Graphic concept of Mast Cell Diseases treatment. There's a graphic of the human body with various treatments surrounding them.

In the latest episode of the “Allergy, Asthma & Immunology Innovations” podcast, we focus on mast cell disease treatment. This is the fourth episode of a series on mast cell diseases. The podcast series is sponsored by Blueprint Medicines.

The podcast is a collaboration between Allergy & Asthma Network and The Itch Podcast. It is once again hosted by The Itch Podcast’s Kortney Kwong Hing and Payel Gupta, MD. In this episode, Kortney and Dr. Gupta are once again joined by allergist and immunologist Joshua Milner, MD.

Dr. Milner, Dr. Gupta and Kortney discuss the steps needed to treat mast cell diseases. They consider histamine blockers, mast cell stabilizers, Xolair, tyrosine kinase inhibitors, and other medications. Mast cell diseases are not one-size-fits-all and no single treatment plan works for everyone. So our podcast hosts explore taking a multidisciplinary approach that can be helpful in managing these diseases.

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Timestamps for Mast Cell Disease Treatment Podcast

  • 0:27 – What are the steps taken to treat mast cell diseases?
  • 1:24 – Histamine blockers: antihistamines for mast cell disease and H2 blockers
  • 3:03 – Mast cell stabilizers: cromolyn and ketotifen
  • 7:39 – What about Xolair?
  • 9:40 – Other medications that have been used, but are not recommended: aspirin, corticosteroids, Singulair
  • 10:50 – Timeframe for MCAS and how to track the medications are working
  • 12:25 – Epinephrine and anaphylaxis
  • 13:35 – Tyrosine kinase inhibitors (TKI) for mastocytosis: avapritinib, midostaurin
  • 17:18 – Safety concerns and side effects of tyrosine kinase inhibitors
  • 18:25 – Multidisciplinary approach to managing mast cell diseases

Full Transcript of Mast Cell Disease Treatment

Kortney Kwong Hing: Oh, so complicated mast cell disease. I wish I could tell you, pop this pill and poof, symptoms gone. But as we’ve seen in the mast cell disease series so far, there is no straight path, and this is also the case with treatment.

Today, we’re diving into the ‘Try and See’ approach Dr. Milner uses to navigate the treatment maze with his patients. This mast cell disease series is made in partnership with the Allergy & Asthma Network, and we thank Blueprint Medicines for sponsoring this episode.

You’re listening to The Itch, a podcast exploring all things allergy, asthma, and immunology.

Payel Gupta, MD: We know that mast cell disease is a large category of diseases, and we’ve discussed that along the way of this series. So what we’re going to be doing today is just going by what Dr. Milner calls as a stepwise approach to how we start treatment for somebody with a mast cell disease, and then we’ll go into specific therapies that are recommended for specific types of mast cell disease.

Let’s get right into it. What is the primary treatment goal for mast cell disease, and how do they differ between the different disorders?

Joshua Milner, MD: Obviously, if your mast cell problem is that you have allergic disease, you get managed as anybody else would for their allergic disease. I think it’s an important point to just make that clear, that your mast cells are causing a problem. But if it’s because you have allergies to things, you manage things as you would allergies.

When you have mast cell activation syndrome, whether because of mastocytosis or the idiopathic mast cell activation syndrome, where we don’t know what the cause is, we usually tend to take a stepwise approach, not just in treatment, but also as part of the diagnostic, because I’m sure you already heard that response to medications that treat this is actually what people tend to have to include in the diagnostic criteria.

How do we do that? How do we figure that out? Whether it’s when you’ve gotten a diagnosis or getting the diagnosis, we try just trying meds. Usually, we start with antihistamines at higher doses than people typically take. I tend to favor the most non-sedating antihistamines, like Allegra. You can take that at high doses and it’s not sedating. Zyrtec and Claritin – plenty of people go on them, just some people say they’re sedating, so they don’t want as high a dose.

At all costs and at all times, I avoid short-acting old antihistamines like Benadryl or Atarax. I really essentially don’t ever want folks to take that. It’s just not helpful beyond what the regular antihistamines do, and can be harmful. I think there’s a lot of thinking in that regard in our field in general, not just for mast cell disorders, to stop giving people Benadryl and Atarax. I think it’s very important.

We just say, take it for a week or two and see what things it helps with. If they don’t help at all, that’s very often a hint that we’re not talking about mast cell problems. They’re not curing anything. But if you feel no different, that is sometimes a clue, and we will sometimes stop right there because however it is that we got there, we thought that this might be an issue of taking high doses of antihistamines. In addition to the Allegra, we always, at the initial time, will say to take what’s called an H2 blocker, like Pepcid or Zantac, or Tagamet. We also take that at about double the dose that is on the way and try that for about a week or two to see how things are going.

If it’s a thing where you only get this awful thing happening once every three months, like anaphylaxis, that’s a different story. But for things that are relatively day to day or happen a couple of times a week, then that’s why we say, ‘Try it for a week or two and see how that does. If there is a response, obviously, if everything goes away, then you’re done. If everything does not go away and you have a little bit of a response, but not everything, then we tend to move to what are called mast cell stabilizers, where in theory, in a test tube, it stops mast cells from releasing all the nasty stuff, not just histamine, but other stuff. So you’re not just blocking histamine, you’re blocking other things that mast cells make that can cause problems.’

And we will tell folks to try something called cromolyn or ketotifen. Those are the main ones. Chromolyn is mostly not absorbed into the body, so it’s really, for the most part, only acting on the gut. And so for folks for whom the gut is the major place where the problems are happening, cromolyn is a decent thing to try.

The only thing with cromolyn is you end up taking a dose four times a day. You really can’t start at the maximum dose because that will make your belly worse. You start with a lower dose and you work your way all the way up to the full dose. Over an eight-week period, it really can help with abdominal things. If it’s more in other systems as well, like if you have more flushing, and itching, and swelling of body parts and things like that, then we might move to ketotifen.

Ketotifen is not made commercially. Cromolyn and ketotifen are prescription, but ketotifen – you can only get it from a compounding pharmacy. Some people go out of the country because some company makes it out of the country, but in the U.S., you can get it. You just have to get it from a compounding pharmacy.

Again, what I’ll say for the cromolyn is once you’re at the full dose, you should know. If it’s not working at your full dose after a couple of weeks, I’d stop. I don’t say stay on all this. I mean, if it’s not working, stop. There’s no point. You should know almost immediately. Same for the ketotifen. It’s just like with the antihistamines. You don’t have to work up for the ketotifen. You can take that every day. I would not generally do ketotifen and cromolyn. I don’t think there’s a value there. The ketotifen, in a week or two, if you don’t notice a difference, it’s not really helping all that much.

Dr. Gupta: So far, you said you would start with the antihistamines, get them up to a dose that’s higher than what patients normally take over the counter. See if that helps for a little while. If that’s not helping, then you would add on one of these mast cell stabilizers like cromolyn, ketotifen, and see how they respond, and maybe the cromolyn for patients with more GI issues, and the ketotifen for more of those other swelling, hives, you said, things like that. Then you would try that for a period. If that doesn’t work, then you would go to the next level for the stepwise approach that you’re taking. Kortney, did you have any questions?

Kortney: Yeah. My only question was really, so the first two, you said antihistamines, and then you said H1 blockers?

Dr. Milner: Sorry, yes. So typical antihistamines like Allegra and Zyrtec and Claritin, those are all H1 blockers. Pepcid, Tagamet, Zantac are all H2 blockers. So people tend to think about them as reflux medications, which they are, but we’re not taking them as reflux medications. We’re taking them as covering a different receptor for histamine that Claritin and Zyrtec can’t block. That combination is blocking the histamine more than just with one. That’s why we usually say to do them together to give it the full college try.

Kortney: So the histamine Type 1 receptor or the histamine Type 2 receptor. So it’s H1 or H2?

Dr. Milner: Exactly. And to the other point, which is if none of those are working at all, if they’re not changing anything, I really would stop there. I’m not trying anything else. There’s nothing more to do in general. If someone has a diagnosis of muscle activation syndrome, they have to have responded some to these to be able to meet the criteria for it. So this is what we will try in someone where I think it might be, this is what we would tell someone to do.

If they have MCAS, it means that we saw a laboratory value that we talked about the last time that went up when an episode happened or if they have mastocytosis, that was diagnosed and that was there.

So generally speaking, at this point in time, if there was absolutely no response, I don’t think I would tell someone to continue those. I’m not even sure, with the exception of mastocytosis, which we’ll get to, I’m not sure that there’s much point in going any farther with any of the other medications. I’d start worrying that the symptoms are coming from something else.

Kortney: Can I ask one more question about the ketotifen? I know that there are ketotifen eye drops. Now, the ketotifen that you’re using in these mast cell patients, is it a liquid form or is it pill form? What is the formulation?

Dr. Milner: It literally gets compounded however wherever you want it by the compound pharmacy. The important point is it’s oral. That’s why, again, ketotifen is available. I should have made clear, oral ketotifen is what’s not available in the U.S. Okay, great. Then, again, if there’s a partial response or if what’s staying around, let’s say, is hives. It’s urticaria. If that is what is persisting, then we might move to something that’s actually approved for urticaria, which is Xolair.

Xolair is an injection. It blocks IGE, which in theory blocks the things that you’re reacting to when you have mast cell activation. So usually you treat it for allergies. So it’s doing its job right there. It’s blocking your allergy to things. It’s approved for asthma, especially allergic asthma, again, because you’re blocking the reactions. But it’s also approved for chronic urticaria that’s not triggered by allergies. And we don’t fully understand exactly how that ends up working. We like to say it cools off the mast cells because there’s no IGE around to even tickle those mast cells, as we say. That’s something to certainly consider in someone who has hives. But other evidence of mast cell activation syndrome is to go on the Xolair injections, and they can be helpful.

I tend not to try Xolair unless there’s some evidence that the episodes are actually anaphylaxis. If they’re happening few and far between, then you wouldn’t be able to tell a day-to-day type of a thing. There have been some trials for people with idiopathic anaphylaxis, which is pretty darn close to what MCAS really is. It’s been a mixed result, but it’s not saying it wouldn’t work. It probably does work some. We don’t fully understand in whom it works. That is certainly an option.

I should make clear that when it comes to MCAS, not because of mastocytosis, we don’t have even one randomized controlled trial for any intervention at all. I think everyone should understand this. That means that the doctor in the end is just trying stuff because there is no evidence right now that points us that any of these things are really working. It’s just things we’re suggesting because we’re following patterns. You can publish a gazillion people who had wonderful responses to stuff. But if you don’t do a controlled trial, especially an allergy, you have no idea. I think it’s really important to stress that point.

There are some other meds that some people will try. Again, since there’s no evidence, it’s all about one’s taste, I guess, as it were. Some people have tried aspirin. Just so many people can’t tolerate aspirin that it’s not even a point in really doing that. Some people will actually go on steroids, which is something people do if it’s bad urticaria sometimes. Again, not a long-term solution, so you have to look for other things to do there.

Then there’s a different mediator blockade called Singular, and there are some others like that. Those have been in the news because they can have some pretty significant side effects relating to behavior and mental illness. Again, I think that the others are so much safer, again, for this where we don’t have evidence that these things work. That’s why I tend to shy away from trying that. I can’t say anecdotally, I have that many people who really think it works all that well. Individual patients, and again, can’t rely on anecdotes, but I don’t even really have that many anecdotes of that.

Those are the main ways that we would manage that. Again, there are other ways to massively manipulate the immune system, which is what steroids are doing or giving IVIG, or giving these shots to hear about online. But at this point in time, I don’t really see much role for those.

Kortney: It sounds like, for mast cell activation syndrome, it’s really just trial or error until you find what combination works for you.

Dr. Milner: Yes, it really, really is. It is also not sitting and waiting, ‘Oh, maybe it’s going to kick in.’ There are short periods of time when these things are going to work. Xolair is possibly the exception where by three months, if you don’t see a change, you stop it. You don’t keep going. But certainly all the rest, one or two weeks once you’re at the full dose, and that would be it. That’s your trial and your error.

Dr. Gupta: I find people, in general, have a hard time figuring out their pre- and post- from medications. Are you using any validated tool or questionnaire to help you understand how much these medications are or aren’t helping the person’s symptoms?

Dr. Milner: I think that would be ideal to do that. I think that that often ends up being rather burdensome for everyone to try and do that outside of a clinical trial. I do tell people to keep a log for the period of time before that I want them to try the medication. So I will often say, ‘If you’re not sure, just keep a log of how much it is and then just pay attention to those things in that log over the trial period of two weeks or whatever it is.’ For people who have nonstop issues, they’re usually pretty attuned to that.

I think it’s more for certain chronic issues where you’re not sure, and it’s, ‘I’m not sure about this, and maybe I did eat something that I’m allergic to.’ That always makes it complicated and makes it a little bit harder. It’s certainly something if someone is able to do that, that’s great to be able to just track what those symptoms are.

Again, though, some people will have muscle activation syndrome because three times in a year, they experience anaphylaxis. In the middle, they have nothing going on except for fear, which I get, which is almost a different treatment scenario in that case.

Dr. Gupta: And of course, those patients are carrying around an epinephrine device.

Dr. Milner: Of course, if we’re talking about treatment, epinephrine is obviously quite important. When it’s clear that it’s bonafide anaphylaxis, and there’s, of course, no question that if it is – and I keep saying bonafide anaphylaxis because I do think it gets misdiagnosed without question – but if it’s bonafide anaphylaxis, the earlier you treat, the better. It’s not worth waiting to see what happens.

If you’ve reached that anaphylaxis plan criteria – which is for the subject of a whole another discussion to have – having that EpiPen and using it early is the most important thing. But there’s not much else besides EpiPen and getting yourself into a safe area are most important. Taking other medications are not that important in a setting of idiopathic mast cell division syndrome.

Again, I stress that there are a lot of folks who are getting misdiagnosed as anaphylaxis and MCAS and trying things. We’re giving up epinephrine many, many times in a week, and that can be bad.

Dr. Gupta: Yeah, I can imagine the cost of that and then just the anxiety surrounding the feeling that you may be having an anaphylactic reaction, that often is also something that will wear on your mental state, which can obviously then wear on your body.

I think the next thing that we wanted to get into was the tyrosine kinase inhibitors. Your thoughts on that and when they should be used and for what specific diagnosis?

Dr. Milner: When we treat mast cell activation syndrome in the context of mastocytosis, or really when we treat mastocytosis, one of the options is tyrosine kinase inhibitors. Midostaurin is one of them. Another one is called avapritinib, which is now approved for two versions of mastocytosis. One of them, the advanced systemic mastocytosis, and others like that where it’s an advancing disease, and indolent systemic where the disease is in terms of how much those mast cells are growing is stable, but you still have symptoms.

In those scenarios where your mastocytosis is being caused by the mutation like D816V or one that’s like that, and that is what’s driving your mastocytosis, which is driving your mast cell activation syndrome, then taking these tyrosine kinase inhibitors will actually not only help calm the mast cells down to stop them from dividing, which is what their primary purpose is, but they also will prevent symptoms and prevent both acute symptoms, including possibly even anaphylaxis. And they will also prevent chronic symptoms like fatigue and depression, even some folks get. And they’ve been measured in the trials to improve, which is very nice. They won’t work if you don’t have those mutations causing your disease because those inhibitors are designed to selectively inhibit the receptor kit, which is what makes mast cells grow when they have those mutations.

That’s how those inhibitors were designed. They don’t inhibit the regular functions because actually that would be bad. The regular functions of that receptor are in other cells as well. Mast cells might use them for bad reasons when you have those mutations, but other cells need that to work. So we would not want to give that to someone who has mast cell activation syndrome. That’s not because of the mutations driving those mast cells. In particular, FDA approved now for indolent systemic, and then there’s several that are approved for advanced systemic, and there are more that folks are trying to bring down the line for that particular purpose.

Kortney: Is there anything else that’s different between mast cell activation syndrome and mastocytosis, specifically?

Dr. Milner: Mast cell activation syndrome can be caused by mastocytosis, or it can be, again, allergies, like I said, just your good old fashioned peanut allergy. But those who have idiopathic mast cell activation syndrome, the way that we manage things besides those tyrosine kinase inhibitors There’s not much of a difference right now because we’re really just trying to manage the symptoms. Do people give Xolair to people with mastocytosis in MCAT? Yeah. You don’t give Xolair for mastocytosis. You’re giving it for symptoms.

Kortney: That’s important to remember that it’s really symptom management here. That’s why you’re always jumping between different things. If one’s not working, you try something else.

Dr. Milner: Exactly. You’re not going to do anything to the mast cells with any of these to stop them from being bad. Even those mast cell stabilizers, you’re not fundamentally changing them. Whereas when you use a tyrosine kinase inhibitor, that’s actually stopping them from dividing, from going after the ones that are causing the problems. If we understood any more about it, we would go after it that way. But yes, that’s why it’s symptomatic in trial and error. It would be even good to have a proper clinical trial to tell us, really, which ones work in the different scenarios of mast cell activation syndrome.

Dr. Gupta: And not to get too far into it, because I know we’d mentioned sedation as one of the side effects of the antihistamines, but for the tyrosine kinase inhibitors, which is a medication that we’ve never talked about on the podcast before, can you talk about some of the safety considerations for these medications?

Dr. Milner: One of the biggest ones is that it’s pressing your bone marrow. I mean, that’s the role that this particular molecule can have is that it is suppressing your bone marrow. It is not as much of a concern with the more specific ones like avapritinib. That’s obviously a major one. There may be some concerns about other types of central nervous system side effects that can end up happening. None of them are thought to be completely severe at the doses that have been given, but they are nonetheless not something you want to put in the water. It’s not like they’re completely safe. They really are potentially interfering with in theory the normal function of your bone marrow and then also certain functions in the central nervous system can cause some mild symptoms that are there.

I think we need more people to get treated with them to really, really get the full sense of what those side effects are with severe ones, because we haven’t seen severe ones with the more advanced ones. But we know that some of the earlier trials really suppress your bone marrow. And that’s why we don’t really often recommend doing those now that we’ve gotten a bit more specific.

Dr. Gupta: We did have one question about allergist, GI, pain management, mental health, multidisciplinary approach. Do you have that approach in your clinic? Because I know that you are focused on mast cell disorders. So are you doing that in more of a multidisciplinary fashion? And do you have a connection with people that are interested in these disorders and are managing these patients together?

Dr. Milner: Yes. Actually that’s why I’m in the Department of Pediatrics, but in our division, we actually have a faculty psychologist, behavioral health person, and we share her with GI, in particular the Functional Abdominal Pain and Dysmotility Group that’s there, because of the way that these overlap. That’s really how we would like to approach it for everyone. It’s not so easy to pull all that together, both in terms of getting personnel and then also having insurance recognize that this should all be part of what the care looks like, but that is certainly a part.

And not only that, rheumatology is in our division. And we have a rheumatologist who has an interest in pain disorders, and she sees those patients as well – the functional pain disorders where we can’t find a source.

And so I do think that that all should be thought of in an integrated fashion. Of course, when it comes to MCAS, it even goes well beyond that. It also goes major. Having behavioral health, having GI, and having allergies on the same page is absolutely huge. And if it’s mastocytosis and then also the neurologic piece, the whole autonomic dysfunction piece – having them all integrated as opposed to going to see this one and going to see that one, I think it is a far better way of doing it.

Dr. Gupta: Great. Thank you so much. Again, Dr. Miller, this was amazing, really helpful, and I think everyone’s going to learn a lot. I know I learned a lot from listening to you, too. So thank you again for being with us.

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