A new study detailed the effects of avapritinib therapy for systemic mastocytosis (SM) on mast cell organization, distribution and clonal architecture, according to the report recently published in Blood Cancer Journal.
As KIT gene mutations are the main driver behind the abnormal mast cell proliferation and tissue infiltration observed in patients with SM, the authors aimed to investigate how KIT inhibition through avapritinib affected the mast cell clonal architecture of four patients with advanced SM associated with a myeloid hematologic neoplasm (SM-AHN).
“ASM-AHN are complex myeloid neoplasms where malignant and normal myeloid cells co-exist with immune cells,” the researchers stated. “To understand the cellular composition of this ecosystem, we performed scRNAseq on the four ASM-AHN patients, using healthy donors and three untreated KITWT CMML patients for comparison.”
What is SM?
Systemic mastocytosis (SM) is a rare hematological disease characterized by mast cells that are overactive and accumulate in different parts of the body such as the bone marrow, liver, spleen, gastrointestinal tract and lymph nodes.
Researchers mapped the genetic landscape of each patient before treatment and detected several mutations, including KIT, TET2, TP53, SRSF2 and CUX1. The authors observed that monocytes in patients formed a very different cluster from healthy controls and that immature neutrophils were present only in patients. Mast cells in two patients expressed similar genes and markers as eosinophils, suggesting that both cells could have a common progenitor.
Read more about SM treatment and care
After avapritinib administration, there was a significant reduction in the proportion of mast cells in the bone marrow. Cells with the KIT mutation disappeared, but the other mutations remained. Furthermore, the proportion of mast cells with eosinophilic characteristics and immature neutrophils decreased.
Before treatment, only 1% of immune cells lacked somatic mutations, and treatment did not alter this proportion; this suggests that KIT is not the founder mutation behind SM-AHN. Larger studies with more patients are necessary to confirm this.
“Altogether, our data suggest clonal dynamics in AdvSM are influenced by multiple factors, including genotype, driver mutation position and tissue environment,” the researchers stated. “ASM-AHN should be seen as a complex myeloid neoplasm with a significant MC component.”
