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The Role of JAK Inhibitors in Treating PV and News on Their Efficacy and Safety

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Published on July 7, 2014

From the 2014 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Dr. Srdan Verstovsek from MD Anderson Cancer Center led an MPN roundtable discussion featuring Dr. Ross Levine from Memorial Sloan Kettering Cancer Center and Dr. Olatoyosi Odenike from University of Chicago Medical Center.  The experts discussed major MPN news reported at ASCO 2014 including results of a study using ruxolotinib (Jakafi®) as a treatment for polycythemia vera (PV) as well as the safety and efficacy of JAK inhibitors.

Sponsored by Incyte Corporation.


Transcript | The Role of JAK Inhibitors in Treating PV and News on Their Efficacy and Safety

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:

Hello, and welcome to a roundtable on novelties in myeloproliferative neoplasms from American Society of Clinical Oncology meeting here in Chicago. We are joined here by Dr. Ross Levine from Memorial Sloan Kettering Cancer Center in New York and Dr. Olatoyosi Odenike from University of Chicago. And I am Srdan Verstovsek from MD Anderson Cancer Center in Houston.

Our topic is to review novelties in the myeloproliferative neoplasms here at ASCO and see applicability of these novelties to treatment of patients with MPNs. So, Dr. Olatoyosi, what is, in your opinion, the major news in the MPN field at the ASCO this year?

Dr. Odenike:    

I would have to say that one of the most interesting and exciting studies presented here at the ASCO meeting is the study evaluating the JAK inhibitor ruxolitinib, otherwise popularly known as Jakafi in patients with polycythemia vera. This was a study that was designed to compare the efficacy of Jakafi against that of the conventionally or more common used treatment options like hydroxyurea (Hydrea).

Patients who were considered eligible or appropriate for this trial were those who already were not very well controlled on the more common therapy like hydroxyurea. Jakafi, there was a striking difference in terms of the efficacy observed between those patients who were on Jakafi versus those who were on conventional therapies.

The benefits that accrued to these patients included significant reduction in the need for phlebotomy, which is what, phlebotomy is basically removal of excess red blood cells, which is one of the hallmarks of polycythemia vera. And so the group of patients who were assigned to the therapy with Jakafi experienced a significant reduction in the need for phlebotomy or removal of blood.

These results, I believe, will change the way oncologists and hematologists—doctors who take care of patients with polycythemia vera—regard therapy for those patients. I believe that this will change our practice, particularly for those patients with polycythemia vera that’s difficult to manage with drugs like hydroxyurea.

Dr. Verstovsek:

This is very exciting news. I was looking at the more detail of the study, and, indeed, this was a study designed to evaluate this new therapy in patients already exposed to Hydrea, Jakafi, refactory or resistant. And what was interesting to me, it was much more than just the early elimination of phlebotomy, which is the golden standard in therapy for PV.

But we were also looking as a co-parameter end point actually, the goal was to combine the benefits in elimination of phlebotomy and the reduction in the big spleen that can be present in these patients, but also, looking at the normalization of the white cells and platelets and improving in the symptoms.

Because these days in patients with myeloproliferative diseases as we look for improvements in myelofibrosis, we also look for the same pattern of improvements in PV; spleen symptoms, white cells, platelets, red blood cells, all five factors to be improved to make it better than what we have done in the past.

And it seems to me that this patient population in particular, second-line therapy for PV, were lacking, and hopefully we’ll see that these exciting drugs translate into the, our ability to prescribe the medications in the future. What do you think, Ross?

Dr. Levine:

I agree, Srdan. I think the most exciting thing about these results was that in a group of patients where very little is particularly efficacious—and you’re mostly waiting for additional complications to ensue—that patients benefited substantively from adding this therapy versus trying an amalgam of different treatments.

I think the fundamental question will be, first and foremost, is it going to be useful if patients who have earlier phase disease, and obviously, we need additional trials, including the [inaudible] trial that is ongoing. We’re all excited to see those results.

But for our patients, the exciting thing is that we get the drug, which is quite efficacious, out of one indication, which is myelofibrosis now, into an earlier phase of disease. And we’re hopeful that will continue. But as you suggest, I think it’s a very substantive accomplishment.

Dr. Verstovsek:

What I noticed in the summary of the results presented at this meeting is that in addition to what we now consider as the normal response criteria, looking at these five factors, there was also a suggestion of a change in the incidence of thrombotic complications—all of that was not formally assessed.

In the comparison, there were six, if I’m correct, yes, six episodes of thrombotic episodes in the best available therapy arm, where there’s only one case in the patients that have treated with the ruxolitinib, which is intriguing because this is the ultimate goal of our new therapy for PV, actually, to decrease the risk of thrombosis.

One interesting observation during the study—the random study between ruxolitinib and best available therapy—as a second line, for patients with polycythemia vera was that, although not formally of value, in any statistical way, their observation was that there were actually less events related to thrombosis in patients that are exposed to ruxolitinib. Only one case in first 32 weeks, versus six cases in patients that completed the best available therapy.

That seems very important, perhaps if we extend that in the future and confirm, because this is the ultimate goal actually of the therapy, in my mind, to decrease the risk of thrombosis. Not just go through all the numbers. It has to be beyond the control of the numbers.

Dr. Odenike:

I would certainly agree with that. I think in the short term, it’s clear that deaths from thrombosis is the critical complication that occurs from a diagnosis of polycythemia vera. In the much longer timeframe, the other potential complication that some patients face is evolution of the disease to a more advanced state, such as myelofibrosis or transformation to acute leukemia.

So it’s very reassuring that early on, we are confirming that patients who have been treated with ruxolitinib for polycythemia vera are not continuing, by and large, to succumb to these short-term complications. It remains to be seen, of course, in the long term, whether the, this drug will be helpful to prevent some of the other long-term complications that I have, that we have, you know, talked about, which include myelofibrosis and transformation to acute leukemia. But this is very exciting times, I would say, for patients with polycythemia.

Dr. Levine:

The other, I think really exciting thing, which fits really well with that is that just as it was in the studies in myelofibrosis, the agent was quite safe. And there really were very few, if any, complications with really modest effects on blood counts, and really nothing else. And I think, particularly as we move a agent to chronic therapy, and earlier phase disease, having a clean safety signal is critical.

And I think it also sets a pretty high bar for the other JAK inhibitors that you really need to demonstrate not only efficacy but a significant tolerability and safety. Because if you want to get these drugs out of the most advanced patients, to earlier patients who need drugs, who want drugs, then you’re going, also have to, have to show that this is safe, and you can take for a long time. So I think that’s a really important aspect. 

Dr. Odenike:

I couldn’t agree with you more, Ross. Given the fact that polycythemia vera is a disease where patients live for decades, it is critical that any new drug that’s been introduced have an excellent safety signal, because patients will likely need to be taking this for a very long time.

Dr. Verstovsek:

So it looks like initial impression is that the value is really there. The safety is there, potential for a great benefit beyond just the control of the numbers. The blood count is good, but we need much more follow-up. It’s a chronic disease. We need a very long follow-up to make sure that this is the real drug. But why does it work in patients with polycythemia vera?

Dr. Levine:       

I think that question’s not different than the question of why it works in myelofibrosis. And also why, for example, this meeting, there was even some data in pancreatic cancer. The idea, when the drug was developed, was that because a subset of patients with these diseases, have mutations that activate JAK2, that we were targeting a mutant cell.

I think what’s become abundantly clear, based on the idea that all patients benefit from the drug, whether they have a JAK2 mutation or another mutation, like the MPL mutation or the recent [discovered calreticulin] mutation, but everyone seems to get similar extended benefit—not just that only the mutant patients benefit more than others. There’s actually very little data I’m aware of at all that the mutations affect the response of any of these agent.

And I think what it suggests is that the JAK-STAT pathway is so important to things like inflammation, thrombosis, growing of the spleen, bad symptoms, whether it’s because of the mutation in JAK2 or something else, but that’s the disease pathophysiology. And the drug is taking care of that underlying root cause or biology irrespective of the specific DNA mutation.

And that’s an exciting idea, and it’s maybe a change from what we thought when the mutations were discovered nine years ago. But the data and patients and in laboratory models that my lab and others have done really does suggest that. So we just have to move from thinking this is a mutation-targeting drug—or rather a JAK-STAT targeting drug that benefits all of our patients.

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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