The discovery of KIT mutations as central to the pathobiology of mastocytosis has prompted development of KIT-targeted agents, including imatinib and midostaurin (approved medications for patients with advanced systemic mastocytosis), and drugs in development, like KITD816V-specific inhibitor avapritinib.
We recently introduced the D816V+ allele fraction as a disease marker in SM using a sensitive and quantitative KITD816V mutation analysis that consistently allows mutation detection in peripheral blood (PB) and bone marrow (BM).
Well-differentiated systemic mastocytosis (WDSM) is a rare variant of systemic mastocytosis (SM) characterized by bone marrow (BM) infiltration by mature-appearing mast cells (MCs) often lacking exon 17 KIT mutations.
We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.
We examined expression of SIRPalpha, SIRPalpha ligand CD47, and Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), a tyrosine phosphatase-type, negative regulator of KIT-dependent signaling, in normal human lung mast cells (HLMC) and neoplastic MC obtained from nine patients with SM.
An acquired somatic mutation at codon 816 in the KIT receptor tyrosine kinase is associated with poor prognosis in patients with systemic mastocytosis and acute myeloid leukemia (AML).
Here we investigated IL1β, IL6, IL13, CCL23 and clusterin plasma levels in 75 SM patients--66 indolent SM (ISM) and 9 aggressive SM--and analyzed their prognostic impact among ISM cases grouped according to the extent of hematopoietic involvement of the bone marrow cells by the KITD816V mutation.
ASqPCR for the KITD816V mutation was a useful adjunct in helping identify those with systemic mastocytosis but not monoclonal mast cell activation syndrome.
Six other patients reported symptomatic improvement, including two with D816VKIT mutation-positive SM (one reported improvement in diarrhea and the other in fatigue).Other patients had no benefit.Imatinib was relatively well tolerated.
We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM.
Somatic activating mutations in the mast cell growth factor KIT gene cause cutaneous mastocytosis in young children and systemic mastocytosis with a more guarded prognosis in adults who may also harbor other gene mutations with oncogenic potential as they age.
In conclusion, we demonstrate that crenolanib is an inhibitor of mutant-KIT D816 isoforms at clinically achievable concentrations, and thus may be a potential treatment for SM and CBF AML as a monotherapy or in combination approaches.
MCP purity (CD117 and Lin2), maturity (CD34 and FcεRI), interaction receptors and ligands (CD154 and HLA-DR), and SM-specific (CD2 and CD25) markers were measured using flow cytometry.