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Developments in Myelofibrosis: Ongoing Trials and the Significance of Mutations

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Published on December 28, 2012

Mayo Clinic expert, Dr. Ruben Mesa provides an update from the 2012 American Society of Hematology Meeting on important news for patients living with Myelofibrosis. He talks about where we are in understanding myeloproliferative disorders and what genetic changes patients experience that could potentially predict the behavior of the disease. Dr. Mesa also talks about combination therapies combating the disease and in some cases, reversing it. He reveals his observations of ongoing trials, drug combinations and explains the significance behind gene mutations.  





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Transcript | Developments in Myelofibrosis: Ongoing Trials and the Significance of Mutations

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:

Hello and welcome to Patient Power.  I’m Andrew Schorr.  We’re on location in Atlanta at the meeting of the American Society of Hematology.  That’s where thousands of doctors from around the world gather, and they discuss blood-related cancers.  Part of the discussion is on myelofibrosis and the MPNs, and a world expert in that field is Dr. Ruben Mesa from the Mayo Clinic in Scottsdale, Arizona.  He joins us now. 

Dr. Mesa, thank you for being with us.  Give us an update on what is being presented at this meeting and what it means for patients. 

Dr. Mesa:

Well, thank you, Andrew.  I appreciate the opportunity to speak with you today.  I’d say that there are several layers of advance.  One, understanding the disease better.  I think we’re having a better sense of the genetic changes that patients can experience and getting a better sense of how they fit together to predict how the disease may behave. 

Two, we’re learning more and more in the laboratory and in preclinical trial models of potential combinations of new drugs that might have a meaningful impact on patients with myelofibrosis, helping to delay progression of the disease perhaps, helping to reverse the fibrosis. 

Next, I would say probably the biggest set of information we have here is really a mature and more evolving story regarding the JAK2 inhibitors.  One, there is the commercially approved drug, the first approved drug in myelofibrosis, ruxolitinib (Jakafi).  With that had updates on the two key randomized phase III trials that led to the drug’s approval.  With both of these trials we are now fairly clearly seeing that individuals who had been treated with ruxolitinib (Jakafi)—now, mind you these were patients with advanced myelofibrosis, intermediate to a high risk—they are living longer having been treated with ruxolitinib (Jakafi) than if they had been treated in an alternative way. 

We had known that before with COMFORT-I, that there was a difference versus placebo, and patients were able to change over.  And, two, being reported today by our colleagues from Europe they saw this in the European study that the control arm was the best alternative therapy, therapies like Hydrea (hydroxycarbamide).  Patients not only did much better on ruxolitinib (Jakafi) but they lived longer if they were treated with ruxolitinib (Jakafi) versus Hydrea (hydroxycarbamide). 

I presented an analysis yesterday at the meeting where we delved into this issue a little further and saw that, indeed, in particular patients that had a reversal of their weight loss with myelofibrosis were living clearly longer, as well as those individuals that had other markers of advanced disease such as a lowered cholesterol were living longer.  I think we’re seeing, clearly seeing that there is a real benefit and the benefit extends well beyond the issue of just the spleen and the symptoms. 

Two other key updates.  We’re learning more about how to optimally dose the drug.  There were a couple of trials presented on use in patients with lower platelet counts, starting at lower dose in increasing, and both of those were very helpful studies. 

I would add that we’re learning more about the other JAK2 inhibitors in development.  There is a drug that completed its phase III trial accrual, SAR302503.  With that they continue to see benefit from the phase II that are being presented here at ASH, and we eagerly await the results of the phase III trial. 

There was an update on the CYT387, a very interesting JAK2 inhibitor.  They continued to see some long-term benefits in terms of anemia with individuals being treated with that drug.  That is a drug that we might expect might have a phase III trial coming up in the near future.  I think we’re seeing a lot from the JAK2 story continue to evolve, and we’re seeing that the impact is really quite substantive. 

Now, much interest focuses on what is the next step.  We’re clearly trying to fully understand all of these drugs that are in development.  But there was very interesting sets of both abstracts being presented at the meeting but as well as in the education session looking at perhaps new combinations of drugs that may be helpful.  There are new pathways involved with how cells grow and divide, that if we block these pathways it might be beneficial. 

Looking at different combinations with drugs ranging from histone deacetylase inhibitors, from heat shock protein inhibitors, PI3 kinase inhibitors, many possible combinations to both complement the obvious additional things that would benefit JAK2 inhibitors such as improving anemia or low counts but also how do we more actively arrest progression of the disease, reverse fibrosis. 

And there were a couple of other sorts of new drugs discussed as well.  There is a drug that is a telomerase inhibitor, somewhat of a different mechanism of action that had shown activity in patients with ET and PV who had had difficulty controlling their platelet counts, it’s somewhat of a new type of drug, as well as further information on interferon in a variety of ways.  There is a long-acting interferon form that is being tested in a trial in Europe. 

I would say having been in this field for many years we are really in an incredibly exciting time in that even thinking back five to 10 years ago we had very little true clinical trial data to really be guiding our treatment of patients with MPNs.  Now we have an approved drug in ruxolitinib (Jakafi).  We have other drugs that may well become approved for the disease.  We have a much better understanding of the disease, the prognosis, and how to treat patients. 

I might make one final comment.  An interesting trial not involving a drug but giving a very interesting insight into the diseases.  There was at this meeting one of the most impactful abstracts found was a trial done in Italy that didn’t focus on a drug but focused on what was the optimal hematocrit target for patients with P vera (polycythemia vera).  Taking care of many patients with P vera, people will frequently ask, What is the optimal hematocrit for me in my disease?  What is safest?  What also impacts on how I feel?  Patients will frequently tell me, I feel better at a certain hematocrit versus another. 

There was a randomized trial in Italy where they looked at two different targets for controlling the red cells through phlebotomy, either a target of under 45 or 45 to 50, recognizing that patients do kind of bounce up and down naturally.  But they were able to find in this trial that there was, one, a key difference, the average in one group was a hematocrit of 44, the other of 48.  And between those two they found that the group with the higher hematocrit had a four-fold higher risk of blood clots than the group that had a hematocrit of 44. 

Very important information, really suggesting that being more strict with the hematocrit than perhaps we had expected to begin with may well be important in that goal of trying to decrease the risk of blood clots. 

Andrew Schorr:

When you put it all together it sounds like there’s more to talk about than ever before.  Do you feel that what you’re discussing will be available to people living with the diseases right now? 

Dr. Mesa:

Absolutely.  To give you a perspective, if I think back, 10 years ago we might have 10 times the amount of really pertinent scientific information being presented at this meeting than we did 10 years ago.  And I think that it’s data that is really going to impact patients right now as well as very much in the near future. 

When I see patients and they have been on hydroxyurea (Hydrea), they have been on interferon, they’ve been on some other therapy, they ask me, Dr. Mesa, am I going to be on this therapy for the rest of my life?  And I tell them, really, no.  I suspect that our therapies are going to continue to evolve.  The old model where you went on a therapy and you stayed on it for 10 years or 20 years or 30 years, that’s a model that really is evolving.  I think we’re developing much more sophisticated therapies, and I think the issue of individualized medicine will be very important for patients with MPNs. 

Some of the work that I have focused on as well in addition to drug trials is really looking at the spectrum of how the disease affects people and their symptomatic burden.  And we see that patients with MPNs are a cross section of our society.  There are young patients.  There are older patients.  There are patients who truly have a very acutely life-threatening illness.  There are others that might live decades or pass away from natural causes. 

It is a tremendous spectrum, and as we learn about the difference in biology, the different ways that the disease affects people in terms of symptoms or risks or spleen size or other difficulties, we will be able to be much more sophisticated in tailoring therapies specifically to the individual. 

Andrew Schorr:

My advice, but I bet it’s yours too, is you have a specialist such as yourself in your corner so that you can get that most precise treatment for you and also have clinical trials be part of the discussion. 

Dr. Mesa:

I think it’s a very important time for us to learn as much as we possibly can.  One, for patients I do think it’s important for them to have someone who really understands these diseases as part of their healthcare team.  I frequently will participate as a member of the healthcare team along sometimes with someone’s local hematologist so that we can work together to try to optimize things for patients. 

Things are evolving very rapidly, there are many therapies, I think a deeper dive into the knowledge for these diseases can be helpful and very necessary in that they’re very complex diseases.  I’ll share with patients sometimes that as you battle against your MF it’s not a sprint, it really is more of a chess match, where we’re making key moves.  And when we make a move or when we choose to make another move or change something, we have to be very mindful, and there are times to make a change and times to hold as one is doing.  It’s a nuanced approach, but I think it’s very appropriate as we recognize the behavior of these diseases. 

Andrew Schorr:

Dr. Ruben Mesa from the Mayo Clinic in Scottsdale, thank you so much for all you do for patients and for updating us today. 

On location in Atlanta at the American Society of Hematology meeting, I’m 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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