Systemic mastocytosis (SIM) is characterized by an abnormal accumulation of mast cells, a type of immune cell present throughout the body that contributes to allergic and inflammatory responses. This condition is often challenging for clinicians to accurately diagnose and treat. For most adults with SIM, the condition is driven by a specific mutation (D816V) in the KIT tyrosine kinase receptor which leaves it in a permanently active state. While targeted therapies are available that can blunt the action of this mutated version of KIT, the drugs also interfere with the activity of other closely related proteins and cause side effects, which limit their effectiveness. Dana-Farber Cancer Institute researchers presented promising results from two studies at the 66th American Society for Hematology (ASH) Annual Meeting: one showcasing the early efficacy of the novel drug, bezuclastinib, and another introducing a groundbreaking mathematical model that accurately distinguishes two key forms of the disease in over 90% of cases.
These advancements could revolutionize diagnosis and treatment for patients facing this challenging condition. A randomized phase 2, open-label, multicenter trial known as Apex, is evaluating the safety and early efficacy of bezuclastinib, a new inhibitor of KIT D816V, in patients with advanced SM. This oral drug is a potent and highly selective inhibitor that targets KIT D816V yet spares other closely related kinases. Dana-Farber researchers are reporting results from part one of the Apex trial focused on dose optimization that identified not only the optimal dose but also remarkable response rates. A total of 32 patients were enrolled and randomized to four different dosage groups. The median age was 68 years, and the median treatment duration was 60 weeks. In all patients across all dose levels, significant responses were observed. Over 90% of patients achieved at least 50% reduction in mast cell burden as measured by laboratory and bone marrow tests.
The part 2 portion of the trial is now underway, involving 55 patients with advanced SM who will undergo treatment with bezuclastinib at the optimized dose. In a second, related study, scientists set out to devise a straightforward, mathematical tool that can help distinguish which patients with SM have the advanced, life-threatening form and which have the less aggressive, so-called indolent form of SM. Currently, these subtypes of SM are distinguished based solely on clinical findings and because the condition is rare, providers often lack the experience and expertise to properly diagnose them. Researchers DeAngelo, Shimony and Volpe combed through data from three previous clinical trials of an earlier KIT D816V inhibitor, called avapritinib. These trials -; EXPLORER (NCT02561988), PATHFINDER (NCT03580655), and PIONEER (NCT03731260) -; helped support the FDA approval of avapritinib for both indolent and advanced SM.
Harnessing these data, the researchers developed and tested a mathematical model, based primarily on measurements from peripheral blood, that can accurately predict which patients have advanced SM and which have indolent SM. Then, using an independent set of SM patient data, gathered from the Dana-Farber’s Leukemia Database, the team further validated their new model. From a cohort of 125 patients, the new tool accurately distinguished advanced SM from indolent SM in 90% of cases. DeAngelo and his colleagues plan to continue refining their mathematical model and make it available online for clinicians to use.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Collins N, Willard N, Pan Z. J Hematop. 2024 Dec;17(4):281-287.
Heiblig M et al. Amer J Hematol. 2024 Nov; 99(11):2127-2139.
Del Rio Verduzco A et al. Leukemia Lymphoma. 2024 Oct 22:1-4.