A detailed snapshot of organ damage in patients with advanced systemic mastocytosis (SM) at the time of enrollment in clinical trials for avapritinib, a selective KIT D816V inhibitor, was recently published in Blood Neoplasia.
Advanced SMAdvanced SM In these subtypes of SM, mast cells begin to damage organs. Advanced SM includes the subtypes aggressive SM, mast cell leukemia and SM with an associated hematological neoplasm. includes three subtypes: aggressive SMAggressive SM A subtype of advanced SM marked by a high mast cell burden that leads to organ damage. Aggressive SM accounts for less than 10% of SM cases. (ASM), SM with associated hematologic neoplasm (SM-AHN) and mast cell leukemiaMast cell leukemia The most severe subtype of SM, caused by the rapid buildup of immature mast cells in the bone marrow and blood. Mast cell leukemia accounts for less than 5% of SM cases and has a poor prognosis. (MCL). Historically, advanced SM has carried a poor prognosis, but treatment with new KIT inhibitors like midostaurin and avapritinib has improved outcomes.
Organ damage, a hallmark of advanced SM, is central to diagnosis and treatment decisions, yet its presentation in clinical trial populations has been poorly characterized in the medical literature.
The authors aimed to address this gap through a retrospective analysis that pooled data from 174 patients enrolled in the phase 1 EXPLORER and phase 2 PATHFINDER trials. All patients had confirmed advanced SM and underwent comprehensive screening including genetic testing, imaging and laboratory analysis.
The researchers analyzed correlations between organ damage and factors such as disease subtype, prior therapy, bone marrow (BM) mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body. burden and mutational profile.
Patients with SM-AHN comprised the majority of the cohort (68%) and displayed the highest white blood cell, monocyte and eosinophil counts, along with the highest KIT D816V variant allele frequency (VAF). In contrast, patients with MCL had the highest serum tryptaseTryptase A protein enzyme that is primarily produced by mast cells and stored in small pockets within the cells, known as granules. High levels of tryptase are a key indicator of SM. levels, BM mast cell burden, and liver and spleen volumes. Treatment-naïve patients were more likely to meet criteria for hepatic organ damage, suggesting previous therapy may mitigate liver involvement.
Notably, molecular profiling revealed that 68% of patients had KIT D816V mutations plus at least one additional pathogenic mutation. The presence of SRSF2, ASXL1 or RUNX1 (S/A/R) mutations was linked to older age, shorter time from diagnosis to enrollment and fewer prior therapies. Importantly, the number of co-mutated genes beyond KIT D816V and BM mast cell burden were both independently associated with the extent of organ damage.
“We found that disease subtype, previous therapy, and molecular profile, in particular, were associated with the pattern and/or burden of organ damage,” the authors concluded.
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