That’s a phenomenal presentation of a very a rare disease. Now, we’re talking about hen’s teeth in a rare disease. I have seen a lot of mast cells, but I have only seen 2 cases of well-differentiated systemic mastocytosis [WDMS], and both were misdiagnosed at the outside center. One of my patients was more of an indolent finding, as you mentioned, these can be very indolent. However, the other case presented with mastocytoma, and she responded well to imatinib. How many cases are you seeing, Dr Wang, for these?

 Not many, but recently we saw another case. We actually have a fellow who just brought it up. It’s another case. We do see it once in a while. I think the important thing is not to say this is mast cell hyperplasia because mast cell hyperplasia sometimes can be associated with a lot of conditions like lymphoplasmacytic lymphoma, and they can have lot of mast cells. Just don’t get confused with that.

I think the important thing here is that the D816V is almost, at least in my understanding, ubiquitously wild type, you don’t see the D816V. And the digital droplet PCR [polymerase chain reaction] is really specific for that, so it’s important to do really a full 

 mutation because you find mutations that are outside of the pseudo activation center within D816V. They are elsewhere within the juxtamembrane, or other components of the gene, so the whole gene really needs to be sequenced, and you can see the different mutations that you’re showing here on these cases.

 A patient who did NGS [next-generation sequencing] would identify this mutation.

Dr Bose or Dr Lugar, any thoughts on this rare entity?

 I haven’t seen WDSM myself. But, of course, I am aware of it, and it’s a great reminder of where imatinib can help. As you said, Dan, it can encompass the entire spectrum of indolent to smoldering to advanced. Speaking of CD30, we had done the trial of brentuximab vedotin, the antibody-drug conjugate, with Jason Gotlib, MD. That unfortunately was disappointing. So far, that approach has not worked.

 That’s correct. I remember many years ago I implemented CD30 to our flow panel. It’s because of that trial. However, we found it was actually very useful for us for diagnostic purpose.

Videos

The panel of experts discuss the clinical differences between well-differentiated systemic mastocytosis and chronic mast cell leukemia.

Well-Differentiated Systemic Mastocytosis vs Chronic Mast Cell Leukemia

I don’t know if anyone wants to make any comments about a mast cell leukemia [MCL] diagnosis. First of all, do you think the only requirement being more than 20% mast cells on an aspirate smear is a good criterion, or that this is just 1 form of aggressive systemic mastocytosis [SM]?

You raise an excellent point as this is an artificial thing, so it’s an aleukemic leukemia, if you will. There is no circulating or very minimal circulating disease, and the mast cells are just really on that bone marrow aspirate. Then, you’re subjugate to the quality of the aspirate because some aspirates are more cellular than others due to the fibrosis. There must be something different about it. In my one hat, I think this is an artificial diagnosis; in the other hat, study after study after study even with these patients with aleukemic leukemia, they seem to have a lower response rate, and you’ve already mentioned that the 

 mutation and CD25 frequency is a little bit different. There is something different about these patients and the ability to have these aspirate smears with 20%, although is 19% really any different than 20%, but 20% is the bar in the sand. Dr Bose?

 You know Dan, I think the main thing here regarding what needs to guide us is what is the survival, what’s the natural history? I think if we go back to the old Mayo Clinic paper as well as the more recent ECNM [European Competence Network on Mastocytosis] paper, they are doing worse generally than ASM [aggressive systemic mastocytosis] and SM-AHN [SM with associated hematologic neoplasm] and I think that is what needs to really set this apart. However, we know about the chronic MCL, which is a variant that seems to behave a lot less aggressively and is not associated with C findings. Clearly, it’s a heterogeneous group.

 Definitely, I think you’re right concerning this point, which is why we’re looking into this mast cell leukemia…cases from MD Anderson Cancer Center. Some are very aggressive, whereas some are very indolent. Actually, that’s why when the people who created these entities realized that some are not aggressive, they then created this chronic mast cell leukemia entity. I think it has a lot to do with the cytology of the cells. They are very roundish, they’re anaplastic. They look much higher grade, and also the underlying molecular genetic findings of this disease. Probably, those dictate the artificial cutoff of 20%.

The panel of experts in SM discuss the diagnosis and treatment of a 68-year-old female with mast cell leukemia.

Case 4: Treatment and Management Considerations in MCL

I think the next case will be right up your alley, Dr. Lugar, in terms of highlighting a case that was a challenge. This is a patient of mine who presented with urticaria pigmentosa, 15 years ago now, 2006; and more prominent symptoms, hive-like symptoms, with heat or after hot water exposure. She had an isolated episode of syncope. She had a tryptase of just about under 80, and a skin biopsy. It’s representative of what she has. She just has spots everywhere. A skin biopsy confirmed urticaria pigmentosa, or cutaneous mastocytosis. Given her tryptase level, she was referred to hematology for a bone marrow exam. That showed about 10% dense aggregates, consistent with systemic mastocytosis. She had a KIT D816V mutation. She had no other mutations, isolated. I’m not going to show you her bone marrow, for brevity, but she had normal counts and no C-findings. She was diagnosed as having indolent systemic mastocytosis and was managed by allergy and immunology with respect to her symptoms with a cocktail; with H1 and H2 blockers and montelukast [Singulair].

She did well. She’s a fourth-grade schoolteacher, and she did well. She developed a cough. She’s a nonsmoker. Sure enough, she had a mass that was biopsied, and she has non-small cell lung cancer with an 

 mutation and was started on erlotinib [Tarceva]. She did great for 3 years when she developed small brain metastases, unfortunately. They tried to make the switch to Osimertinib [Tagrisso], and she anaphylaxed, so they switched her back to erlotinib. Allergy/immunology has been on board all around. They do a desensitization program. I’m not exactly sure what that means. Maybe you can tell us.She has recurrent anaphylaxis, so she goes back to erlotinib, and she has some slight progression.

They tried desensitization in the ICU [intensive care unit] again, and she anaphylaxes yet again, so they’re stuck. Of course, I get paged, and I get called. She doesn’t meet the criteria, so with all due diligence, this is a non-FDA [Food and Drug Administration] approved indication for midostaurin [Rydapt]. She does have systemic mastocytosis, but she has no C-findings, so it’s indolent. But I didn’t know what else to do, so I started her on midostaurin, 100 milligrams, twice daily. I drove down her tryptase, and I’ll show you in the next slide. We were able to start osimertinib at 40 milligrams. I started her in the hospital because I was afraid. She had no reaction. And after a month, I increased the dose to 80 milligrams, and all of her lesions resolved. And this is her tryptase showing a rise to 140 about, and then on the midostaurin, really dropping precipitously to around 20, which is where it is today. There’s a little blip when we went down on the dose of the midostaurin because she was having some GI [gastrointestinal] toxicity. Then, she re-escalated. She had just these very subtle ditzels in her brain that are now really resolved.

She had an MRI [magnetic resonance imaging] just recently, May 2021, showing resolution. Not to highlight the point here, but this is just the cutaneous involvement that I pulled off. This is not her, but somebody else, just showing, again, the H&E [hematoxylin and eosin stain] on the left and the amount of tryptase-positive mast cells. This is a CD25 stain, however, on the right, just highlighting the amount of involvement. This is a flow diagram, which is what we do here, in addition to the IHC [immunohistochemistry staining]. I’m not sure we really need it. But here, you can identify, in the right upper outer quadrant, patients that are CD2, CD117, and CD25-positive cells, which really meets all the criteria. CD117 is ubiquitously expressed, and CD25 and CD2 are often—the one caveat to that is, often, treatment with avapritinib [Ayvakit] or midostaurin will down-regulate the CD25, so it can be hard to follow later. With that, I’m going to stop sharing. Dr. Lugar, thoughts?

 You did a fantastic job, Dan, I have to say.

 I would have done the same thing. Desensitization in mastocytosis is certainly not as successful as somebody without mastocytosis. I had mentioned we sometimes use omalizumab [Xolair], and that’s actually what I thought you were going to say next, but you were even more brilliant because you went ahead and just treated it. I think that’s exactly what you have to do. It makes complete sense that she would’ve responded then with the reduction in mast cell burden. Your only options are to do anything you can to reset that reactivity of the mast cells. You are not going to get around it any other way. We’ve tried desensitization again, and again, and again in these patients that are hospitalized, and it’s very difficult to be successful. It just is. We’re lucky we can do that with venom anaphylaxis. They do respond to allergen immunotherapy. But drug desensitizations are very, very difficult. We just don’t have a lot of success in that venue, so you’re really looking for any other options to mitigate the disease.

 This is a brilliant case. I mean, the midostaurin clearly enabled her to receive a lifesaving or life-prolonging therapy. That right there, it’s a huge deal. And avapritinib, too. Bruce Bochner has published a case where there was recurrent anaphylaxis that was successfully treated with avapritinib, so I guess we’re going to perhaps see more of this use of these drugs.

It’s off label, so for all due diligence, I did say that. But I think when these patients are pushed up against a wall, we really have no option. Sometimes, you have to think outside the box. If the disease is causing the anaphylaxis, treating the disease will help. And we were lucky, and she’s still doing well. Those slides were updated just a month ago.

Dan DeAngelo, MD, PhD, presents the case of a patient with indolent systemic mastocytosis and urticaria pigmentosa.

Case 3: Indolent Systemic Mastocytosis 

Prithviraj, you’re a co-author with me. Your thoughts on this data and the recent approval with avapritinib [Ayvakit]? Anything you’d like to share?

 Yes, extremely exciting, Dan. Of course, it’s been great to be a part of the avapritinib story. I think I find it very impressive that the overall response rate is 75%, not just in the PATHFINDER study, but also in the EXPLORER study, which makes it 85 evaluable patients. I think that is quite striking. Then, as you pointed out, a lot of them are CRs [complete responses]. If I recall right from the midostaurin [Rydapt] data, I think the CR rate was considerably lower…

There were almost no true CRs. The CR plus PR [partial response] rate was about 19%, at least on the label.

 I think this is a drug which is hitting the target to a greater depth. This is, of course, a more potent and more selective inhibitor of mutant KIT, so I hope we are sparing wild-type KIT a little bit more. Not entirely, because we see myelosuppression, but hopefully more than we do with midostaurin. Overall, a very exciting drug.

 Of course, with all due diligence, there are some toxicities of concern that are different from midostaurin. Midostaurin has the GI [gastrointestinal] intolerance, but it’s not as myelosuppressive. This agent is not horribly myelosuppressive, but it is, as you mentioned. But it does have these neurocognitive issues, and there were some cases of subdural hematomas, although those cases were predominantly in patients with thrombocytopenia. With the amendment, we only saw one. But those are issues, and management of that is going to be a thing. We have two FDA [Food and Drug Administration]-approved drugs, which is great. His is also being tested in indolent systemic mastocytosis. I’ll have a case next on that. But your thoughts Dr. Lugar?

 This is, quite frankly, the hope that it gives to patients and physicians alike as a real treatment, certainly a better targeted therapy, is very exciting. We have a number of patients that are very, very interested in getting enrolled in further clinical trials that have indolent. It’s just an incredibly exciting time to be managing these patients. I hope that the same symptom score for indolent as well carries over in further trials because that’s the most difficult thing—managing the chronic symptoms. Even if we know these patients are stable, they don’t have a disease that’s going to be progressive, the majority of them, but managing the day-to-day symptoms is such the burden of disease. And then, as I told you, my cocktail, not only is that exhausting and expensive, but that has a lot of side effects too—sedation, weight gain from antihistamines. It’s not easy to tolerate in seemingly very mild medications, but the burden of treatment and disease is still high on our list.

Well, it’s always nice to have options.

A panel of experts share their reactions to the approval of avapritinib and discuss the clinical implications.

Avapritinib: Approval and Clinical Practice Implications

This woman was started on midostaurin, and she did great for 12 years before she progressed. We were able to wean her TPN [total parenteral nutrition]. She went back to work and off hospice, and her GI [gastrointestinal] symptoms resolved. She was the poster child for our prior story on midostaurin. But after 12 years on midostaurin, she slowly developed—over a year and a half, it wasn’t rapid—more GI complaints, more ascites, more hepatomegaly, tryptase was going up. Then we rebiopsied her, and she was able to enroll in our PATHFINDER study. Prithviraj, I’ll start with you as my [fellow] hematologist here. What are your thoughts on this particular illustrative case?

It’s incredible. It must be so gratifying to having cared for a patient like this. I mean, with the whole hospice transformation.

It adds a little to the story, but it’s a true part of the story.

I’m certain that it is. Also, the duration of response to midostaurin is very impressive. I know you published on the long-term outcomes of the midostaurin. That was phase 2. You said the patient is on PATHFINDER, and I presume she has responded. But there are multiple C findings, so ascites and splenomegaly. I forget her counts. I’m not sure.

Her counts were OK. I forget what they were. I didn’t include that. She was anemic, but I don’t know if that qualified for a C finding. I can’t remember if it was less than 10.

Right. But clearly the ascites, lots of edema all over, lymphadenopathy, and the organomegaly. A remarkable case.

Dr Wang, I tried to highlight a few immuno-peroxidase studies. Any thoughts?

 Yes, I agree. The GI biopsy—we say it’s so subtle. If you don’t think about this disease, you absolutely miss it. As you said, in the mucosa you always have a lot of cells. Also, you have nonspecific inflammatory response. You’re going to have increased…response cells, lymphocytes, and even eosinophils. You can have some allergy reaction. This patient does, when I saw your slides it has a lot of eosinophilia. Sometimes we look for mast cells because the eosinophilia and the mast cells go side to side.

I’m not aware of that. If somebody has not just peripheral eosinophilia but eosinophilia in the tissue, then you’ll think about mast cells?

 Yes. It’s kind of interesting. Sometimes the mast cell aggregates in the bone marrow. It can see the periphery of the mast cell…have a lot of eosinophilia. That’s the time, so some mast cells are probably in here. We start to look for mast cells because they come from the same precursors. There’s 1 type of the SM [systemic mastocytosis]...and that’s another common association with slightly increased eosinophils.

Let me ask a question. This is independent of PDGFRA and FIP1L1 right?

 Yes, we’re not talking about the 1 like…rearrangement, and then they can have increased eosinophils. Usually they aren’t forming SM, and occasionally they can present as SM. Whether they always have…mast cells, they’re scattered in the bone marrow.... They also often have CD25 expression. If the predominant presentation is hypereosinophilia, then with upper mast cells we have to rule out the PDGFRA arrangement. Also, in patients who we said presented with SM, if you really can’t find a 

 mutation, that’s also the time we start looking for this recurring arrangement.

The panel of experts in SM discuss the diagnosis and management of a 46-year-old woman with systemic mastocytosis.

Case 2: Treatment and Management Considerations for SM

Dr Lugar, this patient clearly had systemic disease, so as an oncologist, I think he needs a cytoreductive therapy, but that doesn’t mean that this patient doesn’t still have SM [systemic mastocytosis]. He was having symptoms from recurrent urticaria pigmentosa and hives, allergic reactions, diarrhea. He was still having symptoms of his systemic mastocytosis. What’s a treatment algorithm that you would recommend in terms of supportive care for some of these patients who are not high-grade anaphylaxis but are having symptoms? What would you do?

 That’s interesting because the patients who are so advanced, like this man was in the first case, tend not to have as much presentation of what we consider a normal mast cell. These mast cells are a little different. They’ve matured out of their normal function, so we tend not to see as much anaphylaxis in reactivity or responsiveness. They’re more interested in interacting with the T cell, with other immune cells, and lose some of their normal function. It can be the people who have a tryptase of 25 ng/mL or 45 ng/mL that have a high burden of symptoms. For that, we don’t have too much to offer, and that’s why it’s exciting to be in the realm of other therapeutics: we always start with antihistamine therapy, and we look at mast cell stabilizers. Our usual regimen is antihistamine and mast cell stabilizers. You can look at leukotriene modifiers, and we treat with aspirin. We’ve been using biologics such as omalizumab more recently. Some patients are on a cocktail of all those medications. That can help to some degree with the cutaneous manifestations. It can help with some of the constitutional symptoms, such as the brain fog and the fatigue. It might help a little with some bone pain. These patients are symptomatic from multiple organ systems, so most of our patients receive that whole cocktail, unless we have a more definitive therapy in mind. But that’s generally where we get started, and it’s more of an additive therapy.

I’m glad you mentioned that. This patient was on antihistamines as you mentioned, so both an H1 and an H2 blocker with cetirizine and famotidine. He was also on montelukast for a leukotriene stabilizer, and then he was started on steroids. That’s how I inherited him. With treatment of his disease, we were able to wean off the steroids, prednisone, and then we were able to wean off his montelukast. I was a little afraid about the H1/H2 blocker because he was doing well. That’s something, as we drove down his tryptase, that we could try. He wasn’t having anaphylaxis, so we had not escalated to a mast cell stabilizer.

Patricia Lugar, MD, MS, shares treatment algorithm and supportive care recommendations for a 75-year-old man with systemic mastocytosis.

Case 1: Treatment Algorithm and Supportive Care Recommendations

This is very important to mention. This particular man went on to receive midostaurin. Midostaurin is the FDA-approved agent. Avapritinib, which we’ll talk about with the next case, was just approved. But Midostaurin is approved at a dosage of 100 mg twice daily, which is different from the dose that’s approved in AML [acute myeloid leukemia]. It’s not surprising that this man had some difficulty with nausea. I tried maximizing his antiemetics. I had to reduce the dosage to 50 mg twice daily. Over several months, he was able to tolerate the reduced dosage and antiemetic regimen, and I was able to scale his dosage back to 100 mg twice daily, which I always try. My experience has suggested that patients have a dose-response curve, so I try to get as much drug as I can. After a year and a half of therapy, he had a complete remission with resolution of his ascites, resolution of his hepatosplenomegaly, resolution of his bone marrow infiltrate, and a tryptase that was below 20 ng/mL, at 19 ng/mL. Still elevated but less than 20 ng/mL, and that’s the criterion for remission. He was still doing well on midostaurin. Prithviraj, what are your thoughts on the diagnosis and management?

As you said, this is a very clear-cut case of SM [systemic mastocytosis] meeting multiple criteria. A lot of C findings as well. I noticed ascites. I saw hypersplenism with the low counts and the big spleen and then the 40% infiltrate in the marrow could have also been contributing to the cytopenias. In fact, I meant to ask you, did the cytopenias improve on the midostaurin?

Yes, this is 1 of those unusual cases where the cytopenias—in my opinion, they don’t usually improve—in this case did improve because remember he had a leukocytosis that was probably being driven by this clone. Consequently, that was a peripheral blood NGS [next-generation sequencing] panel and his thrombocytopenia was likely because of his hypersplenism. Thus, when the spleen normalized, his platelets improved.

Right. Going back to your point about the NGS missing the mutation, we too had a number of cases before we started doing the digital droplet PCR [polymerase chain reaction], where we were finding them to be KIT wild type. We’ve gone back and started to reflexively order the digital droplet PCR, or the molecular diagnostics people do, if they find the NGS is negative.

That’s a great point. For any patient referred to us, specifically from our allergy colleagues, just because of the referral pattern much of the time, the patient is going to have a lower volume of disease. We’re dealing with mostly indolent systemic mastocytosis, because if they had C findings, they had often come in referred into a different mechanism. One of the checkboxes is that everybody gets a digital droplet PCR. Dr Wang, 1 of the highlights of this case is that this is not just systemic mastocytosis. This man has these 2 processes. He has some myeloproliferative stuff. He presented with a white blood cell count of 27,000 per mm3 and lots of mutations. How difficult can it be, and how do you make a diagnosis of SM-AHN [systemic mastocytosis with an associated hematologic neoplasm]?

We always like to discuss this among our own pathologists. Usually a patient with indolent SM, the CBC [complete blood count] is almost always normal. When you have significant cytopenia or cytosis, that’s the time you have to look for the underlying disease. Of course, they can be because of the C findings but also the underlying…malignancy. Another thing I’d like to point out is that the pathology I saw was quite interesting. I don’t know if you see patients with mast cell SM, but the bone always has a lot of changes. You can see those on the modeling. That probably corresponds to what you see on MRI [magnetic resonance imaging]. The bone always has a lot of bone changes.

This osteoclast and osteoblast is modular. They become thickened. It’s a very common thing in patients with systemic mastocytosis.

Another thing for the markers—we like to use CD1 c-KIT, CD117, because the tryptase a lot of times, especially when the mast cells become immature or aberrant, can lose tryptase. Tryptase a lot of times is more variable than the CD117. The CD117 usually highlights most of the mast cells.

This patient did have a CD117, but I could put only 4.

The panel of experts in SM discuss the diagnosis and management of a 75-year-old man with systemic mastocytosis.

Case 1: Treatment and Management Considerations

I’d like to go through some cases. These are real cases. These are cases I just pulled out from patients I’ve seen. This is a 75-year old gentleman. He had a 3-month history of abdominal distension and some lower-extremity edema. His blood counts, when he was finally referred in, showed a white blood cell count of 27,000 per mm3 with a hemoglobin of 8 g/dL and a platelet count of 64,000 per mm3. His differential was rather bland, with the exception that he had a nucleated red [blood] cell, no immature cells. The CT scan—I’ll show you a picture in a second—showed diffused lymphadenopathy about 2 to 3 cm, so pathologic lymphadenopathy. He had both small pleural effusion and ascites. The ascites was symptomatic, and he had splenomegaly. Of course, what was the next step? I checked the tryptase level and a bone marrow exam, because I’m a hematologist, so you use the tools in your toolbox. Also, with bone marrow examination, which I’ll show in a second, it showed the hypercellular marrow with 40% mast cells, and they were classic. We’ll have our pathologists comment on it in a second. CD117, and they had aberrant CD2 and CD25. Cytogenetics were normal, but he had a next-generation sequencing [NGS] panel that we call rapid heme panel that showed mutations in 

I hope that you can see the screen, but he had both hepatomegaly and splenomegaly. On this view, you can see some ascites around the liver and the spleen. But there was some more ascites, to the point that he had at least grade 2 ascites requiring diuretic therapy. Also, these are bone marrow exams from this particular patient. Highlighting the hypercellularity of the marrow, this is a low-power view, but with the spindle-shaped cells that were associated with some underlying fibrosis, it’s hard to differentiate what’s going on. The immunohistochemical stains in the bottom with a mast cell tryptase and a CD25 just to show aberrant. I’m not showing CD117 for brevity, but this highlighted the fact that this patient had a substantial population of aberrant mast cells making the diagnosis of systemic mastocytosis. The question, of course, is what subtype. He was at such a hypercellular marrow, it was hard to get an aspirate out of him, which shouldn’t surprise you. This is our next-generation sequencing platform.

Highlighted in red is the characteristic pathognomonic 

 mutation that’s present in about 90% to 95% of patients. This gentleman had a pretty high allele burden, but he also had other mutations, such as a mutation in the spliceosome, a mutation in a DNA transfer TET2 and COX1. This is most consistent, especially giving this person leukocytosis of a subtype of systemic mastocytosis with an associated hematologic neoplasm. Just to take you through this—I’ll pass the baton to Dr Wang in a second—these are the WHO [World Health Organization] criteria for diagnosis. You have to have 1 major and 1 minor or 3 minor criteria. The major criterion is multifocal dense infiltrates of mast cells. I don’t think there’s any question that this person had these huge, dense infiltrates. An infiltrate is defined as an aggregate of 15 cells or more. The minor criteria are 4-fold. One is that a quarter of the cells have to have an atypical spindle cell morphology, which is really hard to see on the photos I showed. There has to be a 

 mutation, and I showed that. There has to be a CD25, which is aberrantly expressed. CD2 is another aberrant marker. This patient had CD25, so that’s a second minor. Then, a tryptase level of 20 ng/mL. This man’s tryptase was in the 100s approaching 200 ng/mL. Consequently, he clearly met 1 major and 3 minor criteria. Any way you slice or dice it, this patient met the diagnosis of systemic mastocytosis.

To highlight what we’ve talked about, this example was not difficult because the majority of the clone, the allele burden, was 35%, which means 70% of his disease was driven by KIT. But it can be very difficult, and Dr Bose had mentioned 1 of his cases. This shows the difference between NGS and the sensitivity of digital droplet PCR [polymerase chain reaction], which can really detect 1 or 2 cells out of a million. As a result, you can pick up about a third of cases with standard NGS, but in digital droplet PCR, you can pick up almost all the cases because almost 95% of cases will have a 

 mutation. This is a very important thing to remember. I get referred a lot of patients, and it would be interesting—after I present this case—to hear what Dr Bose’s thoughts are, on KIT wild-type systemic mastocytosis. But they did a nonsensitive NGS panel, sometimes at a place I’ve never heard of. When we repeat it with our digital droplet PCR, we’re often able to pick up a 

 mutation. This is very important to mention.

Dan DeAngelo, MD, PhD, presents the case of a 75-year-old man with systemic mastocytosis and reviews WHO diagnostic criteria.

Case 1: 75-Year-Old Man With SM

Concerning this newer entity of hereditary alpha tryptasemia, or HAT, how does this play into your algorithm?

We have a few patients we follow in the clinic who meet the criteria for familial alpha hypertryptasemia. Those patients are somewhat easier to care for. Their symptoms are objective, which sometimes can be very helpful because we already know we’re dealing with a mast cell disorder. We try to tease that out when we take that complete history and really look to see if these symptoms occur on an ongoing basis, particularly chronic urticaria, angioedema, and flushing. There’s that familial tendency, so if another family member has experienced it, the tryptase will be helpful to sort that out or other mast cell disorders. Folks with mast cell–activating disorders or mast cell activation syndrome frequently have a normal tryptase. That can be a good place to separate the line with, “How am I going to do my patient education and my work-up from here?” It’s tricky, but it does seem that with true mast cell disorders, you’re going to have physical symptomatology that’s very objective. It will clear to see if there’s a response, and that helps me a lot to put them into 1 bucket or the other concerning where I’m going to go next with their symptoms.

Thank you. Dr Wong and Dr Bose, are you guys checking for hereditary alpha-1 tryptasemia in your institution? We don’t have a test in our institution. For us, it’s a send-out, but this does incur a cost to the patient. I’m not sure what you guys are doing at your institution and whether it’s helpful.

 We’re not. Of course, 1 of the limitations we have as a pure cancer center The University of Texas MD Anderson Cancer Center is that we don’t have an allergy group. That’s a limitation. So far, we’ve tried to screen the referrals that we get and see if they seem to be SM [systemic mastocytosis]. We’ve haven’t been seeing the M [mastocytosis] cases and perhaps the HATS [hereditary alpha tryptasemia syndrome].

 I agree. We’re a cancer center. That’s 1 of our limitations.

We’re a cancer center too [Dana-Farber Cancer Center], but we’re embedded into a general hospital, so that’s probably where the referral patterns are different.

Before we move on to the cases, I want to summarize. As you’re hearing from the 4 of us, this isn’t an easy landscape to toil. These are complex patients and they’re rare, so you’re not going to see a lot of them. It’s important to note some take-home messages from the cutaneous presentations. In thinking about systemic disease—or as Dr Lugar said, patients with these recurrent anaphylactic reactions—I think about whether there’s a clonal or systemic disease. Dr. Bose and I are more cancer doctors. That’s where my interest lies. But the treatment of these patients can be difficult. As Dr Wang outlined, it’s all in the histopathology and trying to make a definitive diagnosis, both from a molecular perspective, as well as from a histopathologic perspective. These are not trivial cases. We’ve tried to outline mast cell involvement and non–bone marrow tissues. If you don’t think about it, the pathologist isn’t going to do their work for you. You’ve really got to help the pathologist out. That’s where the interaction is so important, to talk to the pathologist or your referring physicians.

Prithviraj Bose, MD, and Patricia Lugar, MD, MS, discuss the considerations and testing options for hereditary alpha tryptasemia in patients with systemic mastocytosis.

Considerations in SM: Hereditary Alpha Tryptasemia

It’s an important point. I’ve seen a lot of referrals, and I’d like to get your opinion, Dr Bose, in terms of where patients have had outside GI [gastrointestinal] biopsies or liver biopsies and the referral had no mast cell involvement. The special stains weren’t done, and these diagnoses can be missed. We looked at our database at Brigham and Women’s Hospital and Dana-Farber Cancer Center—the patients we had in NGS [next-generation sequencing] 

 mutation, D816V, went back and looked at the pathology, and we’re able to identify about a third more cases. Is this something people should be concerned about? Prithviraj?

You’re exactly right, especially if it’s a GI or some other nonheme presentation and SM [systemic mastocytosis] is not on the radar, then absolutely it could be missed. Also, what you just said reminded me of the limitations of the NGS panel, so we may miss KIT mutations. Three years ago, we started doing the digital droplet PCR [polymerase chain reaction] here to pick up the 

 D816V. Actually, I had a patient on PATHFINDER who had only GI involvement and no marrow involvement.

Interesting. To throw the baton to you, Dr Lugar, there are two questions that we’re always struggling with. I’ll ask you, when is the appropriate care for patients with mast cell activation syndrome? Some patients with mast cell activation syndrome clearly have systemic mastocytosis, but others don’t. How are you making the diagnosis of this disorder? What’s your approach in terms of treatment? I have 1 follow-up question after that.

Thanks, Dan. That’s often a difficult clinical scenario to work through. You want to make sure that you have the correct diagnosis, but the symptoms certainly mimic many other symptoms that are cardiovascular or have origins in other organ systems; pulmonary; POTTS, or postural orthostatic tachycardia syndrome; and multiple food sensitivities and food allergies. The most important thing is, No. 1, how much do I believe the person has a mast cell disorder? Many patients will come to us with the diagnosis because they have spoken to friends or colleagues at work who have had that diagnosis or have looked on the internet and gotten some information, and they feel like their symptoms might fit a mast cell disorder. It’s quite challenging because, by symptomatology alone, it’s a very confusing space to figure out what the patient is experiencing. And we don’t have a number of fantastic clinical markers or biomarkers to also guide us for mast cell activation, as opposed to a true clonal mast cell disorder.

That’s where I begin, trying to tease out the symptoms, what brings on the symptoms, and what has worked. Then, from a clinical laboratory evaluation, I will measure a serum tryptase at least to get a baseline. If they feel they’ve had anaphylaxis or symptoms that are characteristic, potentially of an allergic reaction, I’ll try to get them to get a tryptase at that time so we can prove that mast cells as a cell of origin are bringing about this complex set of symptoms. Even that can be tricky because we’ve had a number of people with monoclonal mast cell disorders, where the aggregates on biopsy might be quite small or very limited, or with a very small amount seen on pathology. Maybe they meet some criteria, but not others have a mutation at c-KIT that’s characteristic of a mast cell disorder. If the symptoms fit, we check a tryptase. Sometimes, if I don’t really feel like the patient has a diagnosable mast cell disorder, I will go ahead and get the genetic analysis anyway and just look for the mutation. I’m sure we’re going to talk about how best to do that, but I’ll see if that would back it up, fully knowing that may not still be within the limit of detection. But that’s how we really get started. Then, I’ll frequently do an experimental treatment plan and see what the patient is responding to and if that ameliorates some of the symptoms. Thus, it’s probably a long-term thing, where you start with your assessment and you continue to assess and use whatever tools are available to try to nail down and work toward a diagnosis.

I find these to be the most challenging patients, because the patients that I focus on are patients with systemic and mast cell activation syndrome. Of course, as you’re talking, some of these patients will just have mast cell activation syndrome, some with a clonal mast cell process, and some without. But they can be a huge challenge.

The panel of experts highlights the importance of assessing symptomology and clinical characteristics in mast cell disorders.

Considerations in Mast Cell Disorders

® discussion on systemic mastocytosis. My name is Dan DeAngelo from the Dana-Farber Cancer Center in Boston, Massachusetts. My clinical practice is focused on the treatment of patients with acute and chronic leukemias, as well as myeloproliferative disorders. Joining me in this discussion are my colleagues Dr Sa Wang, a hematopathologist from The University of Texas MD Anderson Cancer Center in Houston, Texas; Dr Prithviraj Bose, an expert in leukemia and myeloproliferative disorders, also from MD Anderson Cancer Center; and Dr Patricia Lugar, an expert in allergy and immunology from Duke Health in Durham, North Carolina. Today we’re going to discuss systemic mastocytosis. This is a challenging condition with multiple classifications and presentations. Also, as part of our discussion, our expert multidisciplinary panel will review 6 clinical cases to try to illustrate this important point, as well as aspects of optimal diagnosis and treatment for these patients. Let’s begin. First, I’d like to open it up, to try and tease out some of the epidemiology and some of the referring patterns that each of us has. This is a rare disease. Let me start with you, Dr Bose, in terms of how patients come to your clinical practice, who refers you, and what types of patients are these?

What I’ve seen mostly is that they come to me from another hematologist. Usually, they have been picked up by a dermatologist who has biopsied the rash and sent them to a community hematologist, who then refers the patient to us. That’s what I’ve seen more than other patterns of reference.

Dr Lugar, it’s supposed to be a different pattern for an allergist and immunologist. What about your practice?

We certainly see patients with recurrent anaphylaxis. As part of the work-up, if the story fits with potentially some other symptoms that have been ongoing, we will usually screen for mast cell disorders. We do that quite a bit. The most common symptom besides recurrent anaphylaxis would be reactions to venom stings, like flying insects. When we see individuals who’ve had either profound allergic symptoms during the sting—anaphylaxis or cardiovascular symptoms, syncope, hard to resuscitate, multiple doses of epinephrine—or who’ve had maybe an episode of anaphylaxis that they can identify, such as a sting, or a similar episode that they can’t put their fingers on, those individuals will be screened. We pick up a number of patients based on that.

, do you mean checking the tryptase? Also, when would you check a bone marrow exam or refer to a hematologist to do that?

Excellent question. The screening is the physical exam. We’re all trained to look for the telltale clinical symptoms, such as the urticaria pigmentosa or telangiectasia macularis eruptiva perstans, or TMEP. We do a skin exam, we take clinical history, and then we screen for serum tryptase. We don’t usually do urine histamine or prostaglandins at that point in time. We usually do screening tryptase. Even if the tryptase is not excessively over 12 or 11 or whatever the reference range—or over 20—if the patient has symptoms that have been persistent, such as flushing, or if we see signs of possible lesions consistent with cutaneous mastocytosis, then we might at that point do a c-KIT, looking for mutations D816V and c-KIT by peripheral blood. At that point, if we see signs and symptoms that the person has a mast cell disorder, based on the level of tryptase, we’d recommend a bone marrow biopsy. We do a lot of management locally before we refer. Certainly, that may change as we expand our therapeutics.

Thank you. I work in a general hospital, so my referral pattern is a little different. I get referrals from allergy and immunology. Patients with recurrent anaphylaxis—mostly flying insects—will get referred if they meet those criteria that you nicely outline. But I get referrals from dermatology patients, who are seen in the dermatology clinic, and dermatology will say, “This is a rash. This is urticaria pigmentosa or the telangiectasia macularis eruptiva perstans.” They would also make a biopsy and refer a patient to allergy immunology: patients with irritable bowel syndrome who finally come to an urgent evaluation with a gastroenterologist refer in that way. Then just like Dr. Bose, I’ll see patients who are a tertiary referral from an outside hematologist. I’m seeing patients in all ways. But turning the baton over to you, Dr Wang, as a hematopathologist, what is important to you in terms of really defining a diagnosis of systemic mastocytosis?

I do mostly systematic…everything…in a myeloproliferative neoplasm. Also, SM [system mastocytosis] is 1 of the…in the bone now. For us, it’s easy; you guys only screen. You already have suspicion of SM, system mastocytosis. We know what we do. When we get a specimen, we’re going to automatically run the immunoassay, like a c-KIT and the tryptase and on the bone marrow biopsy. We also have psychometry assays, which look at mast cell proliferation. That’s 1 thing. It’s like a referral… Automatically, we’re going to all these tests. Usually, there’s no suspicion. The patient comes with myeloneoplasms, and then we identify no SM, in association with underlying MPS [myeloproliferative syndrome]/CMML [chronic myelomonocytic leukemia]. That’s something we initiate in the work-up.

Thank you. One of the questions or pet peeves I’ve had is when patients get referred in, not with suspected systemic mastocytosis but a sample. For example, with liver dysfunction and a liver biopsy, where the pathologist may not be thinking about systemic mastocytosis or a colon or rectal or other GI [gastrointestinal] biopsy, maybe the referring physician, the gastroenterologist, in that circumstance did not specify to the pathologist. Also, under H&E [hematoxylin and eosin staining], sometimes these mast cells can be hard to elucidate. Is there something in these tissues, not bone marrow, that will help you try to move down the road to systemic mastocytosis to do this special stain you described?

You’re absolutely right. Mast cells can be very subtle, especially in the GI tract, where they can mimic a lot of things because the submucosa always has a lot of cells, such as stromal cells, like plasma cells. When plasma cells lose the cytoplasm, they can look like mast cells too. We just cannot afford to do mast cell work up for every GI biopsy. We have to have some suspicions. The GI pathologists have to know the typical presentation for mast cells. They have to consider the differential diagnosis to initiate the work-up. Another scenario is in the bone marrow; it’s the same thing. With bone marrow, sometimes you can have patchy fibrosis just not as sensitive. If you don’t do the markers, you may miss it.

Experts in the field of mast cell disorders discuss the epidemiology and diagnostic criteria of systemic mastocytosis.

Prithviraj Bose, MD, MD Anderson Cancer Center

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