Dana-Farber Cancer Institute researchers have presented promising results for bezuclastinib, a novel drug for advanced systemic mastocytosis (SM), along with a new mathematical model to distinguish between subtypes of the disease. The findings, presented at the 66th American Society for Hematology (ASH) Annual Meeting and Exposition, offer potential advancements in the diagnosis and treatment of this rare condition.
Bezuclastinib Efficacy in Advanced SM
Systemic mastocytosis is characterized by an abnormal accumulation of mast cells, leading to allergic and inflammatory responses. In most adults, SM is driven by a mutation in the KIT gene (D816V), a receptor tyrosine kinase. Bezuclastinib is a potent and highly selective inhibitor targeting KIT D816V while sparing other closely related kinases, potentially reducing side effects compared to existing therapies.
The Apex trial, a randomized phase 2, open-label, multicenter study, evaluated the safety and early efficacy of bezuclastinib in patients with advanced SM. The initial dose optimization phase enrolled 32 patients across four dosage groups, with a median age of 68 years and a median treatment duration of 60 weeks. Daniel J. DeAngelo, MD, PhD, Chief of the Division of Leukemia at Dana-Farber, reported that over 90% of patients achieved at least a 50% reduction in mast cell burden, as measured by laboratory and bone marrow tests.
"We observed extraordinarily high response rates in this small, early phase study, including complete remissions," said DeAngelo. "What’s also remarkable is that we didn’t observe the toxicity and poor tolerability that are often reported with other KIT inhibitors, and that’s really exciting."
The part 2 portion of the trial, involving 55 patients with advanced SM, is currently underway, utilizing the optimized dose of bezuclastinib.
Mathematical Model for SM Subtype Differentiation
In a separate study, researchers developed a mathematical tool to differentiate between advanced and indolent forms of SM. The current classification relies on clinical findings, which can be challenging due to the rarity of the condition. The goal was to create a straightforward method based on readily available measurements and laboratory values.
The model was developed using data from three previous clinical trials (EXPLORER, PATHFINDER, and PIONEER) of avapritinib, an earlier KIT D816V inhibitor. By analyzing data primarily from peripheral blood measurements, the researchers created a model that accurately predicts whether a patient has advanced or indolent SM. Validation using an independent dataset from Dana-Farber’s Leukemia Database, consisting of 125 patients, showed the tool accurately distinguished advanced SM from indolent SM in 90% of cases.
"This simple calculator that we have developed should assist clinicians in differentiating between these two distinct disease entities and therefore provide a more accurate diagnosis and treatment recommendations," said DeAngelo.
The researchers plan to refine the model and make it available online for clinical use. The Apex study is funded by Cogent, and the Math Modeling study is funded by Blueprint.
