Bezuclastinib May Reduce Symptoms in Patients With Nonadvanced Systemic Mastocytosis

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The targeted therapy bezuclastinib may be safe and effective at reducing markers of disease burden and improving symptoms in patients with nonadvanced systemic mastocytosis, according to recent findings published by Bose et al at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 77).


Systemic mastocytosis—which can range from nonadvanced to advanced—is a rare disease characterized by the buildup of malignant mast cells in the bone marrow and other tissues. The high levels of mast cells can lead to the release of mediators and can cause a multitude of symptoms such as brain fog, skin rashes, gastrointestinal issues, and life-threatening anaphylaxis.

In up to 95% of patients, systemic mastocytosis is driven by KIT D816V gene mutation. Although therapies targeting this mutated kinase have been used for advanced disease variants, they have been known to cause toxicities that restrict dosing and, consequently, limit efficacy.

There are two variants within nonadvanced systemic mastocytosis—indolent systemic mastocytosis, which affects the majority of patients and is characterized by symptoms related to mast cell degranulation and mediator release; and smoldering systemic mastocytosis, identified by a higher mast cell burden and marked by high levels of blood enzymes such as serum tryptase, but without resulting organ damage.

Bezuclastinib is a type-1 tyrosine kinase inhibitor that works by blocking KIT D816V mutation activity while sparing other kinases, therefore minimizing the potential for off-target side effects. Previous research has shown that the agent may be capable of minimal brain penetration in lab models, with no central nervous system toxicities in patients with advanced systemic mastocytosis.

“The era of targeted therapy offers hope, not just for alleviating symptoms but for getting to the root of the condition,” explained lead study author Prithviraj Bose, MD, Professor of Leukemia at The University of Texas MD Anderson Cancer Center. “Bezuclastinib provides precision targeting without the typical central nervous system or bleeding side effects often associated with similar drugs,” he added.

Study Methods and Results

In the phase II SUMMIT trial, researchers assigned 20 patients—75% of whom had KIT D816V mutations—with nonadvanced systemic mastocytosis and moderate-to-severe symptoms to receive either 100 mg or 200 mg of bezuclastinib or placebo. All of the patients continued receiving their baseline antimediator therapy during the trial period.

The researchers evaluated the efficacy of bezuclastinib through multiple patient-reported outcome measures and changes in markers of disease burden, including serum tryptase, bone marrow mast cell percentage, and KIT D816V mutation allele burden.

The researchers discovered that the patients who received bezuclastinib achieved at least a 50% reduction in the markers of disease. After 12 weeks of treatment, 63% of the patients experienced decreased symptoms, and those who received 100 mg of bezuclastinib experienced a median reduction in symptoms of 48.5%. During the same period, 0% of the patients in the placebo group reported significant improvement in their overall symptoms. However, after transitioning the patients from placebo to bezuclastinib, 67% of them reported an improvement in symptoms after 4 weeks. After 20 weeks, 78%, 33%, and 33% of them experienced decreased dermatologic, gastrointestinal, and cognitive symptoms, respectively.

The researchers noted that the adverse events were generally mild and reversible, including a change in hair color, nausea, and peripheral edema. No severe adverse events related to bezuclastinib were reported in the 100-mg or 200-mg groups.


"[Bezuclastinib] may offer great promise in the treatment of nonadvanced systemic mastocytosis. As we move forward, our aspiration is to optimize the dosage while maintaining a robust safety profile,” Dr. Bose underscored.

The researchers plan to further assess the agent’s efficacy in patients with nonadvanced systemic mastocytosis by comparing bezuclastinib with placebo once the optimal dose is established. The researchers expect to report the results of part Ib of the trial—which will investigate 100-mg and 150-mg doses daily and will use a different formulation of the agent—in 2024.

Disclosure: The research in this study was supported by Cogent Biosciences. For full disclosures of the study authors, visit

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