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Expert Perspective: Encouraging Research Developments in the Treatment of MPNs

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Published on May 22, 2018

On location at an MPN town meeting in Aurora, Colorado, Dr. Naval Daver from The University of Texas MD Anderson Cancer Center, discussed the latest developments in the treatment of myeloproliferative neoplasms (MPNs). Dr. Daver provides an overview of the research being done to improve patients responses and the duration of response to treatment with JAK inhibitors, through combination therapies. He also goes on to explain other therapies being studied, including PI3 kinase inhibitor therapies, immunomodulatory therapies, as well as BCL-2 inhibitors.  Watch now to see a hopeful look at the future of MPN treatment.

Produced in partnership with the University of Colorado Anschutz Medical Campus. Sponsored by Incyte Corporation.

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Transcript | Expert Perspective: Encouraging Research Developments in the Treatment of MPNs

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.

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 with our old friend on Patient Power, Dr. Naval Daver from MD Anderson Cancer Center. Thanks  for being with us once again. Okay, you have a lot of research going on, and that gives us with an MPN a lot of encouragement. We’ve had a JAK inhibitor available to us, some folks with PV and myelofibrosis, ruxolutinib or Jakafi, but there’s a lot of stuff going on. So give us a window into what’s going on that’s  promising in your view.

Dr. Daver:
Sure. So there’s a lot of activity, as you know, going on in the MPNs. So with the approval of the first JAK inhibitor that was kind of the first benchmark with improvement in spleen symptoms, survival, now seen with long-term follow-up. But we knew that the responses we were seeing were about 35 or 40 percent. Also people who responded were maintaining response for about three years, and then that’s immediate. And then there were some who were less and some much longer, but then they would lose response. So the two big things right now that are areas of focus are one, how we can improve the number of patients responding, get it from that 35, 40 percent to maybe 80, 90, 100 percent. And second, how we can improve the duration of response, which basically means prevent the emergence of resistance to the JAK inhibitor, the one approved right now is Jakafi.

So the approaches that are being used are combination therapies, and there are three or four combinations. There are many combination in clinical trials, and we’re involved with most of them. But the three or four that I think are the most exciting at this time are, one is combining Jakafi—ruxolitinib—with a drug called azacytidine. And azacytidine is a drug that’s been approved for another disease called MDS, myelodysplastic syndrome.. It’s also used very frequently in older patients with acute myeloid leukemia (AML). 

And there was another study at MD Anderson about nine, 10 years ago showing that azacytidine as a single agent actually did have activity with a response rate of about 20 percent in patients with myelofibrosis. Then people forgot about it. The JAK inhibitors became more attractive, higher response rates, oral. But then when we had the approval we said maybe if we combine these two agents, they have different mechanisms of action, they have different toxicity profiles, and they’re both quite well tolerable, we can improve response rates. 

And so in this study that we presented a couple of times in an oral presentation last year and will be published soon, we are seeing that the response rates now are coming up to 55, 60 percent. So going from 40 to 60 percent. More importantly, we’re also seeing improvement in bone marrow fibrosis, which is something that we did not see much with the JAK inhibitors. We saw 10 or 15 percent, but now we’re seeing almost 40, 50 percent improvement, so this could be a more potent disease-modifying activity. The second drug or group of drugs that we’re combining are PI3 kinase inhibitors. So there is data from a lot of investigators in California, in Houston showing that the PI3 kinase pathway is overactivated in general in patients with myelofibrosis but is especially overactivated in patients who are failing Jakafi. 

So this was presented and has been published, and this led to the idea that well if we could block the PI3 kinase either in conjunction or in people who have been on Jakafi for a while and are not getting optimal benefit or losing response at that kind of approach, then maybe we could improve the responses. And there were two big national studies going on with two different PI3 kinase inhibitors combined with Jakafi with some early promising data that even people who are getting sub-optimal benefit you could convert that benefit to more optimal. And people who are losing response you could regain response. 

And the third combination that we’re looking at is a combination with a group of drugs that’s been used in myelofibrosis for a long time. These drugs are called IMiDs—immunomodulator drugs—and the two most common ones are lenalidomide (Revlimid) and thalidomide (Thalomid). And there have been a number of Phase II studies using these drugs alone to improve anemia, but they also have a spleen and symptom improvement rate—but small, 20 to 30 percent on their own. So we’ve done combinations of Jakafi with these IMiDs. Again if one is good, another is good, maybe two can be even better for response rate and duration. And we’re seeing some signals that the response rate is better, but we also saw more myelosuppression, meaning drop in your platelets and hemoglobin. And so we are redoing these studies now with lower doses of the IMiDs and doing a window where we do the JAK inhibitor alone and then add the other drug. So I think these three are probably most advanced in the combination arena. 

Now there are other drugs, one that at least from the lab sounds very exciting, and we’re going to have some of these trials opening soon, called the Bcl-2 or Bcl-xl inhibitors. So the Bcl pathway is very active in AML and in myelofibrosis. And in AML as well as in CLL, the Bcl-2 inhibitors, the one that’s most well-known is venetotclax (Venclexta), have really revolutionized the treatment of disease. So they are now being tried in multiple hemomalignancies that have Bcl-2 overactivity, myelofibrosis, acute lymphoid leukemias, lymphomas. And so in the lab it does look like Bcl-2 or Bcl-xl inhibition could really synergize well with Jakafi. So that trial is going to open probably in the next three, four months at multiple centers, including MD Anderson. And that’s probably one that I’m really excited to see as the pre-clinical turns into the clinical. So these are a few, there are others. But these are the most exciting leads at this time, yeah.

Andrew Schorr:
So you use this word exciting. When you put all this together, I think for those of us—and I’m on ruxolitinib, and have been on it for many years—it gives us hope that there’s something waiting in the wings.

Dr. Daver:
Absolutely. I mean, you know this is happening in all kinds of, I think, diseases. I don’t treat much cardiovascular or neuro, but in oncology for sure. But if a patient can stay alive with current treatment for seven to eight years, almost guaranteed by that time there’s gonna be not one but two or three better treatments. So the CLL patients like you had seen or yourself who got FCR—the old chemo—you know at that time we’re like well, we’re gonna do, we’ll see what happens. If they relapse after seven years, now there are ibrutinib (Imbruvica), venetoclax, ofatumumab (Arzerra), idelalisib (Zydelig). It wasn’t curing them per se. But it got them to the point where there are new drugs, and this one may give them another six or seven years, another six or seven. So, I think a lot of people are of course, correctly still wanting the cure, and I don’t know if we’re near a cure at myelofibrosis or CLL. But, if you ask me what are the changes that a myelofibrosis /CLL patient can live a normal life, both in quantity and quality, I think we do have tools now to get that, but it won’t be we treat for a week and stop. It will be long-term treatment but with a normal lifestyle.

Andrew Schorr:
Okay. I just want to ask for everybody, you guys are still working towards a cure, right?

Dr. Daver:
We are, we are. You know, in some—in myelofibrosis for sure but the other leukemia as well, you know, the first step has always been to improve survival—both the duration of survival and then quality of life. And then once we get to that point, then there’s much more focus. In CML, where survival is almost equal to a normal person – 98 percent of people will live a normal life span. There’s a lot of effort now in how can we reduce the duration? I think in myelofibrosis, the focus, number one right now is how can we improve response rates so that we get almost everybody to that 98 percent number and then improve duration? But in parallel, are there some things – and this is immune therapy and others are coming in—that could be cures at least for a subset of population. But we’re not close on that aspect yet.

Andrew Schorr:
Okay. Well, keep working. Thank you so much for all you do. Thanks for all the research at MD Anderson and your collaboration with other centers around the world. Dr. Daver,  thank you so much for being with us once again. I’m Andrew Schorr with Dr. Naval Daver from MD Anderson. 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.