In summary, digital PCR-based KIT D816V mutation burden measurement in the tissue represents a novel biomarker with independent prognostic significance that can also be employed for monitoring disease progression and treatment response in systemic mastocytosis.
This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3-positive AML and for KIT D816V-positive SM.
DCC-2618 is a spectrum-selective pan KIT and PDGFRA inhibitor which blocks KIT D816V and multiple other kinase targets relevant to systemic mastocytosis.
The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis.
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.
Recent studies show that most systemic mastocytosis (SM) patients, including indolent SM (ISM) with (ISMs+) and without skin lesions (ISMs-), carry the KIT D816V mutation in PB leukocytes.
ASqPCR for the KIT D816V mutation was a useful adjunct in helping identify those with systemic mastocytosis but not monoclonal mast cell activation syndrome.
The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, for example, in SRSF2, ASXL1, or RUNX1.
This medication inhibits the notoriously resistant Kit D816V mutant and is approved for the treatment of systemic mastocytosis and is effective against tumors bearing the D816V activation/resistance mutation.
These effects were reduced by KIT inhibition or neutralization and recapitulated by enforced expression of KIT or constitutively active D816V-KIT, a gain-of-function variant associated with 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 KIT D816V-specific inhibitor avapritinib.
This prospective study demonstrates that a D816V-positive result in a screening blood sample identifies SM among patients with hymenoptera venom-induced anaphylaxis in whom the diagnosis would most probably have been missed, with potential severe implications.
Patients with systemic mastocytosis (SM), whose MCs frequently arbor the activating D816V <i>KIT</i> mutation, may have indolent to aggressive diseases, and they may experience MC mediator related symptoms.
In conclusion, KIT D816V mutation sensitized MC to HDACi mediated killing, and SAHA may be of value as specific treatment for SM, although the specific mechanism of action requires further investigation.
Although hymenoptera-induced anaphylaxis is not primarily a mast cell-driven hematological disorder, the latter is present in a significant proportion of patients and has to be excluded by basal serum tryptase determination, skin inspection as well as exclusion of systemic mastocytosis by D816V mutation analysis in peripheral blood and/or bone marrow examination in selected patients.
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 KIT D816V mutation.
Bone marrow (BM) histology/immunohistochemistry, KIT D816V mutation analysis and serum tryptase measurements are mandatory tools for diagnosis of systemic mastocytosis (SM).
These results suggest that both methods provide clinically useful and complementary information through the identification and/or quantification of the KIT D816V mutation in peripheral blood of patients suspected of systemic mastocytosis.