On the Frontlines in Systemic Mastocytosis: The Dermatology Professional's Role in Improving Early Detection

Dr Matilda Nicholas (Duke University School of Medicine): So what is mastocytosis? This is a neoplastic disorder with substantial increase in accumulation of clonal mast cells, and that is important because we do have some syndromes that are a result of non-clonal mast cell activation. But in mastocytosis, we really have this clonal population of mast cells.

As the name suggests, cutaneous mastocytosis is limited to the skin. Systemic mastocytosis would have both skin symptoms and some extracutaneous organ involvement. Most of those patients do also have skin involvement, but it is not required for the diagnosis, and mast cell sarcoma, which we will not be talking about too much tonight.

Systemic mastocytosis frequently does result in mast cell mediator-responsive symptoms. So this is different from MCAS, which is unfortunately a popular self-diagnosis to be made these days out in the social media world, and there are very specific diagnostic criteria for that that you can look up, but that is important to differentiate from mastocytosis, which is really that clonal expansion, whereas the mast cell activation syndrome is the mast cell activation of a non-clonal population.

[00:05:10]

Systemic Mastocytosis: Epidemiology and Unmet Need in Diagnosis

So what about systemic mastocytosis in terms of the epidemiology? The prevalence is about 1 in 10,000. And so, incidents would be about 32,000 people in the United States. The really interesting thing is that there is a huge delay between the onset of symptoms and diagnosis and how many physicians patients seek care with, which makes sense given the huge variety of symptoms people can have. It is about 6.5 years for indolent mastocytosis, which is that first bar. It is even longer, about 12 years. So, a really long delay between the first symptoms appearing and the actual diagnosis being made.

Indolent is by far the most common subtype of systemic mastocytosis. Over 90% of patients will be ultimately diagnosed with indolent mastocytosis. And then there are more aggressive forms, which are thankfully much more rare.

[00:06:03]

Symptoms in the Spectrum of Mast Cell Disorders

In the spectrum of symptoms that we see, we think of, on 1 side, the symptoms that are really related to the mediators that are released from mast cells when they are activated. And then all the way on the other side, these are symptoms and signs that we see because of accumulation of this clonal population in different tissues.

So on the far left is what we will see more often in our dermatology clinic, which are the symptoms from that mast cell activation and the release of the mediators that they hold. So pruritus, flushing, and hives of the skin are very common in these patients. The gastrointestinal symptoms are likewise stemming from the effects of that mediator, which would be vasodilation, edema, and activation of cells.

So the gastrointestinal symptoms are frequently nausea, vomiting, diarrhea, cramping, and heartburn. Cardiovascular effects from that vasodilation: syncope, dizziness, and palpitations. And then, interestingly, a lot of patients, the majority, have neurologic symptoms, which can include memory and cognitive difficulties, depression, headache, and sleep disturbance.

In the middle are symptoms that can be from both the activation and the clonal accumulation, and that can include anaphylaxis. And we will talk about this a little bit more later on. We tend to see more hypotension than angioedema. And these can be provoked from things that we think of as typically causing anaphylaxis, but sometimes can be what we would consider unprovoked without a clear cause. We can also see osteopenia, osteoporosis, back pain, and bone pain. And we can have these general constitutional symptoms as well.

And then on the far right, we start to see effects of that clonal accumulation or the accumulation of clonal mast cells in these specific tissues. So osteolysis with pathologic fractures at younger ages than you might expect, lymphadenopathy, splenomegaly, hepatomegaly, cytopenias, and malabsorption from GI dysfunction. Typically, in the prediagnostic or indolent systemic mastocytosis, which is more likely to walk into your clinic, you are going to have more of those mediator-related symptoms, but you should really be asking and looking for things that could be coming up from more of the infiltration-related symptoms and signs.

[00:08:20]

Symptom Burden of SM

In terms of symptom burden, of course, in dermatology, we are very comfortable with quality-of-life effects and measures, and we see this very profoundly in systemic mastocytosis. So when we look at what is the symptom that bothers you the most, most of them fall into the skin-related symptoms of the disease, with a close second being GI-related. And so these are very likely to present to dermatology groups since it is so common to have skin involvement, and the symptoms of the skin involvement are frequently the most bothersome to the patient.

On the right, you can see some quality-of-life scores. And so in this measure, the EQ-5D-5L, 1 would be a perfect state of health. And so, you can see that there is a significant negative impact in the quality of life that these patients experience.

[00:09:09

Patient Reports of Impact on Daily Life, Work, and Social Activities/Settings, Mental Health

When we ask patients, "How does this disease impact you?" We can see very profound impacts on all of their activities of daily living. More than half report being quite a bit limited in their general activities. That can include work and everything else in their life. More than half report they have reduced their work hours due to these symptoms. More than 40% have significant depression and effects of depression. And then even more than half are reporting limitations at their social activities and pain interfering with work, with up to 85% presenting with cognitive problems. That is a huge burden for people, and it is a really profound impact on their quality of life. Even with a minimal, visible rash, this can occur.

[00:10:00]

Why Is Systemic Mastocytosis Presentation So Heterogeneous?

So why is this presentation so heterogeneous? And certainly, I, in my practice, I have seen the full gamut. I have seen some people with horrible cutaneous disease without a lot of symptoms, and I have seen people with minimum cutaneous disease with really profoundly impactful symptoms and sort of everything in between. So why do we see that?

Well, there is a lot of variability in the mast cells and the activation based on where they are, what surface receptors they are expressing, and all the mediator profiles. We do see a huge range of different impacts in terms of the infiltration of those clonal mast cells in different tissues and organs, which is very variable between patients. We also see a lot of mutational heterogeneity. And so about 90% of patients, and these are adult patients, with systemic mastocytosis carry a somatic point mutation in KIT. And we do see mutations in other genes, and there are some variable mutations. And so, those also have an impact in the way that this disease presents.

[00:11:01]

HCP Perception of ISM Impact on Patients

What about the healthcare professional perception of how indolent mastocytosis impacts patients?

You can see from this publication in 2022, that it is profoundly impactful, and these are our measures, which are usually underestimating how this can impact patients. But at least a good half to more than half are either a great deal or quite a bit impacted in a variety of different domains: pain, the differences in appearance, how burdensome they feel to family and caregivers, financial hardships. I mean, the list goes on and on.

So again, this is just highlighting that really significant impact in the quality of life and function and daily activities that can occur with this disease.

[00:11:47]

Adult vs Pediatric Onset Mastocytosis

There are quite a few differences in adult- and pediatric-onset mastocytosis. In adults, most patients have indolent systemic mastocytosis by quite a large margin. In pediatric patients, most, the vast majority of patients, have cutaneous-only disease. The course in adults tends to be chronic, while in pediatric patients, the vast majority of patients will resolve spontaneously in adolescence, sometimes early adulthood.

Anaphylaxis is much more common in adults. Up to 50% of patients have some history of anaphylaxis, and that can occur in pediatric patients. It is important to ask about it and have families be prepared, but it is less common. The tryptase level is often significantly elevated in adults, although it is not necessarily so, and the elevation of tryptase can vary over time. So we will talk about that in a few minutes. And then in the pediatric population, less commonly elevated, reflecting that cutaneous predominant disease.

In adults, the D816V mutation in KIT is by far the most common mutation that we find. There are others, but that is the very predominant mutation, whereas in pediatric cases, there is a lot more variability, all types of different mutations, and some where we do not find any mutations at all in KIT.

The morphology of the cutaneous lesions is very different as well. So in adults, we have these monomorphic, small papules and macules that can coalesce into larger plaques and patches, predominantly on the torso and proximal extremities, whereas pediatrics are much more polymorphic, much more variable, trunk, head, and extremities.

[00:13:24]

Skin Lesions of Mastocytosis

And we have some photos to share. As dermatologists, we all love photos. So these are some typical skin lesions of mastocytosis.

On the far left, you would see an adult presentation in someone that has a little more melanin in their skin, so more of a skin of color patient. And what you can see is much more prominent hyperpigmentation, which is very common, of course, with inflammatory dermatoses, that post-inflammatory hyperpigmentation. But you can still appreciate that reddy or reddish background to these lesions.

And both that and the picture just to its right, which fits more of a type 1 or 2 skin. You can see that classic small macules and papules, pretty monomorphic with that rusty brown or reddish brown look to them that can at times coalesce into larger plaques. Very classic.

On the right, we have pediatric cases. And so we have a patient with more melanin in their skin that has, again, that more prominent post-inflammatory hyperpigmentation. The erythema is a little less obvious, as will be classic, but note how much more polymorphic these lesions are. They are larger, and they are more variable in their size.

And then to the far right, a patient that fits 1 or 2, which again, you see some macules and papules coalescing to these very large plaques that have those clear excoriations from the pruritus and with some prominent edema as well.

[00:14:49]

More on Typical Cutaneous Lesions of Mastocytosis

So again, in adults, most patients are going to have cutaneous disease. So it is rarely cutaneous only, but most indolent mastocytosis does have cutaneous lesions that are classic, so greater than 80% of patients. And they typically do have those monomorphic, erythematous and brown papules and macules coalescing into plaques and patches. There is Darier's sign, which is that whealing, reddening, and edema on stroking or rubbing, which is just that lowered threshold for mast cell activation, that physical stimulation is causing them to granulate and release their mediators that cause these symptoms.

Importantly, in pediatric cases, the Darier's sign, especially on larger plaques, can sometimes induce anaphylaxis. So you want to be cautious with that. They often start on the thighs or the torso, proximal extremities, and then can gradually spread, but they are rarely outside of the proximal extremities and trunk, although it can happen.

[00:15:48]

Telangiectasia Macularis Eruptiva Perstans (TMEP)

So TMEP, this is a little bit of a touchy subject, I think, still kind of controversial.

The 2016 consensus report does not recognize TMEP as its own separate thing, but there are some people, I am kind of in that group, which think it may be its own thing. It is unclear to me if it is a completely separate entity, if it is on the spectrum, or if it is somewhere in between maybe there are cases of both.

It can present at any age. I see it a lot in young adults, and it can be very subtle. In fact, a lot of the cases that I found have been found incidentally when the patient comes in. They do not even know it was there, so I think it is probably underdiagnosed. But of course, classic would be these macules that have that brown-red color. If you use dioscopy, which is where you push a glass slide against these lesions, that erythema blanches out, and you are able to appreciate the brown discoloration. Darier's signs frequently negative or very minor, and you do need to really carefully evaluate these patients, because there is some data to suggest that at least some portion of them probably does have true cutaneous mastocytosis, possibly indolent mastocytosis, and so they really should be evaluated for mastocytosis systemically.

[00:16:56]

Posttest 1

Okay, so let us return to our pretest question. We are going to do it now that we have seen more about mastocytosis.

Again, which combination of findings in this patient would be most suggestive of underlying mastocytosis, rather than an isolated dermatologic condition?

1. Sun-exposed papules, GERD responsive to PPIs and aging-related osteopenia;
2. Reddish-brown papules with pressure-induced swelling, chronic diarrhea and syncope;
3. Eczematous plaques, bloating related to dietary triggers and fatigue; or
4. Pyritic nodules, flushing triggered by heat, and a mild increase in liver enzymes.

So I will give everyone just a second to answer that question. And I think we can go ahead and close that poll and see how everyone did.

Okay, so we have learned, yes, for sure. So again, that pressure-induced swelling, chronic diarrhea, and syncope, those are signs of that mast cell degranulation, the mast cell mediator activation. So the sun-exposed papules, this is not a photosensitive dermatosis, so you would not expect to see that. Generally, the GERD is less responsive to PPIs and mastocytosis, and we would see osteopenia that is above what you would expect for aging. And then I just wanted to point out too, because the liver enzymes throws people sometimes, you can sometimes see some elevation of liver enzymes if you have infiltration of the clonal mast cells into the liver, but it is not 1 of the very common things that you find.

And with that, I am going to move us ahead and turn it over to my colleague.

[00:18:43]

Digging Deeper: Confirming SM Diagnosis

Dr Thanai Pongdee (Mayo Clinic College of Medicine and Science): Thanks so much, Dr Nicholas. That gets us off to a great start, diving deeper now into confirming the diagnosis of systemic mastocytosis.

[00:18:57]

Patient Case

So with that, we are going to return to our case of May. So again, has the characteristic skin findings, has elevated tryptase and the abnormal DEXA scan. The added piece of information now is that she has undergone a bone marrow biopsy, and on that biopsy is the finding of dense multifocal mast cell aggregates.

[00:19:22]

Question

So with that, we will have a couple of questions. So the first is this 58-year-old individual with the history of spreading small red skin lesions, as we have just described, has additional testing for systemic mastocytosis. So according to the WHO criteria, which of the following is needed to confirm the diagnosis?

1. Dense multifocal bone marrow mast cell aggregates;
2. Dense multifocal bone marrow mast cell aggregates and a serum tryptase greater than 20 ug/ml;
3. Identification of KIT D816V mutation; or
4. Identification of the KIT D816V mutation and a serum tryptase greater than 20 ug/ml?

A few moments to think about that, and then we will move on to our second question. So first, see what the answers were. So the majority take the second option, which is mast cell aggregates and serum tryptase level. We will dive deeper into that in just a moment, but that is a great start to the discussion.

[00:20:46]

Question

The next question will pop up here. So based on our patient's cutaneous findings and systemic symptoms, should she be referred to another specialty for further evaluation? So please choose from the following.

1. No, you can continue dermatologic management with topical therapies and trigger avoidance;
2. No, you could just prescribe an antihistamine and provide dermatology follow-up care;
3. Yes, you would refer to another specialty for further evaluation of mast cell disease; or
4. Yes, you would refer to gastroenterology for chronic diarrhea workup.

Take a moment to look over those, and we will see what the responses were there.

So the vast majority said yes, refer to another specialty for further evaluation, and we will definitely touch upon this in just a moment. So thank you for those responses.

[00:21:56]

Diagnostic Criteria for Systemic Mastocytosis

So we are going to start right with the diagnostic criteria for systemic mastocytosis. So this is divided into what we call major and minor criteria. There are 2 consensus bodies who have established diagnostic criteria. One is the WHO criteria, which is listed at the bottom of the slide.

The WHO criteria have been around for several years. Within the past few years, there has been another consensus group called the International Consensus Classification. They are very similar in nature. They essentially use the same major and minor criteria. It is just how they count these up to make a diagnosis is a little bit different.

But the major criteria are essentially, you have to have multifocal dense aggregates of mast cells, and this is defined as greater than or equal to 15 cells in aggregates. Traditionally, this is found in bone marrow, but you can make this diagnosis in another extracutaneous organ.

The minor criteria are listed here. So essentially positive for KIT D816V mutation or another activating KIT mutation. Again, this elevated serum tryptase level of greater than 20 ug/ml. Again, it is an absence of associated myeloid neoplasm. myeloid neoplasms tend to have quite elevated serum tryptase levels. So in that scenario, you cannot use this criteria. The other 2 minor criteria depend on the morphology of the mast cells and its cell expression. So there is listed aberrant cell surface markers that are listed or a large percentage of mast cells of atypical morphology, and it is classically described as a spindle morphology.

The WHO criteria would say if you have 1 major and 1 minor or 3 minor, you can make the diagnosis. And in the International Consensus Classification, 1 major alone is enough or 3 minor. So again, a little nuanced, but essentially the major and minor definitions are the same.

[00:24:02]

Identifying Systemic Mastocytosis Subtypes

So once you make the diagnosis, then we want to subtype the systemic mastocytosis. So these are listed here. In a broad sense, we divide that into non-advanced and advanced.

As Dr Nicholas mentioned, the vast majority of systemic mastocytosis is the indolent form, which is non-advanced. Again, approximately 90% of cases are in this indolent category. So the non-advanced forms are considered non-progressive in nature and more of a chronic condition.

Advanced forms are much more aggressive in nature, and behave more like an aggressive malignancy. Categorizing the subtype is very important because it has important implications for prognosis as well as recommended treatments.

[00:24:58]

Differential Diagnosis

In terms of the differential, so we have gone over the diagnostic criteria, but it is also important when you are seeing these patients to consider other conditions. You know, given the heterogeneous nature of the presentation, there are a number of other diseases to take into account, which are listed on the right. So certainly lots of chronic skin conditions that may involve pruritus, urticaria, or angioedema. Lots of gastrointestinal symptoms that may suggest a different type of gastrointestinal diagnosis.

Again, with early issues of bone health that may suggest an underlying endocrine disorder. And certainly the cognitive issues that Dr Nicholas mentioned, certain neuropsychiatric diagnoses need to be taken into account. Again, in terms of mast cell activation syndromes, that may be something to consider.

Monoclonal mast cell activation syndrome is a specific disorder where you do have evidence of clonal mast cell involvement. And again, idiopathic mast cell activation syndrome or anaphylaxis are non-clonal disorders, but certainly involve mast cells in the expression of symptoms.

[00:26:20]

Mastocytosis in the Skin: Workup Algorithm

This is a nice algorithm to consider in terms of evaluating mastocytosis in the skin. Please take note of the reference at the bottom from Dr Madigan. It is a great resource. I would highlight a couple of features of the algorithm.

One is the age of your patient. So certainly those that are adults or post-adolescents, close to adult age, if they have mastocytosis evidence in the skin, there is a high likelihood of having a systemic disease. So those, you know, we typically want to screen with serum tryptase, and also go ahead and check for peripheral blood for KIT D816V mutation.

And if those are abnormal, certainly proceed rapidly to biopsy consideration. Again, KIT D816V mutation is the most common mutation found in systemic disease. If you have those that are younger, so again, as Dr Nicholas mentioned, in young kids, mastocytosis in the skin often resolves as they age. So we typically screen those individuals with serum tryptase level. And if normal, generally can be followed if there are no other additional signs of systemic disease.

One key red flag would be any sign of organomegaly or the presence of monomorphic skin lesions in a child. Those are considered higher-risk features. And again, proceeding with evaluation for KIT D816V mutation and consideration for biopsy would be highly recommended.

Again, for more details on this algorithm, please refer to the reference listed at the bottom of the slide. It will be available under Resources.

[00:28:27]

Common Triggers in Systemic Mastocytosis

Moving forward in terms of once you have made a diagnosis of systemic mastocytosis, be aware of common triggers for symptom flare-ups. There are many of these, as can be seen on this slide. And patients often will report stressful events, certainly temperature changes, whether cold or hot. Many are sensitive to a variety of medications, have a significant number of drug allergies. Any type of illness or physical stress may trigger symptoms.

And with that, certainly any type of procedures, especially surgeries. And bee sting allergy is also a high-risk factor for those with systemic mastocytosis.

[00:29:16]

Diagnostic Algorithm for Mastocytosis

In terms of when to consider following the diagnostic algorithm, certainly you have to have heightened suspicions to consider the condition may be present.

So again, an individual who has a number of mast cell activation symptoms. So again, we typically think of skin, respiratory, cardiac, and GI. Skin, typically, flushing, pruritus, urticaria, angioedema. These individuals have lots of gastrointestinal symptoms, abdominal upset, chronic diarrhea. Certainly cardiac, you know, there is hypotension or syncopal events, and certainly respiratory symptoms could be wheezing or coughing and the such. It is severe allergic presentations. We just discussed mastocytosis found in the skin. So again, if that is seen in an adult, they have a high likelihood of having systemic disease.

So if you have these clues from their clinical presentation, the evaluation typically would require a biopsy to meet or address the diagnostic criteria. This most commonly involves bone marrow, but again, could involve an extracutaneous organ. I would say gastrointestinal endoscopy would be one that is commonly looked at if bone marrow is not pursued. Again, testing for the KIT D816V mutation, which is the most common mutation found. There are other sequencing avenues for looking for other KIT mutations.

If there is significant eosinophilia present, screening for the PDGFRA gene fusion product is highly recommended, as that is a type of hypereucyclic syndrome, which has its own specific therapy, but can present with LA tryptase. So that is a condition that has an entirely different treatment and one that you do not want to miss.

[00:31:25]

Mastocytosis Pathology Testing Standard of Care

In terms of the testing involved, there are a lot of things listed on this slide, but I would divide it from left and right. So on the right side, morphology and phenotype, this typically will require a biopsy. Again, bone marrow being the most common. Again, not only looking for the features of mastocytosis, but also to rule out any type of other hematologic disorder or to determine if an associated hematologic neoplasm is present, because again, the presence of that would place that individual in an advanced category.

On the left, laboratory studies that are listed, essentially to look for organ involvement or organ dysfunction, because again, that may place an individual at more aggressive disease. The genetic features, in addition to KIT D816V mutation, again, many of the gene panels available now are screened for associated hematologic disorders.

We have not talked too much about hereditary alpha-tryptasemia, but again, a more recently described as a very common condition, a genetic condition that leads to elevated baseline serum tryptase levels. Very common in Caucasian populations, approximately 6% of the population. So again, something to keep in mind in individuals where you have an elevated screening serum tryptase level.

[00:33:00]

Diagnostic Challenge: Basal Serum Tryptase

So to expand upon that, tryptase is probably the most commonly known lab test associated with mastocytosis. It is important to remember that, again, hereditary alpha-tryptasemia may be found in up to 6% of the general population. So elevated tryptase levels do not necessarily mean someone has mastocytosis, so you need to keep that in mind. And on the flip side, tryptase levels less than 20, which is a minor criteria, does not necessarily exclude mastocytosis.

[00:33:35]

Considerations for SM Management

So considerations for management, again, specialized centers would be strongly recommended given the multiple organs that may be involved. Baseline DEXA scans would be recommended due to the high risk of poor bone health.

Counseling patients in terms of the symptoms that may be expected as well as specific triggers. Because of the high risk of anaphylaxis, again, up to 50%, we always recommend having epinephrine autoinjectors readily available.

[00:34:06]

Addressing SM Comorbidities: Multidisciplinary Care

With the multiple organs, again, being involved, this typically requires multidisciplinary care as listed here. Multiple specialties are typically required to help provide optimal management for patients.

[00:34:22]

Posttest

And with that, we will close with the questions that we posed in the beginning. So this question, again, the 58-year-old patient that we described with characteristic skin lesions. So according to the WHO criteria, which of the following is needed to confirm the diagnosis?

1. Dense bone marrow mast cell aggregates alone;
2. Aggregates and elevated serum tryptase;
3. Identification of KIT D816V mutation alone; or
4. The presence of KIT D816V mutation and an elevated serum tryptase level.

A few moments to go over that. And our results are, let us see.

All right, fantastic. So the vast majority chose the second option. So mast cell aggregates, again, are a major criteria.

Elevated serum tryptase greater than 20 is a minor criteria. So again, 1 major and 1 minor can make the diagnosis. In the WHO criteria, 1 major alone would make it in the international consensus diagnosis. So we go with that.

[00:35:42]

Posttest1

And then the next question we will have here is, based on our patient's findings and symptoms should she be referred to another specialty for further evaluation?

1. No, you would continue dermatologic management with topical therapies and trigger avoidance;
2. No, prescribe antihistamine and provide dermatology follow-up care;
3. Yes, refer to another specialty for evaluation of mast cell disease; or
4. Yes, refer to gastroenterology for chronic diarrheal workup.

And our final responses are, okay, great. So the vast majority, again, chose yes, refer to another specialty for evaluation of mast cell disease.

I think this speaks primarily to the multidisciplinary care that is typically required for these patients because of the vast organ involvement that may be present. And obviously, it is a chronic condition that needs long-term follow-up.

So with that, thank you for listening to this portion of the presentation. And I will hand it over to Dr Madigan.

[00:37:02]

Advances in SM Treatment

Dr Lauren Madigan (University of Utah): Thank you, Dr Pongdee. So in the last 15 minutes or so, we are going to be focusing on advances in the treatment of systemic mastocytosis. And I think this is a really exciting time for those of us that have been participating in the care of these patients because we have now additional options to offer them, not only to increase survival in our patients with advanced disease, but also quality of life in all of our patients.

[00:37:26]

Client Case

So to kick off this last section, we are going to go to our fourth question. So we have now diagnosed May with indolent SM with a KIT D816V mutation. And for 6 months, a combination of anti-mediator therapies did improve her itching and diarrhea well. But unfortunately, now she is having worsening symptoms that are progressing, and she is no longer controlled with these supportive agents. So, we are thinking about selective treatment.

[00:37:50]

Question 4

Based on the PIONEER trial, what statement would be correct when discussing therapy with the selective KIT inhibitor avapritinib for indolent systemic mastocytosis?

1. The bone marrow mass cell burden decreased by greater than or equal to 50% in 23% of patients at 24 weeks;
2. The mass cell burden decreased by greater than 50% in 53% of patients at the same time point;
3. Symptom benefits were limited to improvement in skin symptoms; or
4. Symptom benefits, while significant early, tended to decrease after 1 year.

And I will give you a minute to think about that one and answer accordingly.

Okay, excellent. So most people were divided between these decreases in mass cell burden. And we will talk specifically, of course, about the PIONEER trial as we move forward here.

[00:39:02]

Treatment for Mast Cell Mediator–Related Symptoms

So when we talk about treatment for systemic mastocytosis, of course, we have to think about our mediator-related therapies, our best supportive therapies, including all the things that are listed here.

This is from the NCCN guidelines in mastocytosis. And a lot of agents that most of us are pretty familiar with, and can be very beneficial for patients, particularly with milder disease. So we are thinking about things like H1/H2 antihistamines, often sort of at increased doses, up to 4x standard dose, leukotriene receptor antagonists.

Cromolyn sodium and proton pump inhibitors can be particularly helpful in the setting of GI disease. And omalizumab is something we also use fairly frequently in our clinical practice. And again, for many patients, these therapies can provide meaningful benefit and improvement in quality of life, such as the patient we presented, at least during the first 6 months of her therapy.

[00:39:50]

Other Therapies for SM

Historically, however, if patients did not respond to these therapies, where did they have to go? As Dr Nicholas already outlined for us, these patients often have a very significant burden on quality of life. And patients with advanced disease and organ infiltration obviously have very significant impacts on their survival.

And so where did these patients go? A lot of times those treatments were really reserved for patients with advanced disease due to the toxicity associated. And what were some of those options?

Well, imatinib was the first tyrosine kinase inhibitor to be assessed and is FDA-approved for the treatment of adults with aggressive systemic mastocytosis, either without the KIT D816V mutation or with an unknown KIT mutational status. In a review of 28 patients with ASM, 29% did achieve complete response, with 32% achieving a partial response. Notably, in a smaller study evaluating patients who lacked KIT D816V but met criteria for what we call well-differentiated SM or WDSM, the overall response rate was about 50%, including early and sustained complete responses in 4 patients. That is why it is marked there as 1 of the drugs that we consider particularly for WDSM.

Now, important safety considerations, again, including diarrhea, nausea, ascites, significant edema, dyspnea, muscle cramps, really, again, limited use to patients, again, in these more advanced subtypes.

Midostaurin is an oral multi-kinase inhibitor. This has activity against wild-type and D816V-mutated KIT. This is currently FDA-approved for the treatment of advanced systemic mastocytosis. You can see those categories there.

Midostaurin use was associated with reduced bone marrow, mast cell burden, spleen volume, mastocytosis-related organ damage, and serum tryptase in an open-label phase II trial of patients with advanced SM, as well as improved symptoms and quality of life. Notably, however, toxicity related to midostaurin is pretty frequent, including significant GI side effects, as well as cytopenias, and often this required dose reductions. So again, a medication that can be difficult to apply over larger groups of patients or patients with more indolent disease.

[00:42:06]

KIT Mutations as Drivers of Systemic Mastocytosis

So we are talking a lot about KIT, and we have heard both of our prior speakers say that KIT mutations are really the driver of systemic mastocytosis, and greater than 90% of adult patients are going to have a KIT somatic point mutation. So let us talk a little bit about what KIT is.

Mast cells express many surface receptors that mediate their function. KIT, or CD117, is a growth factor receptor with tyrosine kinase activity. This is a critical regulator of mast cell biology, essential for their survival, proliferation, migration, and differentiation, and it is encoded by that KIT gene. Its typical ligand is stem cell factor, but when you get a gain-of-function mutation, such as this D816V mutation we keep talking about, that leads to constitutive activation independent of stem cell factor, so ligand-independent activation, which gives you increased mast cell survival and accumulation.

Again, D816V is really important because it is the driver mutation in the vast majority of patients, and so, as we talked about, can be important when you are actually screening patients for the disease, but is also a really important potential target for us to treat, and that is where this medication called avapritinib comes in.

Avapritinib is a selective tyrosine kinase inhibitor for KIT harboring the 816 codon substitutions, and it has been FDA-approved at a dose of 200 mg once daily for advanced SM or 25 mg once daily for indolent systemic mastocytosis.

[00:43:40]

Targeted Therapy in Systemic Mastocytosis

So I want to talk a little bit about advanced systemic mastocytosis first.

[00:43:44]

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

This is showing you some data where avapritinib was compared to best available therapy, pooled data from multiple centers in which patients were treated as part of the EXPLORER and PATHFINDER trials for advanced disease. The median overall survival was significantly improved in patients treated with avapritinib, as shown here. The duration of treatment and the maximum decrease in serum tryptase level were also significantly higher in patients treated with avapritinib, and the efficacy of the avapritinib in patients with advanced SM was irrespective of prior therapies that they tried or those other mutational status that they might have had, which is really meaningful improvement.

Across all patients, the most common grade 3 or higher non-hematologic adverse effects were fatigue and vomiting, while the most common hematologic adverse events that were observed included thrombocytopenia, anemia, and neutropenia. There were notably 9 cases of intracranial bleeding in patients with advanced SM, 7 of which were associated with antecedent severe thrombocytopenia, and for that reason, this medication is no longer considered appropriate for patients with a platelet count less than 50. Following a lot of external requests for the inclusion of avapritinib in the NCCN guidelines, the panel did vote to add it as a preferred treatment option for advanced systemic mastocytosis, again, for patients with platelets greater than 50.

[00:45:17]

Insufficient ISM Symptom Control Despite Supportive Care

But what about our indolent patients? As discussed before, these patients often have a lot of polypharmacy, they are on multiple medications, often have a very significant quality-of-life impact, and for many patients with more moderate to severe disease, those best supportive therapies that we talked about, those anti-mediator therapies, just are not sufficient to significantly reduce their disease, as outlined here in this study of 25 patients with ISM, talking about how the ISM treatments really were not sufficient to control their disease.

[00:45:52]

Avapritinib vs Placebo in ISM: PIONEER Part 2—Results

So is there a role for using avapritinib in the setting of indolent disease? And thankfully, the answer for that is yes.

So this is the Phase II PIONEER trial data in which patients with moderate-to-severe ISM, despite prior use of at least 2 best supportive care medications, so these are patients with moderate-to-severe disease that were not responding to those supportive agents, they were randomized 2:1 to receive either avapritinib 25 mg daily or placebo.

At 24 weeks, there was a significant reduction, the first bars on your left, in the patient-reported total symptom score. So the patients are reporting a significant improvement in their symptoms. What we can also see is that at week 24, more than 50% of patients are achieving a greater than or equal to 50% decrease in their serum tryptase level, their KIT D816V variant allele fraction, or the burden of the mutation in peripheral blood, as well as the bone marrow mass cell burden. So this was our question earlier, what kind of reduction was seen in the first 24 weeks of the trial? 53% of patients achieved at least a 50% reduction in the bone marrow mass cell burden.

Thankfully, this was pretty well tolerated. The most common adverse effects that occurred in the avapritinib group included peripheral and facial edema, as well as falling and insomnia.

[00:47:26]

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

So we now have longer term efficacy data as well in avapritinib for the treatment of ISM via the PIONEER. Our data is now a median of about 3.6 years, with some patients with data up to 5 years. And what we are seeing is sustained disease-related symptom improvements.

And you can see from that middle graphic there that those are sustained improvements across different organ systems. So GI, skin, and neurocognitive domains all demonstrating consistent continued improvement. For the skin specifically, ongoing use is associated with consistent mark reductions in skin symptoms, but also in improvements in the color of fixed skin lesions, the surface area of fixed skin lesions, as well as the pathologic mast cell burden within skin biopsies.

[00:48:16]

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

Again, at this longer time point of 3.5 years, avapritinib remained very well tolerated, edema, peripheral and periorbital being the most common. And again, at about the 3.5 year time point, only about 3% of patients discontinued treatment due to a treatment- related adverse event. So generally, again, pretty well tolerated in this patient population.

What do we want to, you know, think about when we think about safety with this medication? Well, I already discussed this a bit with our advanced trials. This risk of intracranial hemorrhage occurred at an incidence of 2.9% in patients with gastrointestinal stromal tumors or advanced SM. And again, that is the higher dose of 200 for the advanced SM patients. And again, now we have those safety guidelines around use in patients with platelet counts over 50. Thankfully, there were no events of intracranial hemorrhage at all in the ISM PIONEER study.

And to date, I do not think there has been a single reported case, even now that it is FDA-approved in patients receiving the 25 mg dose.

Cognitive effects can occur that would require withholding the medication. That depends on severity. This medication also is photosensitizing. So we help to counsel patients in terms of photoprotection. And this is not a patient that we would consider sort of concurrent UV therapy, for example, for.

There are significant embryo-fetal potential risks. And so both cladribine NTKs are generally not recommended in the setting of pregnancy. Again, most common adverse effects for advanced SM, edema, diarrhea, nausea, fatigue, and for indolent SM, periocular edema, dizziness, peripheral edema, and flushing.

[00:49:58]

Bezuclastinib and Elenestinib: Investigational Selective KIT Inhibitors

Okay, let us talk about some of our medications that are investigational that are coming online soon. Elenestinib and bezuclastinib are novel investigational oral next-gen tyrosine kinase inhibitors. And these have minimal CNS penetration. So again, improving selectivity as well as safety.

These have both demonstrated robust reductions in patient-reported symptoms, as well as multiple objective markers of mast cell burden, including tryptase, KIT D816V, and mast cell burden, as indicated here in this graphic. Both agents have been generally well tolerated in clinical trials, with the majority of safety events reported as being low-grade.

For elenestinib, this is, again, a very selective agent. It does not inhibit wild-type KIT. And in the HARBOR trial, there were no drug discontinuations due to treatment-related adverse effects, with things such as headache, nausea, and edema reported in a minority of patients.

For bezuclastinib, again, very selective. This does not hit some of those off-target things like PDGFR or FLT3. With regard to side effects, transaminase elevation was reported. Generally, this is transient. And there were no significant changes in liver functions as measured by coagulation parameters or bilirubin within this trial. All treatment-related discontinuations in this trial were in the setting of transaminase elevation, and they did generally resolve upon discontinuation. Other reported adverse events did include hair color change, as well as taste alteration for this medication.

At the bottom of the slide, I do want to also call out that these are being used, these medications, for advanced SM, even though I just showed you the ISM data. Bezuclastinib in the APEX trial was associated with a reduction in systemic mastocytosis burden, improved progression-free survival rates, and, again, a favorable safety profile.

[00:51:52]

Other Emerging Therapies

Other emerging therapies. Masitinib is in Phase III trials. This is another tyrosine kinase inhibitor. And then we have TL-895 in clinical trials. For instance, here at our Center of Excellence, this is a bruton tyrosine kinase inhibitor assessing in the setting of ISM or myelofibrosis.

[00:52:14]

Shared Decision-making in SM

So shared decision-making is really important in this disease state. So I think as dermatologists, we are very good at assessing quality of life and quality of life impact in our patients' disease. We think about this a lot with all sorts of conditions, HS, psoriasis, alopecia areata. And I think in SM, it is 1 of those other situations where when a patient has indolent disease, it really comes down to the risk-benefit, making sure that the patient is well-informed, making sure that they have all the data in order to make the most important decisions for them.

I think this also goes to why staging is so important, because if you do not accurately stage a person as having systemic disease, they may not have access to some of these clinical trials as well as some of these FDA-approved therapies.

[00:52:58]

Patient Anaphylaxis Education

As discussed earlier, anaphylaxis, pretty high prevalence, up to 50%. And as both Dr Nicholas and Dr Pongdee mentioned, these patients should be given an epinephrine autoinjector pen, discuss the symptoms of anaphylaxis. This particularly carries a high rate of hypotension with their anaphylaxis. Have a treatment plan and really, training on how to use epinephrine autoinjector. And again, considering this as a skin-limited disease can really limit sort of access to these sorts of therapies as well.

[00:53:30]

Patient Support Resources

There is loads of patient resources that are available, and they are listed here. They will be available in your resources. One I want to call out for a provider resource is the American Initiative in Mass Cell Diseases.

If you go to that website, it does list all of the Centers of Excellence and reference centers across the United States. So if you are looking for someone to partner with you, or you are looking for a center that maybe has ongoing clinical trials, that can be an excellent resource to know who in your area might be very interested in seeing these patients and working them up and treating them.

[00:54:02]

Posttest 4

So back to our posttest question, question number 4. And again, the question here is, based on that PIONEER trial, what statement is correct when discussing therapy with the selective KIT inhibitor avapritinib for indolent systemic mastocytosis? And I will give you a minute to respond.

Excellent. So almost everybody got this. Again, we are seeing a really nice reduction in the mast cell burden in the bone marrow biopsy at 24 weeks with 53% of patients achieving that over 50% reduction, which is wonderful.

[00:54:59]

Key Takeaways

So some key takeaways I hope that you got from our presentation here is that most adult patients presenting with fixed skin lesions are going to have meet criteria for systemic mastocytosis. So considering to refer them particularly to a center that specializes in SM care can be really important.

Treatment options can include both anti-mediator and selective therapies, targeted therapies. And so having those both in our armamentarium has really changed the game in terms of taking care of these patients.

KIT mutations, particularly D816V, are drivers of SM pathophysiology and selective KIT inhibitors are important emerging treatment options for this. People with SM commonly receive many treatments and need treatment adjustments, and communication with patients, as well as the larger care team that they are likely going to have is really critical for optimal care. So we always say that mastocytosis is a team sport, and I really truly believe that that is where patients get their best care.

Q&A

So that is all the content that we had for you today. We will move on to a few questions for Q&A and I will invite the rest of the panelists to come back online. There will be a few other kind of housekeeping things that will be coming up in your chat, but I want to get to some of these questions.

So the first question is, is systemic mastocytosis common in patients with hyper IgE syndrome? So maybe Dr Pongdee, as our allergist, you want to handle this one?

Dr Pongdee: Yes, that is a great question. I would consider these 2 different entities. So hyper IgE syndromes primarily are primary immune deficiency. So those individuals do have many skin findings that tend to be recurrent skin abscesses as well as abscesses in terms of lung infections. I would consider those 2 different entities and would not overlap.

Dr Madigan: Wonderful. Thank you. I completely agree with that answer as well.

Our second question, when a patient presents with multi-system symptoms but do not have obvious fixed skin lesions, what other features should prompt a clinician to consider SM? Maybe Dr Nicholas, you would be willing to take this one?

Dr Nicholas: Yes, that is always a very challenging question. So really, it is pretty unusual for a patient to have mastocytosis without any skin findings at all. But that is where some more laboratory evaluation and really doing a very detailed history, I think, can help to guide that workup.

But I am interested to hear what you both think.

Dr Madigan: Yes, I mean, I think there are some tools that can be helpful. So there is something called a REMA score. In the algorithm that we showed, we just basically showed the side where there are fixed skin lesions because that is what we most commonly see in the dermatology space.

But you are going to absolutely use some of those other scoring criteria to help know who is going to be at the highest risk for having SM. I am definitely like hymenoptera, recurrent anaphylaxis, those sorts of things. There are certain things that particularly increase your level of suspicion for SM, but there is some additional tools and resources available there as well.

Dr Pongdee?

Dr Pongdee: Yes, I totally agree. I think, quickly from an allergy perspective, anyone with hymenoptera anaphylaxis should be screened for mastocytosis. And those with early age onset osteoporosis or osteopenia, so that is a red flag that many endocrinologists will actually screen for mastocytosis given that setting.

Dr Nicholas: And it can be helpful to review some of that. Like I said earlier, with the popularity of self-diagnosis of MCAS, sometimes using these tools for patients can be really helpful to reassure them that they do not have anything that is really worrisome for mastocytosis at this time.

Dr Madigan: Yes, that is wonderful. The next question I can take is, how do you decide when symptom-directed anti-mediator therapy is sufficient vs when targeted therapy should be considered? I think this is a particularly interesting question.

And in the setting, again, with advanced disease, it is a little bit different, these patients have really significant either B or C findings, so high burdens of mast cell involvement or true organ dysfunction or an associated hematologic malignancy, mast cell leukemia. Those patients, I think treatment decisions are a little bit more acute, whereas patients with indolent disease, it really is more of a shared decision-making moment where if you have a patient, again, we talked about the criteria for the clinical trial was moderate-to-severe symptoms with at least who had been on at least 2 anti-mediator therapies and did not have sufficient disease control. I think that is a pretty good kind of general outline.

But if you have a patient, we have had patients before that absolutely will not leave their house, they are terrified, sort of the implications of their disease, they hate the way their skin looks, they hate the way their skin responds to things. And for those patients, these therapies can really truly be life-changing. And so again, the threshold for every patient is a little bit different.

And again, it is 1 of those things where if maybe you are not super comfortable doing like avapritinib in your own clinical practice, sending that patient on to a center where there is expertise in the use of these medications can be really meaningful so that they can access those additional options.

And the last one we have, what expectations should dermatologists set with patients regarding the chronic nature of their disease, even with systemic treatment? I do not know, Dr Nicholas, if you want to start that, and we can all maybe jump in.

Dr Nicholas: Yes, sure. So I do tell people that we cannot always predict how this disease is going to behave over time. And that I think we are very used to diseases where what we are providing really is control and not cure.

And that is often how I frame this up with these patients as well, that we want to be vigilant but not hypervigilant about the potential for progression for their disease, but that it is typically something that we have to manage long-term, just like psoriasis, just like eczema. These are chronic diseases that at this point we manage. And so, I frame it in a similar way of actually to a lot of the other chronic diseases that we manage.