A high allele burden of the KITD816V mutation in peripheral blood or bone marrow aspirates indicates multi-lineage hematopoietic involvement and has been associated with an aggressive clinical course of systemic mastocytosis.
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.
A screen of two independent AML databases (AML<sup>databases</sup>) revealed remarkable similarities between KIT D816<sup>mut</sup>/CBF<sup>neg</sup> SM-AML and KIT D816<sup>mut</sup>/CBF<sup>neg</sup> AML<sup>databases</sup> (n = 69) with regard to KIT D816<sup>mut</sup> variant allele frequency, mutation profile, aberrant karyotype, and OS suggesting underlying SM in a significant proportion of AML<sup>databases</sup> patients.
Although the pathogenesis of SM is multi-factorial, the acquisition of KIT D816 V is a relatively frequent mutational event and serves as the target of novel agents.
This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3-positive AML and for KITD816V-positive SM.
Skin KIT mutation (OR: 51.9, 95% CI: 3.9-678, P = 0.001) and high bone marrow tryptase (OR: 97.4, 95% CI: 10.3-915, P = 0.001) were strong predictors of SM.
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.
ASqPCR for the KITD816V mutation was a useful adjunct in helping identify those with systemic mastocytosis but not monoclonal mast cell activation syndrome.
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.
We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n = 102, 94%) with indolent (ISM, n = 26) and advanced SM (n = 83) with (n = 73, 88%) or without AHN.
DCC-2618 is a spectrum-selective pan KIT and PDGFRA inhibitor which blocks KITD816V and multiple other kinase targets relevant to systemic mastocytosis.
The identification of KITD816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis.
Furthermore, HSCs in liver from mice injected with SM-EVs had increased expression of α-SMA and human KIT, particularly around portal areas, compared with mice injected with EVs from normal individuals, suggesting that SM-EVs can also initiate HSC activation in vivo.
In a phase I trial of avapritinib (formerly BLU-285), which targets D816V mutant KIT, for the treatment of advanced systemic mastocytosis, patients experienced rapid and durable disease control.
Several years later, midostaurin was discovered to be a potent inhibitor of the FLT3 tyrosine kinase and to have activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drive advanced systemic mastocytosis (SM).
Recent studies show that most systemic mastocytosis (SM) patients, including indolent SM (ISM) with (ISMs+) and without skin lesions (ISMs-), carry the KITD816V mutation in PB leukocytes.