[ Inglês] Expert Perspective: How MPN Gene Mutations Affect Prognosis and Treatment

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Topics include: Treatments and Understanding

What do JAK2 and CALR mutations mean from a biological standpoint for MPN patients? Andrew sat down with MPN specialist Dr. Jamile Shammo of Rush University Medical Center to discuss the complicated biological mechanisms and pathways of myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET).  Listen as they take the conversation one step further to talk about how this affects patient prognosis and options for an improved quality of life.

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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.

Andrew Schorr:

I should tell you I'm living with myelofibrosis too and have been on a JAK2 three years, so I listen very carefully to everything you say.  So let's talk about the genetics.  So people hear about JAK2, JAK1.  Now they're hearing about CALR, maybe there are others.  Where are we with the genetics of understanding these conditions?  And then, of course, what do we do about it?  

Dr. Shammo:

Actually, I think it's been very exciting actually to start to understand the genetics of all those disorders, and what's interesting is that there are some shared properties between all three diseases that encompass the MPNs.  For example, we knew in 2005 that the majority of patients who have PV have JAK2V617F mutation.  Of course, there's another uncommon mutation that can also be found in PV, but that specific mutation is also shared with ET as well as primary myelofibrosis.  

And so it's very interesting to see that one mutation can give you three different phenotypes, but again not everybody had a mutation until 2013 when the CALR was identified.  And again it's very interesting  the majority of patients who are JAK2 negative did demonstrate positivity for that specific mutation.  

I think it's important to A) identify those mutations, understand the biological differences between patients who have JAK2 versus CALR, and I think we're starting to understand that.  And then more importantly in my opinion I think is to understand what does it mean actually from a biological standpoint.  Is there any therapeutic target that we can be maybe thinking about and hopefully improving quality of life potentially, letting people deal with this disease as a chronic illness?  So I think that's the ultimate goal.   

Andrew Schorr:

All right.  Let's go over this a little bit, because some people they're all new to this.  When we say that we're identifying a certain gene in a disease, we're not talking about genes on whether or you have hair or not or brown hair or dark hair or blue eyes or brown eyes, but we're talking about a gene that's making the cells go wrong, right?   

Dr. Shammo:

Correct.  So these are not hereditary conditions.  I mean there are patients who deal with MPNs, a familial form of MPN, but they tend to be a minority.  

Like I have a couple of families that have—more than one person has an MPN in particular, but in general these are all acquired disorders of hematopoietic stem cells.  So if—I don't think you would find the CALR in let's say an oral mucosa, cells taken out from a different site other than the bone marrow.  In fact, not all the bone marrow cells are positive for CALR or JAK2 for that matter, so you may have a mix of both.  So that's an acquired mutation.  

Andrew Schorr:

All right.  So what you do in research and what the drug companies try to develop is a targeted therapy that sometimes can turn off that cancer gene, right, so you can live longer and live better?  

Dr. Shammo:

For example, when the JAK2 mutation was discovered there was a great deal of interest in developing JAK inhibitors just to see what that would do for the disease, and we know that we have—Jakafi, for example, is the first drug that was approved by the FDA.  

So that's sort of a very positive result of scientific endeavor that resulted in the identification of a mutation, and now you have a treatment for it.  So it will be interesting to see if the same thing will develop in CALR. But I think there it's a little bit more complicated, because we know what JAK2 does, whereas with CALR I think it's unfolding as to what does the mutation do in cells that have that specific mutation.   

Andrew Schorr:

And you were talking about understanding the biology, so you have to understand what's significant, not just identify it.  Is it significant, and then do you treat different patients based on what you find differently?  And it doesn't sound like we quite know that yet.   

Dr. Shammo:

Exactly, because again we learned that from clinical trials.  So if you look at patients who are enrolled on, for example, the JAK inhibitor ruxolitinib (Jakafi), people responded regardless of whether or not they were JAK2 positive.  So it tells you that there are certain pathways that may be active in these disorders that may be turned on by that mutation, but it doesn't mean it's the only reason why those pathways are turned on.  

There may be others.  It's sort of a tree of enzymes that could get triggered on and off for some reason, and the mutation makes it like the most clear pathway, if you will, but I'm sure there are other mechanisms for that activation as well.   

Andrew Schorr:

So will we hear about other acronyms, if you will, going forward, do you think, and we say, oh, we found this gene, and we found that gene?   

Dr. Shammo:

You know, after the discovery of the CALR it left you sort of with maybe 10 percent of patients who have ET and MF that don't have any identifiable mutation, but I bet you that's probably going to be forthcoming in the future.  But right now I think we're working with a pretty sizable number of identifiable mutations that are actually amenable for testing in the laboratory, so we can identify those patients.  The real question is what to do about it.  

Andrew Schorr:

What's significant?  Okay.  But given where we are, and we've seen a wonderful response from a lot of people, I'm among them, and we hope it's lasting… 

Dr. Shammo:

Yes.   

Andrew Schorr:

…and we hope our other blood counts stay stable… 

Dr. Shammo:

Continue.  

Andrew Schorr:

…and we live well.  How are you feeling about things, as someone devoted to this field?  

Dr. Shammo:

I think any time you have an additional therapeutic tool, if you will, it's magnificent to actually have that.  Like when you look at the CML story, it started out with interferon, a very similar paradigm, and then now you have six drugs on the market so—with amazing activity.  So to have more options is always a fabulous thing.  To me, what's important is to understand what option works for what patient, and I think that's where the research is going.  

Andrew Schorr:

Okay.  So I have a little message, and I hope you'll agree, certainly she's a specialist in this.  This becomes increasingly complicated, if you will, in understanding your situation, does it relate to a current therapy or one in a clinical trial.  Who gets what medicine when, and what is your specific situation.  So stay tuned, but if you haven't, check in and at least get a second opinion, I'd say with someone who is an MPN specialist.  Thank you so much for being with us.   

Dr. Shammo:

Thank you.  Thanks for having me.   

Andrew Schorr:

And we'll have you back.  This is a fascinating area, and I wish you well in all the work you do… 

Dr. Shammo:

Thanks.   

Andrew Schorr:

…because that makes a big difference for us.  

Dr. Shammo:

Thanks to you, too.  

Andrew Schorr: 

Andrew Schorr.  Remember, knowledge can be the best medicine of all.  

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 November 18, 2015