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I Have An MPN: Would a JAK Inhibitor Work for Me?

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Published on July 6, 2020

I Have An MPN: Would a JAK Inhibitor Work for Me?

There are many different myeloproliferative neoplasm (MPN) treatment options out there, including a class of drugs called JAK inhibitors. What are they? How can they help MPN patients?

In this segment from our recent MPN Answers Now program, host Andrew Schorr and a patient advocate share their experiences being on JAK inhibitors. They are joined by Dr. Michael Grunwald of Levine Cancer Institute and Dr. John Mascarenhas of Memorial Sloan Kettering. Tune in as the experts explain what a JAK inhibitor is, who it might benefit and side effects management.

This program is sponsored by Bristol Myers Squibb. This organization has no editorial control. It is produced by Patient Power and Patient Power is solely responsible for the content.

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Transcript | I Have An MPN: Would a JAK Inhibitor Work for Me?

Andrew Schorr:
And greetings from Southern California. Welcome to this MPN Answers Now program. I'm Andrew Schorr. Living with an MPN myelofibrosis since ... Well, it's been about nine years now. I want to thank Bristol Myers Squibb for sponsoring this program. We're doing MPN programs, connecting you with experts live every two weeks. So, please join us on a regular basis. Today we're talking about ... “I have an MPN”, which I do, and “would a JAK inhibitor work for me?” Which fortunately a first one and then another have been and I'm leading a pretty full life, so I'm very grateful. But, what are the expectations with a JAK Inhibitor, and what are the limitations, and might they be combined with other medicines as well?

So, we're going to learn about that today. All right. So, let's have our panel of experts join us from Ohio, near the football Hall of Fame in Canton, but in Jackson, I think, is my friend Dave Denny, who's been on two JAK Inhibitors. Dave, thank you so much for being with us.

David Denny:
Thanks for having me.

Andrew Schorr:
Okay. And then I used to live in Charlotte, North Carolina, and my doctor was, and I still have great admiration for him, from the Levine Cancer Institute, Michael Grunwald. So, Michael, thank you for joining us.

Dr. Grunwald:
Hi, Andrew. Thanks for having me.

Andrew Schorr:
Thank you. And then let's skip up to New York. A noted specialist also in the MPNs at Mount Sinai there, is Dr. John Mascarenhas. John, thank you for being with us.

Dr. Mascarenhas:
Thanks Andrew, for having me.

Andrew Schorr:
Okay. Let's get into Dave's story a little bit, and maybe my story. So Dave, you were diagnosed with myelofibrosis I guess first. Right?

David Denny:
Right. But primary myelofibrosis in 2013.

Andrew Schorr:
Okay. And where did the JAK Inhibitor come in for you?

David Denny:
Well, I didn't start a JAK Inhibitor until 2014. I started with ruxolitinib (Jakafi) of course. I was resisting it. I'd heard of people who had had crashes in their numbers. And so, my doctor said, "I don't think you know how good you can feel." And he was right. It really happened that way.

Andrew Schorr:
Okay. And then you went on ruxolitinib or Jakafi for quite a while, and then at some point you switched to another then approved one, fedratinib (Inrebic). Why the switch?

David Denny:
Well, after about five years the Jakafi had just ... It was still working to some degree but it had slowed down, and my spleen had grown back very large, and I wasn't feeling as well, and it was very them to approve Inrebic right when I needed it, and so I started ... I went right over to fedratinib and it did a good job of shrinking my spleen, and I feel a lot better now, so that was good.

Andrew Schorr:
Good. And I know you ride a motorcycle. So, how's your quality of life are you riding the motorcycle?

David Denny:
Well, I do whenever I can. Good weather and nice ... If I can get back on a back road somewhere and be safe, then I love to go out and ride. It's therapeutic.

Andrew Schorr:
Good for you. And I'll just mention about me. So, I was diagnosed in 2011, after many months went on ruxolitinib which had been approved not that long before, did shrink my spleen. It made a difference for me for about six or seven years. Numbers were changing, so I did switch to fedratinib or Inrebic, and right now again in all the cases I've been living well, and I ride my bicycle with a helmet. Careful. All right. Well let's get to it. Let's start with you Dr. Grunwald. So what is a JAK Inhibitor? Maybe you could explain that. And what's JAK? You have a new patient and you're trying to describe this. Where does this come in? What is it?

Dr. Grunwald:
JAK is a receptor on the surface of blood cells, and JAK2 mutations are common in myeloproliferative neoplasms. They occur in many patients with ET and with myelofibrosis, and in almost all patients with polycythemia vera. And there are other mutations that exist in some ET patients and some myelofibrosis patients, but even those mutations, which are usually CALR mutations and MPL mutations, they lead to activation of JAK2, and in patients who have JAK2 mutations, there is this overactive signaling pathway, where JAK activates that. So, most patients, nearly all patients with MPNs, will have an overactive JAK pathway that leads to self-proliferation.

And JAK inhibition is a strategy to, with medication, turn off that signaling and tone it down a bit. This has been an effective strategy for many patients in controlling high blood counts, in controlling symptoms that might be associated with their MPN, and also in controlling spleen size, which affects many MPN patients.

Andrew Schorr:
Okay. So Dr. Mascarenhas so, how would you describe the expectations if you take a JAK Inhibitor, a pill, and the limitations of that too? Because it doesn't work for everybody and it doesn't work for everybody forever.

Dr. Mascarenhas:
Yeah. So, JAK Inhibitors were the class of agents are, as Mike pointed out really designed to aggregate and turn down a signaling pathway that's overactive. So it's very important for patients to understand that these are not always targeted therapies in the way one thinks in terms of they don't go after the mutation, they don't eliminate the mutation, but what they do very effectively is, reduce that signaling pathway that leads to overproduction of blood cells that leads to reduction in splenomegaly, and turns off the elaboration of cytokines, which we know are driving at least aspects of the disease, like the symptom burden.

So what ruxolitinib originally showed now over a decade ago, is that the drug is very effective in improving quality of life and reducing symptoms and spleen burden, which are very meaningful to patients. And fedratinib as another JAK2 inhibitor can do the same thing, and what is I think exciting about 2020 compared to prior to August of last year is now there's another JAK Inhibitor available as you two gentlemen are well aware that allows for patients who may have lost some of that initial response and other patients maybe never got the full response of ruxolitinib to have a second line option, to try to recapture spleen and symptom response and get patients back out into their lives, on their bikes, whether it's a bicycle or motorcycle.

And that's really the benefit of these drugs. It allows patients to feel well, which is very important because patients who feel well, remain active and do well.

Andrew Schorr:
So Dr. Grunwald they don't work for everybody, right? So how do you know?

Dr. Grunwald:
That's correct. They don't work for everybody, especially in myelofibrosis, there are some patients for whom JAK2 inhibitors don't work up front and that there's some intrinsic resistance to, some patients had intrinsic resistance to JAK Inhibitors. However, for the majority of patients, there can be some benefit. And the benefits are usually observed as a reduction in spleen size, and as a reduction in symptoms. I tend to track patients who have myelofibrosis with their spleen measurements and with their symptom scores over time. I also attract their blood counts as well.

And sometimes we'll see that patients will be having high blood counts. They'll be having an enlarging spleen. They'll be having an increasing symptom score overtime. Those are signs frequently that patients are not responding optimally to JAK inhibition. There are a few different mechanisms that might lead to resistance over time, whereas some patients might not achieve a response upfront, it's more common for patients to lose some response over time after they'd been on the JAK Inhibitor. And that could be due to a number of different molecular mechanisms that render the cells resistant to therapy over time.

Andrew Schorr:
Dave, you are one of the leaders of a really large group, I think over 5,000 people with MPNs on Facebook. I'm part of it too. So what are things that come up, not just for you, but recurring things that people are asking about with these medicines?

David Denny:
Well, I think that people who are considering it, new patients who are considering going on a JAK Inhibitor, sometimes are concerned because they've read the label and they read all of these possible side effects. Others are worried about gaining weight. I know Jakafi gave me a great appetite. I myself was worried about my counts maybe crashing. I knew people who had become ... need a transfusions and so on initially. So those are our problems, and some people are just resistant because it's a chemical compound and it's not a natural remedy, they want something that's natural and they say, "Well this isn't natural, this is medicine." Which it is medicine, but it sure worked well for me.

Andrew Schorr:
Right. Well, let's talk about that. So in fairness, you mentioned about weight gain. So yeah, so over seven years, I did put on a little bit of a gut, still remaining active. And it's funny, some of the doctors know this Italian hematologist Dr. [Venuki 00:12:17] in Italy. And I said to him, "Well, I put on weight with this drug." And he said, "Well, it beats the alternative, doesn't it?" Because before these drugs existed, people would waste away. They had huge spleen, stomach was impaired. Didn't feel like eating at all. So, I think we've come a long way. I will say that switching to fedratinib or Inrebic, I haven't had the weight gain, and I worry about other side effects, digestive side effects, stuff like that.

And knock on wood, I have been very fortunate when I did switch. And I don't know about you, Dave, but I went to the pharmacy and I got diarrhea medicine and constipation medicine. And thank goodness haven't used any of them, but I know it varies. Dr. Mascarenhas let's talk about side effects. So, weight gain or digestive issues. These are powerful medicines. There's no free lunch, right?

Dr. Mascarenhas:
Yeah. I mean, there's always a potential downside to any medication we take, including supplemental medications. I would say that ruxolitinib is a relatively well tolerated drug. We've done the studies and over many years of observation, we pretty much know the toxicity profile is, it's easy bruising, it's dizziness, it's headaches in the first month, most patients are really impressed, I think by the improvement in how they're doing overall, that those side effects tend to be very minimal and rarely a reason to discontinue the drug.

There's concern over for long periods of time perhaps because it's also an immunomodulatory drug for infectious risks like herpes zoster or shingles. I always recommend patients should get the Shingrix vaccine to reduce that risk. But there are also reports of increased risk of pneumonia, urinary tract infections. But at the end of the day, it's a balancing act and every physician who prescribes any medication, but in particular ruxolitinib has to balance the potential benefits to the potential risks. And almost always those benefits outweigh the risk, but patients should be aware that they will see some decreases in blood counts.

That's not a toxicity that should warrant discontinuation, because it's an expected toxicity. So, we expect that the hemoglobin will go down. It usually nadirs. So bottoms out usually within two to three months and then sits about one gram less than where it started. The platelets usually decreased about 40%. Those are on-target effects of the drug. I'm always very careful to set expectations to patients because I don't want patients to freak out and say, "Well I came in with this hemoglobin and now I'm coming out with this hemoglobin." But if you prep a patient and have them understand that that's part of the process and by the nature of the mechanism of the drug, you will get some degree of that.

But ultimately the benefit will outweigh the risk that becomes very important. And that has to be individualized for the patient. Fedratinib has a slightly different toxicity profile because it's also a FLT-3 inhibitor. So we do expect more gastrointestinal toxicity, but not everyone gets it. And you're an example where there are about half the patients who may get it half that don't get it, but the patients who do get it and it can be nausea to queasiness, to diarrhea. It's usually within the first month. And for the most part, if you figure out how to take it in your daily routine and maybe have a little imodium say to the side in case you have diarrhea, it's actually very manageable.

It's also again, rarely a reason to come off. So it's really setting expectations. Having patients understand what to expect. For example, I would never want a patient not to go on fedratinib if it's being recommended because of a concern of Wernicke's encephalopathy. I think that maybe warrants at least two seconds of discussion, there was a concern that was brought up early on in development of fedratinib that people could develop - a very small percentage of patients actually, were found to have a neurologic syndrome called Wernicke's encephalopathy that's related to deficiencies in vitamin B1 or thiamine.

With after a lot of critical review and investigation, it was determined that if this risk exists, which is even questionable, it's quite low. So thiamine levels are easy to check. Thiamine replacement with a multivitamin is easy to do. So, that wouldn't be for me a good reason to not consider the drug, but each patient really needs to sit down with the physician and understand what to expect so that they're not thrown off by some worsening anemia. They're not thrown off by some diarrhea that can be controlled with easy maneuvers. Over the years, I've grown to appreciate that patients are obviously not excited about taking medications if they can avoid it.

But I think as both of you have recognized. It's quite impressive and I've been quite fortunate to see patients who don't always realize how good they could feel because they've gotten used to how unwell they do feel regain that. And they get back on the bike and get back into life and engage more. And it's really satisfying to see JAK Inhibitors do that.

Andrew Schorr:
Right. And as I mentioned beforehand, right, Dr. Grunwald, before you had JAK Inhibitors, let's say somebody with myelofibrosis or maybe PV, it was like your quality of life was going down. Right? So this has made a big difference. So Dr. Grunwald, let's just talk about dosages. So for me, and you did it with me when I lived in Charlotte, we moved the dosage around a little bit, and that's going to change. So it doesn't mean the drug isn't working, but sometimes you have to adjust it at different times. Right?

Dr. Grunwald:
I think so. And I think the dosing is often times individual to any given patient. So, there are some patients for whom, if we looked at the package insert, we would see that the recommended dose of ruxolitinib might be 20 milligrams twice a day, but it might be for that patient that they would have fewer side effects and good effectiveness or good efficacy at a dose of 10 milligrams twice a day. And so oftentimes we adjust based on blood counts, based on side effects and based on response up or down, to achieve the optimal dose for that individual. And I think that's true, both of ruxolitinib and fedratinib for myelofibrosis and ruxolitinib for PV.

 


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