Dana-Farber Cancer Institute researchers are breaking new ground in the fight against systemic mastocytosis, a rare and heterogeneous condition that is often challenging for clinicians to accurately diagnose and treat. 

Researchers presented promising results from two studies at the 66th American Society for Hematology (ASH) Annual Meeting and Exposition: one showcasing the early efficacy of a novel drug, bezuclastinib, and another introducing a groundbreaking mathematical model based on recent clinical trial data, that accurately distinguishes two key forms of the disease in over 90% of cases. These advancements could revolutionise diagnosis and treatment for patients facing this challenging condition.

Systemic mastocytosis (SM) is characterised by an abnormal accumulation of mast cells, a type of immune cell present throughout the body that contributes to allergic and inflammatory responses. For most adults with SM, the condition is driven by a specific mutation in the KIT gene (called D816V), a receptor tyrosine kinase, 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 some side effects, which limit their effectiveness — particularly in advanced SM, a life-threatening form of the disease.

A randomised 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 optimisation that identified not only the optimal dose but also remarkable response rates. 

A total of 32 patients were enrolled and randomised 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.

“We observed extraordinarily high response rates in this small, early phase study, including complete remissions,” said Daniel J. DeAngelo, MD, PhD, Chief of the Division of Leukemia at Dana-Farber, who presented the results at ASH. “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 is now underway, involving 55 patients with advanced SM who will undergo treatment with bezuclastinib at the optimised dose. 

In a second, related SM study, Drs Virginia Volpe, Shai Shimony and DeAngelo and colleagues 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. 

“The diagnosis and classification of patients with systemic mastocytosis is rather complicated, and patients are often misdiagnosed as having either indolent SM when they actually have advanced SM, or vice versa, and that means they don’t receive the appropriate treatment,” said DeAngelo. “So, we wanted to create a simple, straightforward method based on readily available measurements and laboratory values that can accurately predict which form of SM a patient has.”

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. 

“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. 

He and his colleagues plan to continue refining their mathematical model and make it available online for clinicians to use. 

Source: Dana-Farber Cancer Institute