Systemic Mastocytosis Mayhem: Clinical Data on New and Emerging Therapies

Dr Jonathan Bernstein (University of Cincinnati College of Medicine): Hopefully, we can discuss some of the nuances of diagnosis and management later. There is different perspectives on how these patients present and how they are managed and how they are screened.

[00:42:15]

Treatment for Mast Cell Mediator–Related Symptoms

Let us talk about the treatments that are currently available for mast cell mediator-related symptoms.

You look at this table, it basically breaks it down into organ involvement, whether it is the skin, the gastrointestinal tract, neurologic system, cardiovascular, pulmonary, or even nasal ocular. The types of current treatments that have been used, traditionally, H1, H2 antagonists, leukotriene receptor antagonists, in some cases, aspirin, especially when patients have markers like high prostaglandins, you can use ketotifen, which has to be compounded. There is various forms of chromolyn sodium. There is not really anything available for topical, but people, they can compound something for topical. But certainly for gastrointestinal, intranasal and inhalational.

Then we have used other therapies, especially omalizumab, which is a IgG1 monoclonal antibody that blocks IgE in the peripheral blood. But none of these treatments are specific or selective for the treatment of mast cell disorders. Certainly, we need to differentiate what was mentioned earlier mast cell activation syndrome from systemic mastocytosis. These are 2 different conditions entirely.

[00:43:56]

Insufficient Symptom Control Despite Supportive Care

This is a nice little study showing that there is insufficient symptom control despite supportive care. You can see that looking at treatment response in a managed care organization, this was a survey of patients with indolent systemic mastocytosis, and this is patients who ever used medications. This was a sampling of 25 patients. 56% said they were same or worsening and 72% somewhat or not at all controlled.

Again, there is a void and a need for treatment for these conditions. Patients often are on multiple medications. Of course, if they have mild symptoms it might help. But in patients with more moderate to severe symptoms, they are still having quite a bit of trouble.

[00:45:08]

          Options Other Than Antimediator Therapies

What are the options other than antimediator therapy? And here we see that there are some. Depending on the type of systemic mastocytosis, indolent systemic mastocytosis has again the preferred regimens vs aggressive systemic mastocytosis. Of course, if you have access to clinical trials, this is always an option. For rare diseases, this is something that should be considered because without patient involvement, we will never have advancements in novel therapies and advanced therapeutics.

Avapritinib is a treatment that had been originally approved for aggressive systemic mastocytosis. Again, it has again indicated for patients with platelet cancer elevated above 50 times 10 to the ninth. The other agent is midostaurin, tyrosine kinase inhibitors. They have used other drugs that are not really directed for aggressive systemic mastocytosis off-label. This is cladribine, which is for multiple sclerosis and interferon-alfa-2 have been used. There is some success with that.

In some circumstances, imatinib. But generally speaking, there have not been really very selective treatments until avapritinib, which has been shown to be very effective. In terms of symptomatic indolent systemic mastocytosis, avapritinib even more recently been approved for this form of systemic mastocytosis as long as patients have retained platelet counts.

But if there is no response or if they have side effects, then obviously there is not a lot of options and some of these off-label therapies or putting them into a clinical trial, which is always an option.

[00:47:23]

          Characteristics of KIT Inhibitors

This is where we are today. I think it is important to look at what these agents are. We are looking at imatinib, which is a c-KIT inhibitor. It was approved for aggressive systemic mastocytosis in adults without a KIT D816 mutation or unknown mutation status.

Midostaurin, which is a multi-kinase inhibitor and has activity against both the mutated c-KIT as well as a wild-type kit, and it was approved for both advanced systemic mastocytosis. All of the forms that were talked about, ,aggressive associated hematologic neoplasms and mast cell leukemia in adults.

Avapritinib, highly selective for just the mutated D816V c-KIT mutation, and negligible activity against the wild-type KIT. This was approved again for all of the more advanced forms of systemic mastocytosis as well as indolent systemic mastocytosis.

However, it does cross the blood brain barrier, so it still has some side effects but has higher potency vs midostaurin, which is based on the inhibition assays using D816V kit mutations.

Then there is some novel investigational therapies, such as elenestinib, which is BLU-263, and this is very selective KIT D816 inhibitor. Then the bezuclastinib, which is from Cogent. It is another selective D816V inhibitor. Both of these have low CNS penetration, so very good pharmacokinetics and presumably lower side effect profiles.

[00:49:41]

Imatinib: Efficacy in SM

What about imatinib? What is the efficacy in systemic mastocytosis? Again, the indication is patients with aggressive systemic mastocytosis without the D816 KIT or other KIT mutations. You can see here that looking at the Y-axis, the percent tryptase and then the sensitivity to imatinib by D816 status. In blue, it is the positives. You can see there is not significant reduction in the percent of tryptase, but in the negative mutations, there was a significant reduction.

Patients, as mentioned, with D816V KIT mutation are not sensitive and should therefore not receive this therapy. There are cases of response or remission in advanced systemic mastocytosis with the FIP1L1::DGFRA mutation.

[00:50:43]

Imatinib Safety and Dosing in SM

No real strong contraindications for this therapy. Again, you can see frequent adverse events and aggressive systemic mastocytosis. Gastrointestinal, muscle cramps, ascites, shortness of breath, fatigue, edema, itching, rash, lower respiratory tract infections.

It is not recommended in children, that is not both meant to be ham, but fetal harm can occur, so we should counsel appropriately in these individuals. It is an oral therapy. Again, it is dosed 400 mg a day. If there is associated eosinophilia, you can start at a lower dose with aggressive systemic mastocytosis and build up to 400 and should be continued if no progressive disease or if there is unacceptable toxicity, then obviously you would stop it. But if it is tolerated, then it seems like it is something that you could use long term.

[00:51:47]

          Midostaurin: Efficacy in Advanced SM

In terms of midostaurin, its efficacy in advanced systemic mastocytosis. Again, international phase II, open-label trials, 89 participants, again, 18% were aggressive. 64% have associated hematologic neoplasm and 18% leukemia. 100 mg twice a day in 4 week cycles. The median treatment duration was about 11.4 months with a median follow-up of 24 months.

There are additional outcomes looking at reversible organ damage across all C findings, reduced mast cell infiltration and serum tryptase improvement in symptoms and quality of life. Here you can see the results in the different subsets of systemic mastocytosis that for aggressive the median outcome survival is not reached. But in systemic mastocytosis with the associated hematologic malignancy, it was 20.7 months and for mast cell leukemia 9.4 months.

Overall, there was a response in these cases and more severe cases. Fortunately, these latter 2 were extremely rare and even aggressive as rare as 85 or 85% of these patients have indolent systemic mastocytosis. But these are very sick patients and certainly need treatment.

[00:53:16]

          Midostaurin: Efficacy in Nonadvanced SM

This is looking at efficacy in non-advanced systemic mastocytosis. Again, 20 subjects. These patients had indolent or smoldering systemic mastocytosis, severe symptoms, refractory to antihistamines. Again, 100 mg twice a day. Antimediator therapies were continued and they were given the antiemetics 2 hours before treatment.

There was a 35% reduction in symptoms, severity and symptom improvement for 75% of patients and significant improvement in quality of life and significant reductions in tryptase levels.

[00:53:52]

          Midostaurin: Safety in SM

What about safety indicated for advanced systemic mastocytosis, all of the different subtypes? Also there is some evidence of embryofetal toxicity, pulmonary toxicity, but the most common adverse reactions were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infections, constipation, pyrexia, headache and shortness of breath.

Gastrointestinal reactions were over 15% of patients. Again, high rates of gastrointestinal reaction limits the usefulness in indolent systemic mastocytosis. This is why we need newer therapies.

[00:54:53]

Targeted Therapy in Systemic Mastocytosis

This shows you targeted therapy in systemic mastocytosis, which led to the development of avapritinib, which targets the c-KIT mutation D816V. There is a number of receptors on mast cells and it is interesting that a lot of these have been targets for advanced therapeutics. Studies are ongoing with the MRGPRX2 receptors. There have been attempts to look at tryptase receptors, but right now for systemic mastocytosis, the most promising receptors seems to be c-KIT, although people are also looking at Bruton tyrosine kinase receptor inhibition as well. This is another area.

You can see that as a result of activation in mast cells, which from these, look at the cell, they are very promiscuous cells and can be activated in a number of different ways and they can cause symptoms based on the release of these bioactive mediators, which are illustrated here.

[0:55:58]

Avapritinib vs Placebo in ISM: PIONEER Part 2

Avapritinib has been studied in the PIONEER Part 2 studies. This was a large study, 212 patients with moderate to severe indolent systemic mastocytosis treatment. The severity scores were quite high, 28 or higher. Patients had uncontrolled symptoms despite 2 or more antimediator drugs and they were randomized 2:1 avapritinib 25 milligrams once a day in 141 patients and 71 patients received placebo best supportive care.

After 24 weeks with avapritinib where placebo patients were eligible to receive avapritinib up to 5 years. It was a nice 5-year extension study.

Avapritinib vs Placebo in ISM: PIONEER Part 2—Results

You can see looking at the different parameters measured, patients who had over 50% reduction as illustrated. Avapritinib patients improved in total symptom score serum tryptase, which significantly was reduced.

The KIT mutation, at least that marker was decreased significantly and bone marrow mast cell burden was significantly decreased. That essentially it is killing the mast cells and reducing mast cell burden.

[00:57:16]

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

In terms of quality of life, there was also improvement at 96 in 144 weeks in total symptom scores. There is significant changes, but individual domain symptom scores, gastrointestinal skin domain, neurocognitive domain also continued to improve out to 144 weeks.

In terms of quality of life, you can see on the far right, much significant improvement, significant change from baseline out to 144 weeks. It continues to improve.

[00:57:52]

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

Now when you look at pooled data, the avapritinib vs best available therapy in advanced systemic mastocytosis, this is looking at the phase I EXPLORER, phase II PATHFINDER study. Again, it was a retrospective chart review, 6 sites, and they compared the outcomes of avapritinib vs best available therapies.

You see that there was better survival hazard ratios were significantly improved for avapritinib vs best available therapy over the 16-month period and so forth. The survival was much better. There was a longer duration of treatment and 60% greater reduction in serum tryptase levels. These response rates were also high in patients who received prior systemic therapy. It seemed to be a consistent persistent response over time.

[00:59:03]

Avapritinib: Dosing and Administration

In terms of dosing for indolent systemic mastocytosis, 25 mg once a day. For advanced systemic mastocytosis, it is 200 mg once a day. It should be administered on an empty stomach at least 1 hour or before or 2 hours after a meal. It should not repeat the dose if vomiting occurs and should not be taken. It is not recommended to make up for missed dose within 8 hours of the next dose.

[00:59:31]

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

Again, this is safety warnings and precautions, common adverse reactions. Again, no contraindications, but the most common reactions in clinical trials for advanced systemic mastocytosis was swelling, diarrhea, nausea, fatigue, ischemia. Whereas in indolent systemic mastocytosis, it was eye edema, dizziness, peripheral edema and flushing. But other side effects can occur and one should always know what the side effect profile of drugs are before prescribing and to review it with patients.

[01:00:02]

Bezuclastinib and Elenestinib: Investigational Selective KIT Inhibitors

Now, the investigational therapies, these are currently in progress. The elenestinib is the HARBOR study. This is from Blueprint. Basically it showed improved symptoms, reduced tryptase, reduced KIT 816 mutation and mast cell burden and had a favorable safety profile, whereas the SUMMIT trial for bezuclastinib showed, again improved symptoms, reduced tryptase, c-KIT burden and mast cell burden, and a good favorable safety profile.

That is all very encouraging. There is some now ongoing phase II studies for advanced systemic mastocytosis with bevacizumab. This has also shown to reduce systemic mastocytosis burden and was associated with progression-free survival rates of 82% at 24 months and had a very favorable safety and tolerability.

[01:01:10]

Other Emerging Therapies

There are other emerging therapies. Mastinib, which is in phase III trials for severe indolent or smoldering systemic mastocytosis. Then the TL-895, which is Telios. This is a phase II/III study looking at a Bruton tyrosine kinase inhibitor for indolent systemic mastocytosis, but also looking at myelofibrosis.

[01:01:37]

Considering KIT Inhibitors for SM

I think this is my conclusion. This is the last slide, which considering KIT, you have inhibitors for systemic mastocytosis. Like anything else, you have to weigh benefits vs risks. Does it improve symptoms, quality of life, decreased skin lesions, decreased polypharmacy vs risks, the adverse events, long-term safety, reproductive risks, and the burden of monitoring these patients over time.

Speaker: Thank you for that. Actually,  Dr Bernstein, I want to go back and just for our audience, we go through clinical trials and we did do that in the HS session. But 1 of the things that I really would like to point out and have your take on is when you were presenting the clinical trials, I am not sure how many folks, and maybe everybody did, but a lot of these were open label trials. They were not double-blinded, placebo-controlled, randomized controlled trials. They were open-label trials, especially for all the advanced SM patients. Right?

Would you elaborate on the reason for that?

 Dr Bernstein: Well, these are very rare. I mean, if you see, first of all, you are dealing with systemic mastocytosis in general, it is a rare disease. When you start looking at these subtypes, it is exponentially rare. It is hard to find these patients. Plus they are very sick. They need treatment and there is not a lot of options. Either you enroll them compassionately to try to find something that is going to help improve their survival or not.

These are a part of the rules of investigation for very rare life-threatening conditions. Fortunately, we do not see a lot of mast cell leukemia because these patients would typically require bone marrow transplants and more aggressive therapies and even the associated malignancies version. But certainly we always are watching for those individuals. That is the rationale.

Of course, the indolent systemic mastocytosis, there are more patients with that. Of course, it takes a lot of centers because most of these centers are only recruiting 2 or 3 patients at a time for each study. You can imagine how many centers that takes, but they can be compared to current standard therapies.

Speaker: Yes, and I noticed in the indolent phase III trial for avapritinib, they did have a placebo arm. That is because the indolent course has a much more, or has a similar longevity profile or survival rate to population.

 Dr Bernstein: People with indolent systemic mastocytosis do not die from their systemic mastocytosis. It is a significant impact on their overall wellbeing. They do suffer, but they do not die.

[01:06:55]

Skill Building and Feedback II: Assessing Clinical Data

Let us assess that clinical feedback that we just heard.

[01:07:03]

Case II: Introduction to 28-Yr-Old Woman Referred by Gastroenterology

We have case 2. This is a 28-year-old woman referred by gastroenterology. She has a history of abdominal cramping, diarrhea over the past 2 years. Negative assessments for inflammatory bowel disease. She had some benefit with short-term systemic corticosteroids, but she had no benefit with biologic therapies like adalimumab or vedolizumab.

She was referred to dermatology for present of intermittently raised itchy rash that has been spreading over the last 6 months to a year. Her triggers for this have been temperature change, alcohol and friction. She is also reporting stuffiness and nasal allergies. She will use diphenhydramine occasionally, which also seems to help calm her itching.

[01:07:51]

          Case II: Work-up and Diagnosis of 28-Yr-Old Woman Referred by Gastroenterology

When we start to work her up, because she was referred to us, the skin biopsy was positive for dense mast cell aggregates. From there it was suggested we go ahead and send her for a follow-up bone marrow biopsy and an associated studies, which showed that she did have the KIT D816V mutation. She was positive for that.

She had aberrant CD2 and CD25 expression. She had a borderline high mast cell burden. Her serum tryptase was 22, and the SM was diagnosed based on the 1 major and multiple minor criteria.

I think before we even talk about the questions here, I mean you can see this as a case where we are trying lots of different things with her. GI started out because that was her predominant symptoms and then she started having cutaneous findings. It is somewhat of a team approach. If you are not looking for it, you cannot find it.

[01:08:57]

Case II: 2-Yr Follow-up

We definitely start those antimediator therapies. An H1 blocker was something like fexofenadine. H2 blocker like famotidine, cromolyn sodium and an oral corticosteroids. Symptoms were better for about 18 months, but they worsened in the last six months.

Additional findings we had in those patients was she had increased mast cell burden via the serum tryptase and serum bone marrow biopsy and hepatomegaly.

 Dr Bernstein, is this something that you would typically see, like these therapies started and then it works for a little bit and then progresses?

 Dr Bernstein: Yeah. Certainly, depending on how these people present, but they do help block the effects of histamine. Cromolyn sodium, it does work variably. In some people, it has benefit. They like to use it intranasally inhalation as well as through ingestion, but it does not work in everybody. It is very heterogeneous.

We try to avoid oral corticosteroids in these individuals because they are already prone to osteopenia and osteoporosis, due to their high mast cell burden and release of heparin, which is promotes osteoporosis in these patients.

One of the things we did not really talk about is that these patients that have baseline bone densities to make sure that see what the status of their bone is. It is in a compromised state. Yes, this is how we see it and there is not usually a dramatic effects. They feel a little better, but they are still quite impaired.

Speaker: Right. Just for the audience as well, when you are looking at these antimediator therapies, are they at standard doses or at they much higher doses than you would typically use?

Dr Bernstein: We tend to dose higher. The current guidelines for urticaria is up to 4 times the recommended dose of a second generation H1 antihistamine. We tend to go up to 4 times the dose. We try to stay away from the first generations because they have a lot of cognitive impairment and fatigue, and these patients already have that. They already have a lot of brain fog and fatigue and such. We try to stick with the non-sedating or low sedating antihistamines.

In terms of famotidine, pretty much stick to standard doses, 20 mg twice a day, although I have seen some patients who have responded to 40 mg twice a day. But most of the time standard doses. Again, leukotriene modifying agents may help as well in these circumstances. The problem there is there is a box warning and you have to really make sure patients do not get vivid nightmares or start hallucinating or having other side effects. A small percentage of patients, but again, marginal effects in these individuals.

Dr Bernstein: Yeah, I think the nice thing is that over time these treatments do continue to improve. The question is when do you stop them? We do not really have a good endpoint now. The mast cells, again, there is some data show that they can obviously come back and so forth. They will regenerate and so forth over time. It is not particularly a curative therapy.

It does help reduce antimediator therapies. But patients still get some inherent benefit from antihistamines because their skin is very itchy. They are itchy people. I do not know how much that is the end game, but certainly the first 3 are very appropriate. There might be an ability to step down on these other therapies as well over time. That is a clinical decision.

Speaker: Sure. Yeah, definitely that shared decision-making with the patient as well as the clinician for sure.

 Dr Bernstein: Yeah.

[01:17:04]

Special Considerations for Patients During Pregnancy

I am going to go through the special considerations for patients during pregnancy, but definitely I want to open this back up to our faculty because this is a special case in dealing with these patients who have indolent SM and what are they going to do because they still want to live a normal life and do all the things that patients without systemic mastocytosis do.

At this time, we really have insufficient data regarding SM diagnosis resulting in increased rates of adverse maternal or fetal outcomes compared to the general population. Data does not suggest that the SM diagnosis negatively affects fertility. But absolutely, I feel like this is something that should be done with everything just about, but definitely with SM.

The preconception pregnancy peripartum period should be managed by a multidisciplinary team, including high-risk OB, anesthesia, and allergy. Disease management should include symptom alleviation related to mast cell activation and titration of acceptable medications to minimize potential harm to the fetus. Avoiding triggers and using prophylactic antihistamines, as-needed corticosteroids and epinephrine on demand during pregnancy.

For patients with severe and treatment for refractory disease, cytoreductive therapy with peginterferon-alfa-2A is an option. Cladribine and tyrosine kinase inhibitors are absolutely not recommended at this time. There is not sufficient data to establish peginterferon-alfa-2A used in pregnancy, but if the benefits outweigh the risk to the fetus, then you can definitely consider this. What has been your experience with this?

 Dr Bernstein: My experience is that most of these patients are older, and so that just tends not to be as big of an issue. We do have younger adolescent, young adults that look like they have ISM, and so that would be a consideration. I would say that one should also consider the effects. We do not see any evidence on spermatozoa or anything of that nature in the map. It is a bit of a concern, but it is like anything else. These are never going to be studied in pregnant.

They are in fact no double-blind placebo controlled trials in pregnant or anything. We have to be cautious. There does need to be a lot of counseling, genetic counseling and discussion, shared decision, as you mentioned, with the patient. Fortunately, the patients I see, they tend, because of the diagnosis has been so delayed and there have not been available treatments until the last couple years, this has not been as big of an issue.

But some of them have been exposed to very toxic drugs, like some of the earlier therapies. It is not just for avapritinib. It is for all the therapies that were used. These amenities are indicated in pregnant women. We just have to be cautious and look at the risks, benefits, and have shared decision-making.

I would say for indolent, my inclination would be saying, we treat symptomatically until pregnancy is over, rather than starting drugs, stop the drug and then afterwards, because these patients are not at risk for dying. In fact the H1, H2 blockers, the leukotriene antagonist[?], they prevent the anaphylactic episodes. They are less susceptible to that, but they have the other clinical symptoms that are cumulative and those could be addressed after pregnancy.

Speaker: We already have pregnancy data. For a lot of these antihistamines, the H1s and the H2s have been around for enough years that we have some experience with that. The OBs can work very closely with the team to potentially use these safely.

 Dr Bernstein: Yeah, those treatments all have favorable ratings in pregnancy. We use them routinely in pregnant women and such.

Kristine Kucera: In dermatology, we do see several things that can happen during pregnancy that cause women to itch and, my goodness, they are miserable. We definitely want to keep the baby safe for sure, but give them their quality of life back if we can.

Speaker: Yeah, absolutely. Peginterferon-alfa has been around for quite a while as well, so we do have some data there, but Kristine, to your point, we have to a lot of times in derm.