Expert Outlook: New Avenues in MPN Treatment

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Topics include: Treatment

Are there new JAK inhibitors in development for myeloproliferative neoplasm (MPN) patients? What treatment options are there if JAK inhibitors stop working? MPN experts, Dr. Angela Fleischman from UC Irvine Health, and Dr. John Crispino from Robert H. Lurie Comprehensive Cancer Center, discuss the latest MPN treatments, both approved and in development. Dr. Fleischman explains how JAK inhibitors work differently to target specific pathways and are uniquely suited to individual patients. Watch now to find out more about effective avenues of therapy for your MPN condition.

This is an MPN Research Foundation program produced by Patient Power. We thank Incyte Corporation for their support

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Transcript

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:         

So these JAK inhibitors, so they’re inhibiting something that seems to be active, not for all patients with an MPN, right? But with a lot of it? So if you can tamp that down, we can live better, right? But we’ve had one approved drug, ruxolitinib (Jakafi), so is the idea we would do well if we had other options as well, and if there are some coming, where do we stand?

Dr. Crispino:              

Yeah, so I would first stay that it’s clear that pretty much all patients with the MPNs have activated JAK-STAT signaling. So whether you have a JAK mutation, a calreticulin mutation, or a MPL mutation, we know that the signaling pathways are activated in distinct manners, but certainly it’s all the same. So conceptually, a JAK inhibitor should work in all patients.

Now, as you probably are aware, these inhibitors don’t work in people forever. It may work for a year, two years, and you mentioned five years, and that’s outstanding, but we want it to work for much longer. And what we find with some of these other inhibitors, such as fedratinib, that they will work in patients in which ruxolitinib does not work anymore. And so it’s like many other cancers where you’ll treat with one drug, and then we can switch to a different agent. Now, obviously, we can’t do that yet, but the hope is that fedratinib will be approved and available as a second line therapy, and then subsequent other JAK inhibitors may also be used second or third line. 

Andrew Schorr:         

Hmm, okay. So fedratinib was a drug that looked like it was headed to approval, and then there was a concern by the drug company developing it about it and it was stopped, but as you said, there was information about it. So that may be around the corner, or do we even know?

Dr. Crispino:              

From what I understand, andit’s obviously up to the company and the FDA, but the data that you’re referring to I guess is presented as this Wernicke’s encephalopathy, which is this horrible side effect that was reported to happen in these patients, whether or not it actually is caused by the drug is now unclear. In fact, evidence suggests that it’s not caused by this drug, which would then hopefully lead to a rapid approval. Again, it depends on the company’s data and then the FDA, but we’re certainly hopeful—and I speak for the MPN Research Foundation—we’re very hopeful that this drug does get approved soon.

Andrew Schorr:         

Okay. Dr. Fleischman, so then there’s another drug, another JAK inhibitor, pacritinib, that was on hold that’s now back in trials, and I even heard at the ASH meeting that they’re opening up trials in Europe as well. These drugs don’t work exactly the same, so for you as a physician, would that provide some advantage that if one, let’s say like Dr. Crispino was saying, one kind of poops out on you in a way, that there may be another option? Maybe you could explain that.

Dr. Fleischman:          

Yeah, and actually thank you, that’s the perfect question that I want to answer, actually. I think it’s important to know that although all of these drugs are labeled as JAK inhibitors, they’re clearly not the same, and there are a lot of JAKs as well as different pathways that each of these drugs hit. Each drug has a slightly different profile of at what strengths it hits each of the JAKs.

So I think an important point to make is that all MPN patients are unique, and so one person, for example, may have severe symptoms and their primary problem be anemia; whereas another person will have a very large spleen and have very high counts, so it’s clear that those two people will have very different needs in terms of helping out their disease

And different JAK inhibitors that are being tested have slightly different things that they really do help out with, so it would be very nice as a physician to have in one’s toolkit multiple JAK inhibitors so one could tailor the choice of JAK inhibitor for that specific person’s needs.

Andrew Schorr:         

So if one was working, like I’m on ruxolitinib right now, if my cancer sort of starts getting around that somehow, would another JAK inhibitor possibly be able to pick up the load, or would it mean that JAK inhibitors are no good for me anymore? 

Dr. Fleischman:          

That’s a very good question. Ideally if one JAK inhibitor stops working, that another one could potentially be helpful.

In the clinical trials using second-line JAK inhibitors, many of the people who enroll in those trials are people who have already tried ruxolitinib and have failed or are intolerant, can’t take ruxolitinib for one reason or the other. Clearly there are people who have failed ruxolitinib who, for example, fedratinib helps out. I’m sorry I’m not really discretely answering your question, but it would be hopeful that for the majority of people who have failed one JAK inhibitor, they could obtain a nice response to another JAK inhibitor.

Andrew Schorr:         

A couple of years ago, we were hearing about a telomerase inhibitor. I’m not sure exactly what that is, but I know it’s different from a JAK inhibitor, and they were thinking, “Well, could we deal with these MPNs in more than one way?”

We’re gonna talk about other approaches too. So what’s happened with that? Or when you were alluding to things beyond JAK inhibitors, what were you talking about?

Dr. Fleischman:          

So there are a number of clinical trials—I have them written down here—and actually just looking at what the themes are, so there’s givinostat, which is a HDAC inhibitor working on, I guess simply putting it, changing a gene expression. Maybe that’s sort of a simplistic way to put it. Nutlin, which is an MDM2 antagonist, which upregulates p53, which can be abnormal in MPN patients. Also getting at more of—for patients with anemia, a TGF beta blocker; TGF beta is thought to play an important role in fibrosis in myelofibrosis.

And then also a hedgehog inhibitor, which is another sort of approach to counteract the abnormal ways that MPN cells stay alive. Also getting at basically trying to kill specifically MPN cells, because they’re trying to act sneaky by not dying when they should, a drug called LCL161, which is in a clinical trial at MD Anderson. That induces apoptosis, or that’s called programmed cell death, specifically in MPN cells. And I have a particular interest in LCL161 because my lab is also looking at that in the lab, and we do find that cells with the JAK2V617F mutation are much more sensitive to that drug as compared to normal cells, so I was really excited to see that.         

Andrew Schorr:         

Let’s go back to something that Dr. Fleischman was talking about a minute ago for her lab, but also she mentioned MD Anderson. Was it called a SMAC inhibitor or whatever this SMAC term? But the idea is…so the cancer cells that are replicating and causing scarring and all that, all our problems in our bone marrow, they don’t want to die like normal cells. So that’s the idea. Is there something that selectively can kill them, but not affect healthy cells? 

Dr. Fleischman:          

Correct. I guess with the SMAC mimetic one can think of it is that the JAKmutant cells upregulate certain proteins to help them stay alive. And then the SMAC mimetic will get rid of those proteins that are inappropriately allowing the mutant cells to stay alive. 

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 March 22, 2018