CE
Pharmacists: 1.00 contact hour (0.1 CEUs)
Released: May 22, 2025
Expiration: May 21, 2026
Patient Introduction: Sandy
Ryan Haumschild, PharmD, MS, MBA, CPEL:
It is helpful for HCPs, including pharmacists, to recognize SM diagnostic criteria. Before discussing SM treatment and the newer therapies that are evolving in the SM landscape, let’s review a patient case.
Sandy is a 26-year-old patient who was prescribed an oral corticosteroid for a breakout with intense itching on her back. Her breakout lesions are characteristic of mastocytosis. She has also sought over-the-counter remedies for frequent diarrhea. Sandy was referred to an allergist, who suggested a workup for SM.
With this diagnostic workup, ISM was confirmed based on bone marrow biopsy and the findings of a KIT D116V mutation. The allergist’s consultation also identified triggers (temperature change, stress, alcohol use), as well as additional SM-related signs and symptoms that interfered with Sandy’s daily activities. Signs and symptoms included pruritus, urticaria, abdominal cramping, diarrhea, lightheadedness, insomnia, migraines, and nasal congestion.
Considerations for Nonadvanced and Aggressive/Advanced SM
Ryan Haumschild, PharmD, MS, MBA, CPEL:
When considering SM, HCPs should ensure that they are referring patients to specialized centers, which is strongly recommended. Although this diagnosis can be made via tryptase levels and bone marrow biopsy, it requires some expertise.
HCPs should complete a baseline DXA and counsel patients regarding signs and symptoms of this disease. It is very important to counsel patients to avoid known triggers of mast cell activation, such as extreme temperature fluctuations, stress, and insect stings or venom. In addition, it is critical for people with SM to carry injectable epinephrine with them; they should have 2 auto injectors to manage anaphylaxis since it is so highly associated with this disease.
Finally, HCPs must monitor patients’ symptom burden and quality of life. There are questionnaires that you can use to do this, as well as evaluate improvement over time once patients start pharmacotherapy.12
Treatment for Mast Cell Mediator–Related Symptoms
Ryan Haumschild, PharmD, MS, MBA, CPEL:
Organ involvement is a great place to start in terms of treating mast cell mediated symptoms. If there is pruritus, flushing, or urticaria in the skin, HCPs should follow a stepwise approach with H1 and H2 blockers, a leukotriene receptor antagonist, aspirin, ketotifen, or topical cromolyn sodium. For GI symptoms, you can use H2 blockers, cromolyn, sodium, proton pump inhibitors, leukotriene antagonists, or ketotifen to address diarrhea, abdominal cramping, nausea, or vomiting. Addressing these symptoms is important because they can be uncomfortable, affect patients’ quality of life and their ability to go to work and perform activities of daily living.
For neurologic symptoms like headache, poor concentration, and brain fog, you can use H1 and H2 blockers, cromolyn sodium, aspirin, or ketotifen. And cardiovascular symptoms (eg, presyncope, tachycardia) can present, and patients could also have underlying comorbidities that HCPs need to be aware of when analyzing these details. This is where treatment with H1 blockers, H2 blockers, corticosteroids, or omalizumab can be introduced.
Considering pulmonary symptoms, HCPs should ensure that patients have epinephrine available to treat anaphylaxis. For less severe symptoms, H1 blockers, H2 blockers, inhaled corticosteroids, and possibly bronchodilators can be used. For naso-ocular symptoms, such as stuffiness and pruritus, intranasal H1 blockers, intranasal corticosteroids, and cromolyn sodium are treatment options.12
What Would You Do for Sandy?
Ryan Haumschild, PharmD, MS, MBA, CPEL:
Now, let’s return to the patient case to discuss Sandy’s treatment plan. What are some treatment recommendations for this patient?
Jonathan A. Bernstein, MD:
It is good to think about the treatment options, making a concerted effort to consider the whole patient, including all the affected organs/systems. The biggest trick here is to really have a high level of suspicion when patients present with nonspecific symptoms. HCPs should not dismiss them as simply having anxiety or other psychological issues. I see this a lot, and it is what delays the diagnosis.
H1 and/or H2 blockers are certainly a mainstay treatment. I tend to use second-generation nonsedating antihistamines. Also, it is important to dose patients higher than the recommended dose. For example, I follow the guidelines on chronic urticaria if they have skin involvement, which is up to 4 times the recommended dose.14 That makes a difference; using cetirizine up to 20 mg or fexofenadine 360 mg twice daily.
I do caution patients about leukotriene-modifying agents because of the boxed warning. Sometimes these agents can increase anxiety, depression, or sleep disturbances like vivid dreams, so patients can have bad experiences.15 I might not necessarily jump on board with that treatment right away with Sandy.
Try to get diagnostic biomarkers like methylhistamine, prostaglandin F2-α, and leukotriene E4 from 24-hour urine as an adjunct diagnostic test. In this case, I might put patients on a low-dose aspirin or something to block prostanoids.
If possible, document mast cells in various organs/systems. Patients have often had previous biopsies for other reasons, so we can get these stained for mast cells and look at the numbers. For example, for patients with GI issues, increased mast cell numbers in a GI biopsy could help determine if cromolyn sodium would be helpful, which can be dosed orally up to 4 times daily before meals. I usually start with that and see how well it helps patients.
I avoid oral corticosteroids because patients with high mast cell burden are prone to osteoporosis. They produce a lot of mediators like heparin, which is osteoporotic; therefore, I suggest avoiding oral corticosteroids. And unfortunately, we do not have good topical treatments for skin lesions in SM. Topical cromolyn sodium does not work well for CM. However, there are some novel targeted therapies that could be useful in this context that will be discussed.
That is where I would start. I also would follow up with Sandy because a lot of times these patients have difficulty tolerating medications. HCPs should be cognizant of this and ensure that they are using shared decision-making principles, so patients understand why they are being prescribed certain treatments.
Ryan Haumschild, PharmD, MS, MBA, CPEL:
A couple of things stood out to me in this case. Getting her to see a specialist or someone who specializes in treating SM is important. HCPs should ensure that the patient is being worked up for an accurate differential diagnosis and being prescribed the right therapies since multiple organs/systems may be affected.
One main thing that I think about, as a pharmacist evaluating patients in conjunction with a specialist, is to ensure that these patients are on the right treatment. I appreciated the mention of second-generation antihistamines because I do not want the treatment to cause drowsiness or affect patients’ ability to function. Even with H1 blockers or cromolyn sodium, patients need to be aware of anaphylaxis and carry epinephrine on them in addition to receiving any supportive care therapies.
Jonathan A. Bernstein, MD:
I agree with you. It is important that patients have an epinephrine injector on hand. For patients with SM, we’re not just talking about treating typical or isolated hives. SM is a systemic condition where syncope and anaphylaxis are certainly something that can occur and require immediate attention.12
Patient Follow-up
Ryan Haumschild, PharmD, MS, MBA, CPEL:
Moving on to the patient follow-up with Sandy, she was prescribed several medications, such as an H1 blocker, H2 blocker, cromolyn sodium, and oral corticosteroid. Her symptoms include GI issues, itching, and lightheadedness, which continue to interfere with her activities of daily living. She has received these frontline therapies and is not really seeing adequate improvement.
Options Other Than Antimediator Therapies
Jonathan A. Bernstein, MD:
SM treatment advancements include selective therapies for this orphan disease. This is important because we have not had a lot to offer patients.
For patients who present with symptomatic indolent or smoldering SM, HCPs can either offer them a clinical trial, if there is one available, or avapritinib, a selective KIT inhibitor that has been approved by the FDA to treat both ISM and advanced SM, including aggressive SM, SM-AHN, and mast cell leukemia.16 Again, HCPs should monitor patients who are receiving this therapy to determine if they have a good response or do not tolerate it well.
Some therapies included in guidelines, such as cladribine, are not specific for SM, and other KIT inhibitors have been approved by the FDA for advanced or aggressive SM, but they are less selective than avapritinib. Let’s look more closely at KIT inhibitors as treatments for SM.12
Characteristics of KIT Inhibitors
Jonathan A. Bernstein, MD:
The table on this slide compares KIT inhibitors approved or under investigation for the treatment of SM. Midostaurin is a multikinase inhibitor with activity against both D816V and wild-type KIT protein. It is approved by the FDA to treat adults with advanced SM, including aggressive SM, SM-AHN, and MCL.17 Imatinib, which has been around for a while, is a KIT inhibitor approved by the FDA to treat adults with aggressive SM without the D816V mutation or with an unknown mutational status.18 And avapritinib has been mentioned already. It is a much more highly selective KIT inhibitor. There is negligible activity against the wild-type KIT, and it now has FDA approval to treat adults with ISM, as well as adults with advanced SM, including SM-AHN, and MCL.16 Avapritinib does cross the blood–brain barrier, and it has a higher potency vs midostaurin based on its inhibition of D816V.19
There are also investigational selective KIT inhibitors. Elenestinib has limited central nervous system penetration and is dosed daily; bezuclastinib has low central nervous system penetration, high selectivity, and favorable pharmacokinetics.19
Avapritinib vs Placebo in ISM: PIONEER Part 2
Jonathan A. Bernstein, MD:
The PIONEER Part 2 study compared avapritinib vs placebo in ISM. It enrolled 212 patients with moderate to severe disease who had a total symptom score of ≥28 and uncontrolled symptoms despite use of 2 or more antimediator therapies. They were divided via a 2:1 randomization to receive avapritinib 25 mg once daily or placebo (best supportive care). Following the 24-week treatment period, patients were eligible to receive avapritinib for up to 5 years in an open-label extension study.20
Avapritinib vs Placebo in ISM: PIONEER Part 2 Results
Jonathan A. Bernstein, MD:
This study found that avapritinib provided significantly greater improvement in symptoms and measures of mast cell burden compared with placebo. Significantly more participants receiving avapritinib experienced ≥50% improvement in total symptom score compared with people in the placebo group. In addition, indicators of mast cell burden, including serum tryptase levels, KIT D816V variant allele faction,(VAF), and bone marrow (BM) mast cell burden, were reduced by ≥50% for most patients.20 The bone marrow mast cell burden findings are quite remarkable because the mast cells, especially if there was skin involvement, would be significantly reduced on biopsy.
Long-term Improvements in QoL and Symptoms With Avapritinib in ISM: PIONEER
Jonathan A. Bernstein, MD:
The PIONEER study also evaluated the long-term improvements in quality of life and symptom burden with avapritinib. It found that at both Week 96 and Week 144, total symptom scores were significantly reduced. Individual domain symptom scores (GI, skin, neurocognitive) were further improved at Week 144 vs Week 96. Then the mastocytosis quality-of-life score, which is a validated tool, also showed continuous improvement from Week 96-144.21
Avapritinib vs Best Available Therapy in Advanced SM
Jonathan A. Bernstein, MD:
Pooled data from several studies of avapritinib vs best available therapy for advanced SM are also available. The avapritinib group data are taken from the phase I EXPLORER and phase II PATHFINDER studies, and the best available therapy data were pulled from a retrospective chart review from 6 study sites. This analysis found that patients had better survival with avapritinib vs best available therapy (HR: 0.48; P = .004). Patients also had a longer duration of treatment and greater reduction in serum tryptase levels with avapritinib compared with best available therapy.
These were all statistically significant findings. The graph shows that avapritinib was superior to best available therapy over time.22 In addition, responses with avapritinib were significant in patients who received prior systemic therapy for their mast cell disease.23
Avapritinib: Dosing and Administration
Jonathan A. Bernstein, MD:
For ISM, the recommended dosage for avapritinib is 25 mg daily. The recommended dosage is 200 mg daily for advanced SM. Avapritinib should be given on an empty stomach at least 1 hour before or 2 hours after a meal. It is not recommended to repeat treatment if vomiting occurs, and patients should not make up for a missed dose within 8 hours of their next dose. Patients should be counseled to review information provided in the prescribing information.[Avapritinib PI]
Avapritinib Safety: Warnings and Precautions, Common Adverse Reactions (No Contraindications)
Jonathan A. Bernstein, MD:
HCPs and patients certainly need to be aware of potential safety issues. For example, intracranial hemorrhage was reported in 2.9% of patients in clinical trials for GI stromal tumor and advanced SM. No events of intracranial hemorrhage were reported in the ISM study (PIONEER). Further, fatal events occurred in <1% of all patients in the avapritinib trials.
If a patient experiences cognitive effects, dose reduction, interruption, or discontinuation may be appropriate, depending on the indication and severity of the effect. Because avapritinib may cause photosensitivity reactions, HCPs should advise patients to avoid direct ultraviolet exposure. With respect to embryo-fetal toxicity, avapritinib can cause fetal harm. Therefore, it is critical to advise patients of reproductive potential of the potential risks to a fetus and to use effective contraception while receiving avapritinib and for 6 weeks after the final dose.
The most common adverse events reported in advanced SM were edema, diarrhea, nausea, fatigue, and asthenia; and eye edema, dizziness, peripheral edema, and flushing were the most commonly reported adverse events in ISM.16
Bezuclastinib and Elenestinib: Investigational Selective KIT Inhibitors
Jonathan A. Bernstein, MD:
Other selective KIT inhibitors under investigation for nonadvanced SM are summarized on this slide. Early data show that these agents improve symptoms; reduce tryptase, KIT mutations, and mast cell burden; and have favorable safety profiles.24,25 The ongoing phase II Apex trial for advanced SM found that bezuclastinib reduced SM burden and was associated with a progression-free survival rate of 82% at 24 months.26
Other Emerging Therapies
Jonathan A. Bernstein, MD:
Other emerging therapies include masitinib in phase III study for severe ISM or smoldering SM, and TL-895, a Bruton tyrosine kinase inhibitor in phase II study for ISM and myelofibrosis (NCT04333108, NCT04655118). These data are forthcoming.
KIT Inhibitor Therapy for Sandy
Ryan Haumschild, PharmD, MS, MBA, CPEL:
It’s noteworthy that data on the selective KIT inhibitors show improvement in total symptom scores and mast cell burden.
In thinking about an innovative therapy like this that is more targeted, what are your thoughts when you are looking to prescribe a KIT inhibitor for a patient who continues to have symptoms beyond just using an H1 blocker?
Jonathan A. Bernstein, MD:
There certainly are major advancements in terms of how we can manage patients today. I discuss the selective KIT inhibitors with patients. Although the results of these studies have been very encouraging, I think patients get worried about adverse effects and other things when reading the package inserts. So HCPs have to frame this treatment within the proper context. In general, most patients are receptive to starting this treatment if they are not in a clinical trial. I am encouraged by what I am seeing in terms of clinical effectiveness. With that experience, HCPs also can reassure their patients about safety and tolerability.
Ryan Haumschild, PharmD, MS, MBA, CPEL:
KIT inhibitors seem to provide the opportunity to keep improving patients’ lives and providing hope, and I am excited to see how this treatment landscape continues to evolve.
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