative neoplasm (MPN) patients should be aware of besides JAK, calreticulin or MPL? How do these mutations affect disease progression? MPN experts Dr. Angela Fleischman from UC Irvine Health and Dr. John Crispino from Robert H. Lurie Comprehensive Cancer Center discuss the latest MPN prognostic tools and how mutational status can be used to assess the risk of disease progression and identify an appropriate treatment plan. Dr. Fleischman and Dr. Crispino also share findings on patient response rates to therapies from recent clinical trials and research projects from each of their labs. Watch now to learn more about diagnostics and treatment for MPNs. 

This is an MPN Research Foundation program produced by Patient Power. We thank Incyte Corporation for their support.

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Transcript

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

So prognostic tools; do you have anything there? You were saying, “Well, we’re trying to figure out who’s gonna progress, or where you are in the course of your journey with an MPN.” Have we come anywhere with that? We mentioned some of us have been tested. I just got a rejection from the insurance company for the Foundation Medicine test that I had a while ago. It’s kind of frustrating, because they say some of these tests are not FDA approved, etc. There’s a lot of frustration there, but yet these genes are being identified. Can that help us know where we are with our journey and where are we with prognosis and testing?

Dr. Crispino:       

Well, certainly knowing what other mutations are present besides JAK or calreticulin or MPL are very important in determining where you stand in terms of the risk profile.

Some of these genes that we know about, TET2, for example, or DNMT3A, or what we call splicing mutations; some genes that regulate how genes are spliced together. I won’t go through that detail. But knowing those can help us decide where you might be in the progression of the disease. And Dr. Fleischman might be able to comment a little bit more on that aspect. 

Andrew Schorr:

Sure, please.

Dr. Fleischman: 

Yes, and I agree. I think that’s an emerging – I think that’s where science is moving forward in terms of we’re starting to learn that the mutations that an MPN person has, besides their JAK2 or their calreticulin or their MPL, are very important for their disease in terms of sort of predicting what’s in store for them in the future, as well as I think potentially really informing what sort of therapy would work best for the person. 

I was struck by, in a lot of these clinical trials, although the numbers are small, there were a few people that really—of a group of 30 clinical trial patients, a few people had a great response. If we could identify what is special about I guess you could say the super responders in each of the clinical trials and say, okay, maybe they had a certain set of genes that were mutated, so how I envision maybe in the future a person would know exactly what their whole mutational profile is, and then we could decide that they would be best suited for X or Y treatment. I think the mutations have importance, not only for prognosis, but potentially also for helping us guide treatment for the person.

Andrew Schorr:

Okay, so are we gonna have calreticulin inhibitors or a MPL inhibitor, or where are we headed with that?

Dr. Fleischman: 

So because calreticulin, the mutations make a new protein, so a little snip of a new protein that’s different from the normal calreticulin, it makes a lot of sense to try to use immunotherapy. I know in the news there’s a lot of —heard about these CAR T cells, as well as immunotherapy. Immunotherapy has been very successful in other types of leukemias, in particular lymphoid leukemias, so obviously there’s a lot of enthusiasm to try to use immunotherapy in myeloproliferative neoplasms. Calreticulin seems like a very good target.

Not necessarily in the clinical trial abstracts, but in more of the basic science, there has been some significant progress developing immunotherapy approaches for MPN, in particular calreticulin-mutated MPN.  

I guess that’s what—not exactly answering your question, but getting at sort of approaching calreticulin mutated patients with immunotherapy. In terms of MPL, maybe John can comment on this a little bit more. I know from Ron Hoffman’s group, I had seen some presentations previously about some MPL antagonists or MPL blocking—an approach to blocking MPL. I did not see any abstracts on that approach this year. 

Andrew Schorr:

Dr. Crispino, just to set that up for patients, so over the last two, three years at ASH, we’ve been hearing about these other genes that seem to be active in us with MPNs.

I know you try to figure out who’s sort of driving the bus, who’s really responsible for the problem, even whether they’re there or just along for the ride or whether—but so where are we now then? The community discovered the JAK gene, and we inhibited that, and that’s helped some people. It would make sense, it would seem, if you inhibit some of these others, that would be to the good. 

Dr. Crispino:       

Yeah, that’s absolutely where the research has been heading. I would say two things. First of all, there is a lot of work using animal models to see, when you combine JAK2 with some of these other mutations, such as splicing factor mutation, does that cause a worse disease? In many cases, we do see that. Let me just focus on the splicing factors again. There are drugs that will target what we call the splicing machinery in cells. Cells that already have a mutation might be more sensitive to these inhibitors than normal cells. There are studies, not in myeloproliferative diseases, but in other forms of hematologic malignancies, that suggest that these drugs might help.

And so we used that same theme cutting across the MPNs, that other pathways that are affected in some way might be more sensitive to those therapies than normal cells. We call that synthetic lethality. We do see a lot of people using those approaches these days.

Andrew Schorr:

Now this is in the lab, so how do these concepts that you’re talking about, how do we get them out of the lab and at least in trials for us? How does that happen?

Dr. Crispino:       

So you just set me up to talk about my own research, which we work on an aurora kinase inhibitor called alisertib. So about 10 years ago, we initiated a project to develop drugs that would target the abnormal megakaryocytes that are in patients with myelofibrosis. You may know that megakaryocytes are the cell lineage that make platelets, and they’re abnormal clearly in myelofibrosis. So we embarked on a program to figure out how we could eliminate those cells and discovered a drug called alisertib that that has this activity in animal models.

In collaboration with clinical colleagues, including Ayalew Tefferi at the Mayo Clinic and Brady Stein here at Northwestern and Ronan Swords at University of Miami, we have been able to bring this to a Phase 1 study. We just completed enrollment at 24 patients. We presented some of the preliminary data at ASH, and it’s very exciting. But as I think you mentioned earlier, you’re hoping for a home run. It’s not a home run, but it looks like it has a very interesting, unique activity in the bone marrow to correct these abnormal megakaryocytes. So as this study matures, we’ll have a better sense for what happens when you do eliminate these megakaryocytes. How does that help fibrosis in the disease? 

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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Page last updated on March 28, 2018