Carole Bitar (Tulane University School of Medicine): We are going to go ahead and start with the session. What is mastocytosis? This is an important definition. Mastocytosis is a neoplastic disorder. It is not just like a dysfunction of the mast cells. There is increase in number and accumulation of those clonal mast cells in different parts of the body. It can be divided into cutaneous mastocytosis, where you have skin-only involvement. You can have systemic mastocytosis, where you have other extracutaneous involvement like liver, spleen, bone, and other internal manifestations as well.

Then you can have mast cell sarcoma, which is a super rare disease, and it could be really aggressive. Systemic mastocytosis is really not the same as mast cell activation syndrome, where mast cell activation syndrome, you can have symptoms of mast cell activation. Then systemic mastocytosis could have symptoms as well, but not all MCAS would have a clonal distribution, and you have an actual clone in MCAS. Not all of them will have that, so this is an important distinction.

[00:19:43]

Symptoms in the Spectrum of Mast Cell Disorders

Symptoms in the spectrum of mast cell disorders. As you can see they can be multiple symptoms. That is why the patients are most of the time delayed to be diagnosed, because you do have symptoms all over the place. You can have in the skin pruritus, flushing, and hives. Then the patient would mention nausea, vomiting in the GI tract, diarrhea, abdominal pain. Also, neurologic is very important. They have memory fog. They feel like down or sleep disturbances, or headaches.

Then the cardiovascular is a big 1 as well, so they can have syncopes, dizziness, and palpitations. Then, if they do get on the more severe side, they start having anaphylaxis, where hypotension is much more prominent than angioedema, and that is a very important distinction. They can have this bee sting. Does that ring a bell for you all? Also, that bee sting as a sign, drugs, and food allergy or anaphylaxis to those.

Then you can have bone involvement as well, where you have osteopenia, osteoporosis, back pain, and bone pain. Then they have these like constitutional symptoms, very nonspecific fatigue, weakness, malaise. Then, when you do actually have like a more progression and organ involvement for these mast cells, you can have actual pathologic fracture because of the involvement of the bone; lymphadenopathy, splenomegaly and hypersplenism, and hepatomegaly, as we talked before, cytopenias. Then also you can have protein-losing enteropathy when you have a GI involvement.

It goes on the spectrum from that disease burden from prediagnostic systemic mastocytosis to indolent, like most of our patients are in that family smoldering systemic mastocytosis. And you can have the aggressive type where you do have associated hematologic neoplasm, and then you can go all the way to mast cell leukemia, which is really aggressive where you have involvement of multiple organs as well.

[00:21:43]

Systemic Mastocytosis: Epidemiology and Pathway to Diagnosis

Systemic mastocytosis, again, is considered an orphan disease, so prevalence about 32,000 people in the US. Then you have prevalence of 1 in 10,000 in the diagnosis within the systemic mastocytosis, as I mentioned before, is usually indolent, more than 90% of systemic mastocytosis patients. Then you have with heme disorders, about 6%, which is very rare. Then the mast cell leukemia, which is super rare, is 0.5%. Again, it takes a long time before we get a good diagnosis about a mean of 6.5 years from the onset of symptoms to the actual diagnosis. This is again because of all these different nonspecific symptoms that can happen in this setting of this disease.

[00:22:36]

Adult vs Pediatric Onset Mastocytosis

Mastocytosis is divided into adult and pediatric onset. Some people think these are 2 different diseases because they do manifest differently. They actually have a little different prognosis. In adults, as we just mentioned, if you do have a cutaneous manifestation, most of the time you could find an indolent systemic mastocytosis. It is a chronic disease. There is a higher risk of having anaphylaxis, up to 50%.

Tryptase level is usually high in adults compared to kids, more than 20. In kids, most of the time, it remains in the skin and actually resolves as they get older, and then the anaphylaxis is much less likely. The KIT mutation is most of the time in adults, the D816V like the famous mutation. However, in pediatrics, you either do not find a mutation or you have other exams, 8, 9, 11, 17. Then the morphology of the lesion also is different. Then we are going to talk more about that in adults.

You do get these orangey brown monomorphic papules and macules all around the trunk area. In kids, you have more polymorphic lesion, much larger. They can look actually more scary in kids, but and it actually behaves really fine. Size of the lesion, much smaller in adults, larger in kids. Then the distribution is also very important. You start on the thigh and move up to the trunk in adults and in kids you can have that head involvement. That is very characteristic in kids, especially in that forehead distribution and the scalp distribution. This is also important. This distribution you do not really see in adults with mastocytosis.

[00:24:20]

Skin Lesions of Mastocytosis

This is the typical lesion that we just mentioned. Monomorphic small lesions like reddish, brownish. They look all cookie-cutter on that trunk in adults. In kids, you see those bigger patches and plaques. You can have Darier's sign that we are going to talk about in a minute, and in kids actually it can blister. You can have bullous mastocytosis as well.

[00:24:47]

More on Small Monomorphic Maculopapular Lesions

Again, like all adults with cutaneous mastocytosis, you really need to rule out an internal involvement, especially with the bone marrow, to rule out an indolent systemic mastocytosis. It is very rarely a cutaneous disease. It presents more than 80% of patients where they have cutaneous lesions. Darier's sign could be present where you rub a lesion, and you form more wheeling of the lesion. Then again, they start on the thigh and go up to the trunk and distal extremities and neck, usually no head involvement, no acral involvement for those.

[00:25:21]

Diagnostic Criteria for Systemic Mastocytosis

The diagnostic criteria so that was another focus for us today. How do you diagnose those patients with systemic mastocytosis? If you are using the WHO classification, you need 1 major and 1 minor criteria, or more than 3 minor. The international consensus, you can use 1 major criteria or more than 3 minor criteria. The main major criteria is those multifocal dense aggregates of mast cells, more than 15 cells, and the aggregates in the bone marrow and/or other extracutaneous organs. That is number 1 major criteria.

Then the minor criteria are multiple. More than 25% of the mast cells with atypical morphology. They become a little spindly, they look a little different than your regular egg-shaped mast cell that you are used to see. They do have aberrant expression of CD2, CD25, and CD30 on the mast cells, and this is more important on the bone marrow than on the skin. I do not really test those markers on the skin.

The KIT mutation D816V is another minor criteria. This is tested on the bone marrow. It could be tested on the skin as well. Is more accurate on the bone marrow. Then the baseline serum tryptase of more than 20 is another minor criteria. Definitely in the absence of other associated myeloid neoplasm, because this could contribute to the tryptase level and at that point does not count as a minor criteria. You need 1 major and 1 minor to diagnose systemic mastocytosis.

[00:26:53]

Differential Diagnosis

Differential diagnosis, it is all over the place again, like the symptoms. You can have other mast cell disorders, so you have mast cell activation. You could have anaphylaxis, or you can have other conditions that give you symptoms that look like mast cell disease. That is why we get to see a lot of these patients. So, chronic spontaneous urticaria, atopic dermatitis, rosacea, all of these could present with flushing and redness and rashes that comes and goes. You could have thyroid disease. Thyroid is a big 1 here.

Adrenal insufficiencies, you could have carcinoid syndrome that also can present with flushing GI. They do have a lot of GI complaints. Definitely, you want to make sure you do not have IBD or IBS. Neurologic is another big 1. I do have a lot of patients that come in, and they were like, oh, they think I am crazy. I am having seizures, or psychosis, or anxiety, or panic attacks. This is very important to rule out other things before we label these patients into these categories and these families.

[00:27:57]

Adult-Onset Mastocytosis

Adult-onset mastocytosis, they usually present with cutaneous lesions again. This is the new terminology of maculopapular cutaneous mastocytosis. This is the bigger term now that can encompass every single lesion of mastocytosis, except for kids, you could still have mastocytoma and diffuse mastocytosis, which we are not really going to discuss today. But those monomorphic lesions that we talked about, if you see them in a patient, you have a biopsy on the skin that favor cutaneous mastocytosis, you really are to look for indolent disease.

This is the workup that I usually do for my patients. I get a serum tryptase, make sure to get the KIT mutation, you can do it again on the skin and the bone marrow, a skin biopsy, and definitely a bone marrow with other appropriate studies. Then, definitely like a DEXA scan as well to look for bone involvement.

[00:28:53]

Identifying Systemic Mastocytosis Subtypes

These are the subtypes. You have multiple. What we see mainly is that indolent systemic mastocytosis, where you have you have non advanced disease. You have the typical skin lesions, so these are the most common that present with cutaneous lesion. Less likely to have B signs like cytopenia, hepatomegaly, splenomegaly, or lymphadenopathy. You can have high tryptase in those patients as well.

The bone marrow mastocytosis is a tricky one because, really, you do not have skin lesions, and you do not have any B or C findings, but you have some cells in the bone marrow, but they are not fitting all the criteria. That one is in the middle. Then you do have the smoldering systemic mastocytosis where you start having more B findings, but no C findings.

Then, as you get more advanced in this disease, you get actually like more infiltration of other organ and damage. Then this is where you can get all the way to MC leukemia, where you have bone marrow involvement. You might have peripheral blood involvement. I think about it like that. If you are really in that indolent family, you can have cutaneous lesion. As you go more deep, those mast cells can leave the skin, and they go internal. This is where you less likely have actually skin lesion when you have more advanced disease, and then you end up with more internal involvement. Then other involvement like liver, spleen, bone marrow, and all of those.

[00:30:25]

Posttest Question 1

Back to our question. This is the 36-year-old man who presented with these, what look like red skin lesion. They look acneiform. He was treated for acne for 2 years not getting better. He is having these hyperpigmentation on the trunk. Which of the following most strongly indicates that he should be assessed for systemic mastocytosis and not acne?

1. Absence of Darier's sign;
2. Occasional, once weekly double vision;
3. Severe hornet sting allergy; or
4. Telangiectasias.

I like it. We have definitely some improvement there. 74% did agree on that hornet sting allergy, which is the right answer there. Darier's sign is a plus if we have it, but if we do not have it, that does it not really rule out mastocytosis, and then double vision it is not really a sign or symptom. Telangiectasias is a tricky one because you can see it on the skin a lot of time, but really, it is not a diagnostic criteria for mastocytosis.

As we just mentioned, this is 1 of the signs of mast cell activation.

[00:31:51]

Posttest 2

Question number 2, we are going to look at the WHO criteria to qualify this patient for systemic mastocytosis.

1. Dense multifocal bone marrow mast cell aggregates;
2. Dense multifocal bone marrow mast cell aggregates and a serum tryptase of more than 20;
3. Is identification of the KIT D816V mutation; and then
4. Is identification of the KIT D816V mutation and serum tryptase of more than 20.

We do have some improvement there. I know you really like that mutation. That get everyone every time. The mutation is actually a minor criteria, not a major criteria. So together with the tryptase, makes it 2 minor criteria, and you need 3 to make a diagnosis. You need really to have that bone marrow infiltrate multifocal and 1 minor criteria which in this question was serum tryptase 20. Just remember that the mutation is very important, but really it is not a major criteria because we are still discovering more and more mutations for this as well.

With this, this is the rationale that we just talked about. You need either more than 3 minor. That is why D is wrong because it is only 2 minor. Then B is the right answer, 1 major and 1 minor.

[00:33:29]

Section 2: Clinical Data on New and Emerging Therapies

Then I am going to hand over for clinical data on new emerging therapies.

Dr Matthew P. Giannetti (Brigham and Women's Hospital): Thank you, Dr Bitar. As we discussed before, my name is Matthew Giannetti. I am from Brigham. I am an Immunologist by training. My section of the talk will be here to discuss on clinical data regarding the new therapies for mastocytosis, as well as a couple of slides on the basic therapy for all patients with mastocytosis.

[00:33:57]

Pretest Question 3

Before we start, let us do a couple of pretest questions. First one, which approved targeted therapy specifically targets the D816V mutation?

Good answers. Pay attention to approved, so FDA approved here. We will circle back to these in a little bit at the end of my talk.

[00:34:33]

Posttest Question 4

Question 4, your patient has indolent systemic mastocytosis with the KIT D816V mutation. For 6 months, a combination of anti-mediator therapies improved itching and diarrhea, but now symptoms are worsening. Based on the PIONEER trial, what statement would be correct when discussing therapy with the selective KIT inhibitor avapritinib for indolent SM?

I will let all of you read the questions and answer A, B, C, or D.

Great, B. We will again circle back to this once we have completed my section of the talk. Let us talk about some of the actual data.

[00:35:33]

Treatment for Mast Cell Mediator–Related Symptoms

First off, before we get to the new novel therapies, I think it is important to start with the basics. When I think of treatment for mastocytosis, I think of 2 pathways. Pathway 1 is going to be treatment of the mast cell mediator-related symptoms, so blocking the bad things mast cells release. Then path 2 is going to be cytoreduction of mast cells, and we will talk about that in terms of the novel therapies.

For the first path here, treatment for mast cell mediator-related symptoms, I like to think of a specific organ and therapy for that organ. For example, for the skin, most commonly people will have pruritus, itching, flushing, hives. They often term flaring of their cutaneous lesions or flaring of their spots. Typically, for this, H1 and H2 are very helpful, so I like second-generation antihistamines.

My go-to regimen is cetirizine 10 mg twice daily. Then you can go up or go down, depending on how the patient is doing. Leukotriene receptor antagonists also can be quite helpful. Aspirin, ketotifen, these are probably more in the domain of allergy, I would say. Second, for GI symptoms, probably the second most common organ system involved in my experience in mastocytosis, many patients have received long lists of diagnoses, from ulcers to irritable bowel syndrome, etc.

We do see a lot of acid hypersecretion in mastocytosis, so histamine actually directly activates parietal cells, the acid-producing cells of the gut or of the stomach. H2 blockers can be really helpful in this regard, typically famotidine. Many patients will need to be escalated to proton pump inhibitors as well.

Then, finally, I am not going to cover all of the rest of these. It is basically H1, and H2 is what I would say, really, for everybody. If they have a lot of symptoms, a good starting regimen is twice daily H1 and twice daily H2. Then, depending on how they are doing, adjusting from there, both above more meds as needed or less meds.

Then 1 final call out here for omalizumab. This is really helpful for anaphylaxis, for patients who have had hypotensive syncope or, truthfully, really poorly controlled skin lesions and flaring of their spots, often with some hives despite antihistamines. Omalizumab is an excellent option.

[00:37:49]

Other Therapies for SM

Moving more towards the cytoreductive therapies. A couple of older medications. Imatinib was really first reported in the 1990s for mastocytosis. As it turns out, most people with systemic mastocytosis have the KIT D816V mutation. You can see here the indications. Adult patients with aggressive, or there are non-aggressive forms as well that I will use imatinib, but very importantly, without the KIT D816V mutation. You need to check for it. You need to check for it using a PCR-based method. D816V is resistant to imatinib. It is really important that we have the molecular diagnostics correct before using imatinib.

Midostaurin is a recently approved medication for advanced aggressive mastocytosis. It is approved for all the aggressive forms of mastocytosis or the advanced SM forms. It is only other approval is FLT3-positive AML. It has a considerable amount of toxicity associated with it, but in the more aggressive forms, it is quite useful.

[00:38:56]

KIT Mutations as Drivers of Systemic Mastocytosis

Let us spend the bulk of our time talking about KIT mutations and then, specifically, how we can target KIT mutations with our novel therapy. As I mentioned before, most everybody who has systemic mastocytosis has an activating mutation in the KIT protein. Classically, we think of KIT D816V, depending on the data you look at, really, between 85% to 95% of patients have KIT D816V. If you focus here on this little graph to the right, you see KIT protein. It is a dimer.

When stem cell factor binds it comes together and then sends an activation signal down here. What KIT D816V does is this is just constitutively active. It is always on. It is always sending a signal. It is always telling the mast cell to grow and divide, and proliferate. There are very few diseases that have 85% to 95% of the disease caused by a single mutation. This observation led to the genesis of these targeted tyrosine kinase inhibitors.

[00:39:56]

Targeted Therapy in Systemic Mastocytosis

Moving forward, on that note, the first targeted therapy we had against the KIT D816V was avapritinib. It received FDA approval about 2 and a half or so years ago for indolent systemic mastocytosis. You can see here in this pictorial graph of a mast cell KIT D816V. KIT protein is here. It is an intracellular protein that spans the membrane, but the intracellular part is a D816V part. Avapritinib basically fits into that pocket and blocks activation or blocks signaling through the mutated KIT protein.

I will not talk too much about all these chemicals that mast cells release, but it is important to note a couple of things. One, histamine. Why we give antihistamines these people? Two, leukotrienes. Probably most of us have heard about montelukast or Singulair. Also, another medication that can block mast cell mediators such as leukotrienes. And finally, prostaglandins. These patients release a lot of prostaglandins. We used to use aspirin therapy much more in the past. We use it a lot less now, but aspirin blocks cyclooxygenase and inhibits synthesis of prostaglandins. So, important to have a general understanding of the things mast cells release mostly, so we can contextualize why we are giving these medications.

[00:41:16]

Avapritinib vs Placebo in ISM: PIONEER Part 2—Results

Moving on to the medications that have recent clinical trial data. Avapritinib was studied in the PIONEER trial. This was published in 2023 in the New England Journal of Medicine Evidence. It is a pretty large study, large, at least in terms of mastocytosis. 212 patients with moderate to severe symptoms. They all had to fill out a symptom survey and screen in based on the severity of their symptoms, and maybe more importantly, they had to be on at least 2 medications and have uncontrolled symptoms despite these 2 medications.

What do we look for in this trial? The primary endpoint is the leftmost column here. Total symptom score. This was that TSS score. It is a series of about 11 questions across skin, GI, anaphylaxis, cognitive, lots of different physical symptoms. You can see here a significant reduction in this primary endpoint. The secondary endpoints there are 3 primary secondary endpoints, all related to the quantity of mast cells that each person had. Serum tryptase, KIT D816V, and bone marrow mast cell burden all decreased, indicating that avapritinib was effectively cytoreducing or killing off, to use a more colloquial term, mast cells.

[00:42:35]

Long-term Improvements in QoL and Symptoms With Avapritinib in ISM: PIONEER

Moving forward. There is also been shown that these responses are both durable and in fact, improve over time. Avapritinib at the approved dose of 25 mg works quite well. In many patients with a chronic disease, some of the other questions are how long does it last? Do patients lose response? As it turns out, with 96-week follow-ups, they consistently have an improvement in their TSS score over baseline, and somewhat surprisingly, over the longer term, it continues to improve.

There is a couple of theories behind this, probably related to dose, etc., but you can see, though, that patients do not lose response. At least most patients do not lose response to the medication over the course of a couple of years. If you start breaking those down into individual symptom domains, you can see that in the GI, skin, and neurocognitive domains, symptom scores maintain significant improvement and in fact, deepen in all 3 domains over time. Then same thing in quality of life. This is a more general score about how is your quality of life, are you impacted in daily living activities, etc.?

[00:43:45]

Avapritinib vs Best Available Therapy in Advanced SM (SM-AHN, ASM, MCL): Pooled Data

Moving a little bit more forward towards the oncologic data. Avapritinib was also tried in the more advanced cases of mastocytosis. You can look here at the Phase 1 EXPLORER and Phase 2 PATHFINDER study. This is a very different population of people. These people were pretty sick. SM-AHN is mastocytosis plus another blood cancer, aggressive systemic mastocytosis 16%. These people have organ failure, typically fulminant cytopenias, hepatic failure with portal hypertension, and mast cell leukemia is really invariably fatal at this time.

In this very sick patient population, avapritinib pretty significantly extended the survival rate of these patients. Again, when we think of the trials with indolent systemic, we are looking at symptom improvement because these patients have a normal life span. In this data, the outcome is very different. We are looking at survival because life expectancy of patients with advanced mastocytosis is quite a bit shorter. I think for most of the audience here, this is a little bit outside the scope of what they will be prescribing. We will move on to the next slide here.

[00:44:54]

Avapritinib: Safety—Warnings and Precautions, Common Adverse Reactions (No Contraindications)

Cautions and warnings with avapritinib. A couple of adverse reactions that we see. Intracranial hemorrhage was first reported, this has been reported really only at higher doses of the medication in patients with more advanced disease. From a practical standpoint, for people with ISM, normal functioning bone marrow and normal platelets, I have never seen any of this, nor has anything ever been reported in the data. I think this is more a dose and disease-dependent phenomenon.

Maybe some of the more practical things that we will see. So, cognitive effects, some people do describe a little bit of forgetfulness, difficulty remembering things, particularly early on. Photosensitivity, I do not really counsel patients on this. I am not sure that I have seen much photosensitivity. I think at all times, people should be careful, particularly with mastocytosis, given they have an active skin disease. Maybe the dermatologist can comment more on this. I do not tell people to avoid the sun on avapritinib.

Then the last one here. This is an important one. This is absolutely a teratogenic medication, so you cannot have children while on this. There is been reported harm in animal studies. It is an absolute contraindication probably during pregnancy.

[00:46:14]

Bezuclastinib and Elenestinib:

Investigational Selective KIT Inhibitors

Bezuclastinib and Elenestinib in Nonadvanced SM

In addition to avapritinib, we have a couple of other clinical agents that are in clinical trials or recently completed clinical trials. As I mentioned before, avapritinib is currently FDA-approved for indolent systemic mastocytosis. These 2 newer medications, bezuclastinib and elenestinib, are not FDA approved. Bezuclastinib’s large study has completed in the end of 2025, so we are waiting on more information. Elenestinib is currently enrolling patients for a Phase 2/3 clinical trial, the HARBOR trial.

In the early data, for both of these medications, you can see here, looking at the endpoints we talked about before, symptom improvement, primary endpoint for all of these trials, reduced tryptase, reduced KIT D816V, and reduced mast cell burden, all secondary endpoints in markers of mast cell burden. You can see X's across the board, so these medications do all of it. The main benefit of these 2 new medications is that they do not cross the blood-brain barrier, so we see much less cognitive effects. Theoretically, the risk of intracranial hemorrhage should be zero. Probably more coming in the next couple of years on these medications.

[00:47:30]

Other Emerging Therapies

Other emerging therapies. Masitinib, had a Phase 3 study a while ago. This does it not hit D816V. It hits a little bit of chemicals downstream, they are called the Src kinases. Maybe some mixed use. We have not had final data yet from the trial. I think the jury is still out there. This is a different drug, TL-895. It is a BTK inhibitor. There is a good bit of precedence for the BTK inhibitors in the oncology literature, particularly in B cell cancers. This has some positive early data, but it is still very early in clinical trials. Much more to come on this. I think it is still a little bit early to comment too much on it.

With all that said, let us circle back to some of the questions here. Post test question number 3. Again, please pay attention to the verbiage and the wording here. Which FDA-approved targeted therapy specifically targets the KIT D816V mutation?

We have learned stuff. Avapritinib, yes, is the correct answer. It is FDA approved, and it does specifically target the date D816V. Imatinib is important because it does not actually target the D816V mutation. Rationale: avapritinib is the only FDA-approved one here for that targets D816V.

The second pretest question, let us repeat that here. For this patient with indolent systemic mastocytosis starting on or talking about avapritinib, which would be correct when discussing therapy with the selective KIT inhibitor avapritinib?

Basically, everybody chose mast cell burden decreased. Clinical trial data here shows that the mast cell burden decreased by greater than 50% in 53 patients. The reason why we reported this is oncologic convention. We report things as greater than 50% improvement, and so in more than half of the patients, we reduce their bone marrow mast cell load by more than 50%.

With that, thank you so much for your attention. I will hand the microphone and speaker presentation over here to Dr Ungar.

[00:50:24]

Section 3: Patient-Centered Management Strategies in Systemic Mastocytosis

Dr Benjamin Ungar (Icahn School of Medicine at Mount Sinai): We are going to be discussing patient-centered management strategies in systemic mastocytosis. Before jumping in, we will do a couple of pretest questions.

[00:50:39]

Pretest Question 5

A 46-year-old patient presents to your dermatology clinic with persistent red-brown macules on the trunk with a positive Darier's sign, flushing unexplained GI comfort. Which of the following referral pathways is most appropriate to ensure timely and accurate diagnosis of systemic mastocytosis?

1. Refer to gastroenterology to evaluate abdominal symptoms while managing cutaneous findings in dermatology;
2. Continued dermatologic management and repeat biopsy in 6 months;
3. Refer to endocrinology to evaluate for flushing-related hormonal disorders; or
4. Refer to allergy immunology for mast cell disorder evaluation while managing cutaneous findings in dermatology.

Give everyone a moment to answer. The majority of people have selected the last option. Allergy immunology.

[00:51:36]

Pretest Question 6

Then we will go on to the next question. How confident are you in applying shared decision-making strategies to reduce disease burden experienced by patients with systemic mastocytosis?

1. Not at all confident;
2. Not very confident;
3. Somewhat confident;
4. Confident; or
5. Very confident.

Again, we will give everyone a moment to answer. A mix of confidence.

[00:52:10]

Considerations for SM Management

With that said, we will proceed. There are a few, I think, themes that I want to touch on here. Three in particular. The first being the multidisciplinary aspect of care that this condition requires. The second thing we are going to talk about is shared decision-making with patients, which really ties into a lot of that. Then ultimately, what we can do as dermatologists in terms of ensuring these patients get the care that is needed.

Some of the considerations for the management of systemic mastocytosis. Again, as derms, we may not be necessarily the lead or focal point for all of these individual aspects, but it is important to know about them and ensure that patients are getting connected, either doing it ourselves or connected with someone who can ensure that they are getting that management and care.

Whenever possible, referral to specialized centers is strongly recommended. That is certainly something to keep in mind if that is at all an option. Because of the osteoporosis baseline DEXA scan is warranted. Patients need to be educated, counseled on signs and symptoms of the disease. Given how complex this is, how many organ systems can be involved, often the relatively unclear nature of some of the symptoms, it is important that they are aware of what aspects might be affecting them, even if they have not fully connected the dots yet, or have not yet experienced those symptoms.

Certainly important to counsel them to avoid known triggers of mast cell activation, and we will go into some more of the triggers. Many times, patients will be aware of triggers that are associated with worsening of their disease or symptomatology, but it is not always so clear-cut. There are certain things, like bee stings and so on, that they may not have experienced yet, and they need to be aware of in advance of having that experience.

Every patient needs to have injectable epinephrine, so they need EpiPens to manage anaphylaxis, very high risk. Then, in general, this is a disease with a very high symptom burden, quality of life impact, and so quantifying that, measuring that, and ensuring that we are actually tracking and improving using quality of life instruments can be very helpful.

[00:54:35]

Common Triggers in Systemic Mastocytosis

Some of the triggers we mentioned the last slide but true here as well. Temperature changes, stress, fatigue, certain foods and beverages, certain medications, infections. Obviously, a lot of these triggers are going to be ubiquitous, and patients are often going to already know the specifics that affect them. Hymenoptera, venom, bee stings, wasps, very important. High risk of anaphylaxis. Then surgery procedures, anesthetics, and so on may be triggers and patients, and then ultimately when they speak with their surgeons and so on, need to be aware of the potential risk with their systemic mastocytosis.

[00:55:19]

Patient Anaphylaxis Education

One of the maybe most important things that we can do as dermatologists from the get go is educate about anaphylaxis. Patients with systemic mastocytosis are extremely high risk. Up to 50% of people will experience anaphylaxis. They are using epinephrine frequently. They need to know what anaphylaxis looks like.

We need to ensure that they have access to an EpiPen. And, because anaphylaxis is an emergency, symptoms come on rapidly. It can be extremely stressful. It is important that patients know in advance, when they are not in that stressful environment, what to do. How to deal with it. How to use the EpiPen.

You can imagine if you are not trained and experiencing anaphylaxis, you are not going to use the EpiPen correctly, so having that in advance is crucial. Here is 1 tool that can help in a more formal way this Anaphylaxis Emergency Action Plan, to go with the patient to understand here is what happens if the symptoms of anaphylaxis develop, or there is an exposure like a bee sting or wasp sting, that may be very high risk.

[00:56:30]

Addressing SM Comorbidities: Multidisciplinary Care

We have talked, I think, pretty extensively, and it is worth highlighting that the aspects of patient's health that are affected by this are quite varied. The reality is, very often it is not going to be 1 specialist that is managing everything. One of the crucial things is that patients have that multidisciplinary care to ensure that they are getting the holistic approach needed for their condition.

That is the benefit of specialized center where that is actually streamlined. We have people who are specifically focused on treating that whenever possible. This is just an example of some of the specialists that may be involved in care. We talked about osteoporosis. Vertebral fractures can be quite common. That is often very debilitating, so having an endocrinologist ensure that they are on top of care for osteoporosis. Allergists, immunologists, they are going to play a crucial central role in the majority of cases in treating this, and that is whether it is specific allergies, Hymenoptera, management of the mast cell mediator related symptoms, anaphylaxis, and so on.

Certainly, as dermatologists were treating the cutaneous lesions. Psychiatrist, GI doctors, pathologists who know what they are doing in specifically with systemic mastocytosis. It is very complicated. The more connected and streamlined we can get, the better off patients will be again, in terms of their holistic care.

[00:58:02]

Addressing SM Comorbidities: Polypharmacy Is Common

With such a complicated condition, it is, I think, easy to imagine that patients are going to be getting a lot of medications, particularly if they have not really been formally diagnosed or they have been bouncing around in a really disconnected set of specialists. Go to a GI doctor for the GI symptoms, and that is not necessarily being connected to the endocrinologist, and so on.

Even when things are streamlined, patients are going to be getting a lot of medications, and this is just 1 example of the various types of intervention. Bisphosphonates, certainly the epinephrine antihistamines, topical therapies, and all that. Polypharmacy is very common. You can see here 50-plus percent are using at least 3 prescription medications and over-the-counter medications. There is a high risk of polypharmacy.

When there is not this maybe centralized or streamlined process of care, that is going to be a high risk of things falling through the cracks. Not to mention drug interactions and so on. This is probably in most cases too complicated for a primary physician to care for, or really to, I would say to oversee, and that is why specialized care is needed.

[00:59:14]

Shared Decision-making in SM

Part of the process of achieving, I think hopefully, optimal care is shared decision-making. Shared decision-making as a concept is not unique to systemic mastocytosis. This is hopefully something that is being integrated really into care across different diseases. I think it is fair to say that there are certain conditions where it may be even more important to integrate, just because this is very complicated and there are a lot of moving parts.

Shared decision-making really means, as the first box here says, seeking the patient's participation, having the patient be actively involved in their care, whether that is involved in decisions of treatment, understanding which specialists they are connected to, who is taking the lead on their care, which aspects of their specific experience are affecting them the most.

Part of it is educating on risks and so on, but also what they are experiencing. Patient values, preferences, challenges, hurdles. It is easy to say, oh, go see XYZ, and if they have logistical hurdles to doing that, ultimately that is not going to be an effective treatment. The only way really to understand that is to engage with that dialog with patients, eliciting their perspective, priorities, and personal experience.

Then ultimately, when there are various treatment options, various parts to this, when patients participate in the decision to pursue a certain treatment, and so on, the likelihood is that they are going to be more adherent to treatment. They have buy in to the process. They say to themselves, I am part of this, and it is not just someone telling me what to do with my life and my condition, but I am involved in that. Ultimately, that is going to just lead to better outcomes. Integrating that with a multidisciplinary care, I think, works together to achieve the goal of addressing the huge symptom burden, quality of life burden that these patients experience.

[01:01:19]

Importance of Shared Decision-making

The shared decision-making, we talked about this, but I think the individualizing treatment is at the core of this. Yes, education is important. Having patients understand what is happening to their disease, what treatments are available, what the evidence supports monitoring, follow-up support resources. But ultimately that is all going to center around individualizing treatment for that patient and what really works best with their life.

[01:01:47]

Patient Support Resources

Patient support resources can be extremely helpful. This is complicated. Often, we are not going to have time to sit for 2 hours to go through various aspects. Part of the education process can be done with the patient at their own time. Here is a list of some resources that can be available.

[01:02:10]

Posttest Question 5

With that said, we will return to the question. A 46-year-old patient presents to your dermatology clinic reddish-brown macules on the trunk with a positive Darier's sign, flushing, unexplained GI comfort. Which of the following referral pathways is most appropriate to ensure timely and accurate diagnosis of systemic mastocytosis?

1. Refer to GI for the abdominal symptoms while managing cutaneous findings by derm;
2. Continued dermatologic management and repeat biopsy in 6 months;
3. Refer to endocrinology to evaluate for flushing-related hormonal disorders; or
4. Refer to allergy immunology for mast cell disorder evaluation while managing cutaneous findings in dermatology.

We will give everyone a moment to revisit this.

The vast majority of people identified allergy immunology, and I certainly would agree with that. I want to emphasize 1 of the points, it is multidisciplinary, but someone in a sense needs to take the lead, and typically speaking, allergists, immunologists are going to be positioned to do that.

[01:03:22]

Posttest Question 6

Question 6. Again, how confident are you in applying shared decision-making strategies to reduce disease burden experienced by patients with systemic mastocytosis?

1. Not at all confident;
2. Not very;
3. Somewhat;
4. Confident; or
5. Very confident.

Again, give everyone a moment to answer this.

We have a shift in confidence from less confident to more confident, excellent.

[01:04:02]

Key Takeaways

Some key takeaways, just to round this out. Refer patients for further assessment if you suspect systemic mastocytosis. Again, dermatologists can play a role in the potential diagnosis with skin biopsy and evaluation of skin lesions, and referral, preferably whenever possible, to a center that specializes in systemic mastocytosis care. Treatment options for people with systemic mastocytosis include anti-mediator and cytoreductive therapies.

KIT mutations, particularly KIT D816V, are the drivers of systemic mastocytosis pathophysiology, and that mutation in the vast majority of cases. Because of that, selective KIT inhibitors are important emerging treatment options or emerged treatment options in some cases. Patients with systemic mastocytosis commonly receive many treatments and need treatment adjustments, communication, and reassessment with patients and the care team, and so having that care team well set up is crucial for optimal care.

Q&A

With that, we will go to the Q&A session and doctors Bitar and Giannetti will join there.

Dr Giannetti: I can handle the first. I see a couple of questions here. The first 2 questions are mostly the same with a little bit of permutation. Maybe I will go ahead and handle these, and then I will pass over to doctors Ungar and Bitar. The first question is what is the cause of osteoporosis, and the second is how often should patients have a bone density scan done?

Bone density scan is first most important because that is how you get the diagnosis of osteoporosis. In general, for everybody with systemic mastocytosis, I will order it at diagnosis. If it is normal, I check it every 5 years. If there is any evidence of osteopenia, I do vitamin D calcium, and then check it every 3 years or so. Anybody with osteoporosis really mandates therapy, so I send these patients to endocrine.

I do have a couple of youngish males, 30, 40 year old with vertebral fractures. So even in atypical populations, you can absolutely have fractures. What is the cause of osteoporosis and vertebral fractures? Active area of research. The real answer is it is unknown. It is related to mast cell burden. Probably mast cells release a variety of chemicals, cytokines, chemokines that put a little bit more pressure on osteoclasts to break down bone, rather than osteoblasts to build up bone. I think the pathogenesis is not completely understood, is what I would say at present.

For next question, maybe Dr Bitar, I am going to pick on you. Why don't you handle 1 of the remaining questions?

Dr Bitar: I do agree with what you said regarding the bone. This is what I do too. I think the second one is referral to allergy immunology always the gold standard when suspecting a patient who has systemic mastocytosis or symptom-specific. What I typically do for my patient with systemic mastocytosis, I do have allergy immunology involved all the time, so that will make Dr Gianetti really happy, which is what I usually do.

In our institution, we do have some GI that do have specific interest in mast cell disease, so I do tend to refer to GI that do have that specific interest, and they know about the disease more than any regular GI. Endocrinology, I do not think they are involved all the time, depending on the symptoms that we are seeing. I do have heme-onc involved as well, obviously, for the bone marrow and all of that.

Dr Ungar: Maybe Dr Giannetti, do you want to take the next one?

Dr Giannetti: Yes. Do you ever see patients with hereditary alpha tryptasemia who do not have SM at the time of diagnosis go on to develop SM? No. They are totally separate. They are related because you have an elevated baseline serum tryptase, but hereditary alpha tryptasemia is not a clonal mast cell disorder. It is a genetic trait. It is not currently considered a disease. Approximately 5% to 7% of the United States has hereditary alpha tryptasemia.

You could maybe make the argument that people who have very severe anaphylaxis have a low burden of SM, that we can pick up with some of our fancy tests in the future. What I do in clinic, I try to bucket patient in 1 or the other. They can both overlap, and you can have patients with both. In general, if somebody has a mild elevation in tryptase, they have the appropriate tryptase genotype. That is enough for me to satisfy myself. Probably allergy can answer this question. This is more in our domain with tryptase and anaphylaxis, etc.

Dr Ungar: I see a question here. Would everyone who has had anaphylaxis or angioedema more than once be recommended to check for systemic mastocytosis? I will briefly answer. Dr Giannetti, as an allergy immunologist, probably should weigh in as well. There are obviously many causes of anaphylaxis and angioedema that are not systemic mastocytosis-related.

I do not think the assumption is necessarily that if the presenting symptom is anaphylaxis, that patients have systemic mastocytosis. We talked about the prevalence of skin lesions, so I think it is reasonable to think about that as a potential etiology for anaphylaxis. A lot of that will also depend on history. If someone has an exposure to a food or so on in a repetitive scenario, there may be more likely explanations for anaphylaxis, but having it in mind, particularly in the context of other symptoms that may point to it, the GI flushing and so on. I think it is something to keep in mind. Dr Giannetti or Bitar, I do not know if you have a different perspective.

Dr Giannetti: Yes, I agree. There is lots of reasons to have anaphylaxis if you can find a clear trigger, if somebody ate a peanut, they have a known peanut allergy, and they have anaphylaxis, probably, we do not need to be looking for systemic mastocytosis in that person. It is more like the idiopathic anaphylaxis, where we really have no specific reason for this. Maybe even more particular, the type of anaphylaxis and mastocytosis involves cardiovascular symptoms. It is often hypotensive syncope without hives. In our domain, in allergy, it is pretty unusual to have people passing out without hives. That particular type of anaphylaxis should trigger a little bit more of an evaluation.

Dr Bitar: I agree. Every time they come in with anaphylaxis, I do try to tease out if it is more with cardiovascular symptoms or actually with skin symptoms, because whenever it is with skin symptoms, it is a little easier for us to figure out that. It could be urticaria, angioedema, or other exposure-related rather than really mast cell activation. If you do have a lot of cardiac involvement and cardiac signs, I would err the side of definitely look out for more for those patients.

Dr Giannetti: With that said, it looks like we have some questions here to wrap up for the discussion. Maybe we will ask our final polling questions. It was a pleasure speaking to everybody today.

Dr Bitar: You will want to try to do these last 2 questions about - we have 2 more about experience of patients who got undiagnosed for a long time. I would say, most of the patients are in that bucket, unfortunately, because a lot of physicians are really not aware of this condition. That is the goal of these seminars and webinars to try to get people to know more about this condition and try to suspect it as early as possible without just dismissing the patient.

Dr Giannetti: Maybe 1 final question here. Are there recommendations for patients in the perioperative phase in reducing mast cell reactions? Yes. Typically, it is like the contrast protocol that we use in allergy, so it involves oral antihistamines, often cetirizine 10 mg or Benadryl 25 mg, and prednisone 40 mg, typically given at 13 hours and 1 hour before. Some people will add 7 hours before as well. But the general thought is that by giving them steroids and some antihistamines, you are anticipating adverse reactions. I do not do it for everybody. People who have a history of anaphylaxis or clear-cut reactions, I will often premedicate, but I would say it is not mandatory, and it is best utilized in higher-risk patients or patients with a clear history of having adverse reactions during surgery or some other procedures.