How Gene Mutations Are Affecting Diagnostic and Therapeutic Approaches in MDS and MPNs

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Topics include: Treatment

Patient Power was on site at the inaugural U.S. Focus on MDS/MPN Meeting in Dana Point, California. Dr. Srdan Verstovsek from MD Anderson Cancer Center and Dr. Ruben Mesa from Mayo Clinic Cancer Center joined Patient Power to discuss how new understandings of complex gene mutations are impacting diagnostic and therapeutic approaches for MPNs. 

Sponsored, in part, by Incyte Corporation with additional funding through an educational grant from Geron Corporation.

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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.

Dr. Verstovsek:

Okay.  Hello and thank you for joining us here in sunny California.  My name is Serge Verstovsek.  I'm a professor in the leukemia department at MD Anderson Cancer Center in Houston, Texas.  I'm joined here with my friend and colleague, Dr. Ruben Mesa. 

Dr. Mesa:

Hello and, Serge, it's a pleasure to join you.  I'm Ruben Mesa.  I'm one of the hematologists at the Mayo Clinic in Scottsdale where I'm a professor of medicine at the Mayo Medical School and someone focused on the interests of patients with both MPNs and MDS. 

Dr. Verstovsek:

Yes, indeed.  We are here at the first United States Focus on the Myeloproliferative Neoplasms and Myelodysplastic Syndromes meeting, and we are happy to report on the new developments in the field.  We have two days of intensive talks and discussions, talking about the biology and therapy of MDS and MPN.  The first session was quite interesting, a lot of discussion about the new developments in our knowledge about the biology, developments of mutations that we are now aware of in MDS and MPN and how this possibly can impact our diagnostic and therapeutic approaches. 

What did you find specifically relevant at this point in time in our understanding of complexity of myeloproliferative neoplasms?  Now that we know about so many mutations, what do we do about it? 

Dr. Mesa:

Well, it's a good question and one that I discuss with my patients when I visit with them as well.  We're in a period where we have learned more about the genetics of the diseases of myeloproliferative neoplasms, MDS, and this related family of diseases that affect the bone marrow more than ever before.  I do share with them that I think they're going to be very impactful, but it's an evolving process. 

So at the moment, one can think about it that we're trying to put together one of these 500?piece puzzles.  Let's say we're building a picture, a picture of an elephant with these 500 pieces, and what we're finding is we're finding more and more of these pieces.  What we still don't have is how necessarily all of the pieces fit together and how do we look at the entire puzzle as one picture, so how it relates to one individual patient.  Does that change how we treat them?  Does it change how we think about their disease?  I think we're learning that in pieces. 

I think from the discussion, which was a very good one, we're finding that certain puzzle pieces, even as we stand, might have importance in terms of being certain about the diagnosis or about how we might predict the disease might behave or even some early information about treatment.  But I think where we are is we're in the middle of a journey where the end hopefully has us having genetic information be a strong guide.  At the moment, I think it's an evolving process.  In some patients, the genetic information is more informative than others. 

Dr. Verstovsek:

Now, we all know about the cascade of proteins that is inside the bone marrow cells that activates the cells to make them grow.  This is so?called JAK?STAT pathway, and in all the myeloproliferative neoplasm patients that is the main problem. 

We learn about two types in a way of mutations—one that activates the JAK?STAT pathway, makes cells grow.  These are exclusive mostly of each other and are very useful for diagnostic purpose.  We now know about many others that are not exclusive of each other.  They may be or may not be present in many patients all alone, and they may acquire [things] that are related to the genetic expression of different genes that we don't even know about. 

And something like that has already been discovered and is being evaluated for prognostication in myelodysplastic syndrome.  It looks like we are trailing a little bit behind, but we are catching up. 

Dr. Mesa:

Correct.  I think what patients should feel reassured about is that as we learn about diseases that are related to one another those observations can be very relevant.  So there are some things that we have found that have been more specific to MPNs, like let's say the JAK2V617F, and others that can be present in related diseases.  So we can learn a bit from each other as they're all kind of members of a different community of individuals with overlapping diseases. 

So some of those findings that are in MDS, one can show us the road in terms of finding the mutations, but do some of those mutations themselves such as TET 2 or ASXL 1, they may have relevance in both camps. 

Dr. Verstovsek:

And in the myelodysplastic syndrome session there was a lot of discussion how the genetic complexity of each individual patient may or may not affect the outcome of the therapy.  We are not there yet with the MPN therapies because we don't even have too many, but there were a lot of discussions how the azacitidine and decitabine, the two medications approved as a therapy for MDS fare in the different populations of the patients based on the genetic profiling. 

And in these overlap syndromes that you mentioned, there is a group of rare diseases that have characteristics both of myelodysplastic syndrome and myeloproliferative neoplasms like chronic myelomonocytic leukemia. There are publications that clearly delineate that genetic complexity will result in a different outcome when patients are treated with one particular medication. 

Dr. Mesa:

I think it's a very informative time.  I think similar to as we've seen discussed in MPNs where at the moment these genetic mutations are helping us refine our understanding or predict things of response.  Just as we've seen patients with MPNs, let's say myelofibrosis, where there has been traditionally prognosis separated by mainly clinical features such as blood counts or symptoms or blasts, where now these features might help to delineate even in people that have low risk by the traditional criteria, they might have slightly higher risk disease. And we might need to consider more aggressive therapy based on a certain genetic profile.  So it's—it's really a period of rapid growth of information.  

Dr. Verstovsek:

Dr. Stephen Oh had a nice presentation on exactly this point, how we are at a fast pace of acquiring knowledge about the biology and complexity.  On the other hand, there was a discussion whether is it really at a time now to already incorporate genetic profiling in our decision?making, what to do with the patients, which is reflective also in myelodysplastic syndrome area because there are not too many medications to choose.  So genetic complexity, prognostication based on mutational analyses, is it time to apply to when you don't have medications to really affect it? 

Dr. Mesa:

It's difficult.  When the bench of options are few, it's very difficult to exclude patients from a certain therapy on this basis.  These studies are interesting, but largely they're really looking in the rearview mirror.  In terms of patients who have already been treated, we looked at their profile at any point along the way and saw how they behaved.  That's slightly different than if we typed everyone ahead of time and then chose therapy up front and saw who did better and who did worse.  So it's a subtle difference, but how predictive they are is something I think we'll have to learn a little bit as well. 

I do agree with you. If I'm a patient and the only therapy available to me is a hypomethylating therapy, I'm not quite sure that just the genetic profile would be the reason I would want to be excluded from receiving the only therapy I'm eligible to get. 

Dr. Verstovsek:

And in myelofibrosis, it seems that the genetic complexity does not really influence the outcome of therapy with ruxolitinib. 

Dr. Mesa:

Correct, and I think part of that might really be the overlap where the different aspects of the genetics still are feeding at the same trough.  So the ruxolitinib (Jakafi) in particular since it inhibits the JAK pathway, and all of these different mutations seem to be inhibiting that pathway, it may just be a reflection that no matter how you're inhibiting the—affecting the pathway through the mutations the pathway still matters, so inhibiting it is beneficial almost regardless of how you got there.  

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 September 10, 2014