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Advances in SM

CE / CME

Advances in Systemic Mastocytosis: Getting to the Root of Disease With New and Emerging Targeted Treatments

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurses: 1.00 Nursing contact hour

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

ABIM MOC: maximum of 1.00 Medical Knowledge MOC point

Released: December 16, 2024

Expiration: December 15, 2025

Matthew Giannetti
Matthew Giannetti, MD
CME/CE Information

Activity

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Following up With Leslie

Let’s return to our patient case.

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Which of the following is the most appropriate next step for Leslie? 

Approach to Mast Cell Mediator–Induced Symptoms in Mastocytosis and MCAS 

First, triggers should be identified. Common triggers include hymenoptera venom, nonsteroidal anti-inflammatory drugs, and vancomycin, among others.26

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Treatment Options and Long-term Management 

Long-term therapy decisions are guided by symptoms. Shown here are cardiovascular manifestations, which can be treated mostly with H1 and H2 antihistamines. Corticosteroids are useful for emergency, difficult-to-control situations, and epinephrine is useful for acute anaphylaxis. Pulmonary symptoms include mainly shortness of breath, wheezing, and anaphylaxis.26

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Off-label Treatments  

Midostaurin, a multikinase inhibitor, is currently approved to treat 2 conditions: aggressive/advanced SM and FLT3-positive acute myeloid leukemia with an FLT3 mutation. It is not approved by the FDA to treat nonadvanced SM.27

Imatinib is also a multikinase inhibitor used to treat patients with mastocytosis, particularly those without the KIT D816V mutation. The D816V mutation is resistant to imatinib, so it is important to ensure this mutation is not detected using a high-sensitivity assay with a bone marrow aspirate sample.28 

Omalizumab may be effective to reduce anaphylaxis and other mast cell activation symptoms. Although it is not FDA approved for this use, evidence suggests that omalizumab can be helpful for patients with clonal mast cell disorders.29

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Patient Perspective: Ongoing Disease Burden and Polypharmacy

Watch this brief video to hear from an actual patient about their treatment journey.

Targeted Therapy in SM

Shown in this slide is a mast cell with granules. KIT with the D816V mutation can also be seen. KIT with the D816V mutation can be inhibited with avapritinib or any of the other targeted TK inhibitors. Avapritinib does not inhibit TK at the cell surface; it works intracellularly. The goal with targeted therapy is to kill mast cells directly, which results in decreased mast cell burden and thus decreased production of leukotrienes, histamine, IL-6, prostaglandins, and so on. This approach is functionally different from other approaches, such as with antihistamines, acetylsalicylic acid, and omalizumab. Basically, with those agents, mast cell activation is blocked, or the mediators that mast cells release are blocked, whereas with avapritinib and other TK inhibitors, mast cells are killed. The hypothesis is that with fewer mast cells, there are fewer factors that would otherwise be blocked.30

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PIONEER: Effect on Avapritinib on Symptoms of ISM  

The placebo-controlled PIONEER trial led directly to the FDA approval of avapritinib for ISM. The primary outcome of this trial was the Indolent Systemic Mastocytosis Symptom Assessment Form score, a proprietary scoring system developed by Blueprint Medicines that measures symptoms across multiple domains.

Shown here are spider plots across the 11 domains. The blue line indicates the baseline scores. The circle contracts after avapritinib treatment, showing the degree of improvement in these symptoms. The goal is to see a small dotted circle and a large blue circle representing people who experienced improvements in symptoms following treatment.

Conversely, on the right-hand side, the circles are not directly superimposable, meaning that placebo did not significantly improve patient scores in most of symptom domains. In fact, some domains showed worsening of symptoms (eg, nausea, because of the direct effect of the drug on the GI tract).31

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PIONEER: Effect of Avapritinib on Objective Measures of ISM Disease Burden

Again, the primary outcome of the PIONEER trial was disease symptom scores, in which patients rated symptoms on a scale from 0 to 10 via a handheld electronic device daily.32 The investigators also looked at objective markers of improvement: serum tryptase level, the number of mast cells in the bone marrow, and KIT D816V allele fraction.

The first graph on the left shows a decrease in serum tryptase levels from baseline for all patients receiving the drug; for patients receiving placebo, the decreases are much less. The same was true for mast cell burden in the bone marrow.

Avapritinib is a targeted therapy: It targets D816V directly. One would expect the D816V allele fraction to decrease with drug therapy, as shown here, particularly compared with placebo use.31

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Long-term Data Demonstrate Sustained Improvements in Quality of Life and Symptoms With Avapritinib  

This slide shows longer-term data from the PIONEER trial. The primary outcome was assessed at 16 weeks. At 48 and 96 weeks (shown on the left), patients experienced deepening responses, with an almost 20% improvement in symptom scores. In individual domains (ie, GI, skin, and neurocognitive), there was a slight improvement at Weeks 48 and 96.33 According to anecdotal reports, people treated with avapritinib improve the most rapidly during the first 6 months, but for people who receive low-dose avapritinib or 25 mg, a deepening of response can be observed during the course of 1 year or even 2 years.34

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SUMMIT: Bezuclastinib Improved Mast Cell Burden for Patients With Nonadvanced SM   

Bezuclastinib is also a targeted TK inhibitor. Early clinical trial data show similar benefits as with avapritinib. The changes in serum tryptase level are dose dependent. Patients receiving 100 mg are shown in light blue, those receiving 200 mg are shown in turquoise blue, and 1 person receiving 400 mg is shown in dark blue. All 3 doses significantly reduced serum tryptase levels, the KIT D816V variant allele fraction, and mast cell burden as compared with placebo.35

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SUMMIT: Bezuclastinib Safety

Regarding safety, patients in the SUMMIT trial did well. Although many (nearly 40%) experienced changes in hair pigmentation,36 these effects are dose dependent and related to KIT inhibition. KIT is essential for melanocyte growth, giving pigmentation to a variety of cells, including those in the skin and hair.38 

In this study, there were a handful of grade 1/2 changes but nothing particularly severe.

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HARBOR Part 1a: Elenestinib Improved SM Biomarkers After 12 Weeks

Elenestinib, previously known as BLU-263, is another targeted TK inhibitor and was investigated in the HARBOR trial. It is a second-generation TK inhibitor that selectively inhibits KIT D816V. The goal was to design a drug that is potent against disease in patients with the D816V mutation but does not cross the blood–brain barrier. As with the other drugs described above, treatment resulted in reductions in tryptase levels (left), KIT D816V variant allele frequency (center), and the number of bone marrow mast cells (right).35

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HARBOR Part 1a: Elenestinib Safety   

Similar to bezuclastinib, elenestinib was well tolerated. Some leukopenias developed in a dose-dependent manner. As with all TK inhibitors, there were more adverse effects at higher doses.35

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Other Emerging Therapies  

Other emerging therapies include masitinib, which was assessed in a phase III clinical trial (NCT04333108), and TL-895. TL-895 is a Bruton TK inhibitor and is currently in a phase II/III clinical trial for ISM (NCT04655118).

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Special Considerations for Patients During Pregnancy

For many patients, a detailed review of all the medications they are currently receiving may be sufficient. A person cannot receive targeted TK inhibitors during pregnancy because of their teratogenic properties. This conversation should happen well before initiation, especially with women of childbearing potential.39 Omalizumab can sometimes be used in pregnancy.40 There are no data to suggest that mastocytosis changes outcomes during pregnancy.

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After this program, I am now familiar with key data for new and emerging targeted therapies for ISM and apply them to optimize care of patients. 

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