For patients with systemic mastocytosis (SM), living with the disease used to mean relying on antihistamines and careful trigger avoidance to manage symptoms. However, a new group of drugs targets the disease itself, rather than just the allergic-like reactions it causes.
SM is characterized by an excessive buildup of mast cells in the body, which release histamine and other chemicals, causing symptoms such as skin reactions, digestive problems, and potentially severe allergic-like reactions. Traditionally, most SM treatments have focused on easing symptoms after mast cells release these chemicals.
Symptom Management vs. Targeted Therapy for SM
According to Farnaz Tabatabaian, MD, a board-certified allergist-immunologist, symptom-directed therapies help manage the effects of mast cell activation, such as itching, flushing, abdominal pain, diarrhea, or anaphylaxis. These treatments include histamine-1 (H1) and histamine-2 (H2) antihistamines, leukotriene modifiers, cromolyn, and omalizumab, a biologic that targets the antibody immunoglobulin E (IgE).
Dr. Tabatabaian notes that these treatments do not target the root cause of mast cell overactivation. Targeted therapies, on the other hand, aim to inhibit the disease’s molecular driver, often a mutation called KIT D816V. This mutation keeps mast cells switched on, telling them to grow and survive, and targeted drugs block that faulty signal.
Targeted Therapies for Systemic Mastocytosis
Three targeted therapies are currently approved by the U.S. Food and Drug Administration (FDA) for systemic mastocytosis: Avapritinib (Ayvakit), Midostaurin (Rydapt), and Imatinib (Gleevec).
The FDA approved avapritinib for advanced SM in 2021 and for indolent SM in 2023, based on results from the PIONEER trial. Dr. Tabatabaian notes that avapritinib was the first treatment approved for indolent SM based on a randomized, placebo-controlled trial, and it has shown clinical benefits in reducing serum tryptase levels and the number of mast cells in the bone marrow.
Other targeted therapies, such as masitinib, dasatinib, and nilotinib, have been studied in SM but are not FDA-approved for it.
According to Dr. Tabatabaian, results from the phase 2 SUMMIT trial have been positive so far, suggesting that bezuclastinib could become another targeted treatment option for patients with SM. The development of new targeted therapies provides patients with more options to target their underlying disease.
Michael Hochman, MD, a board-certified hematologist, notes that targeted therapy is not right for everyone with SM.
Dr. Hochman considers certain symptoms, such as skin problems, digestive issues, bone pain, and brain fog, when deciding whether to recommend avapritinib. He also notes that avapritinib may benefit bone health by increasing bone mineral density, which could be a meaningful benefit for patients with thinning bones or at high risk of bone loss.
The decision to start targeted therapy requires a careful conversation with a care team, considering the potential benefits and drawbacks. If current treatment is not providing enough relief, it may be time to ask whether targeted therapy could help.
Avapritinib is a once-daily medication that is generally well-tolerated, but patients must remember to take it every day, even if SM causes brain fog or makes it hard to concentrate. Dr. Hochman reminds patients to continue avoiding triggers, as it is not clear that the drug decreases the risk of anaphylaxis.
While they may have serious side effects, such as memory problems, low blood counts, and bleeding in the brain, these risks are associated with higher doses used to treat advanced SM.
Precision medicine has changed the way doctors treat SM, and more targeted treatment options are emerging.
Dr. Tabatabaian’s patients with SM may soon have another treatment option, as bezuclastinib is under FDA review. The potential approval of this new therapy could provide patients with an additional choice to manage their disease.