Systemic Mastocytosis, KIT and the Effects of KIT Tyrosine Kinase Inhibitors on Mast Cell and Basophil Activation

Systemic mastocytosis (SM) is a protean hematologic disorder characterized by uncontrolled expansion and accumulation of tissue mast cells (MC) in various organs, including skin, bone marrow, spleen, and gastrointestinal tract. In most cases, neoplastic cells exhibit the transforming KIT mutation D816V. Clinical symptoms arise from organ infiltration by neoplastic MC and/or pro-inflammatory mediators and cytokines released by these cells. Indeed, in a majority of the patients, acute or chronic mediator-induced symptoms are recorded, and in some instances, symptoms are severe and drug-resistant or even manifest as life-threatening anaphylaxis. In this article, we review the role of MC and basophils in anaphylactic reactions in patients with SM and the impact of genetic variables, co-morbidities, specific IgE, and factors counteracting MC activation. Whereas avoidance of all known and potential triggers of MC activation is crucial in the management of anaphylaxis in SM patients, specific therapy is also standard, including histamine receptor blockers, other anti-mediator-type drugs and drugs suppressing MC activation and/or expansion. Novel KIT D816V-targeting drugs can potentially decrease the anaphylaxis risk by reducing the MC burden and by targeting KIT-dependent and IgE-receptor-dependent signaling processes in neoplastic MC. Application of such drugs often leads to sustained responses and an increase in the quality of life in these patients.