Mast cell disorders are defined by an abnormal accumulation of tissue mast cells (MCs) in one or more organ systems. Symptoms in
mastocytosis result from MC-derived mediators and, less frequently, from destructive infiltration of MCs.
Cutaneous mastocytosis (CM) is a benign disease of the skin and may regress spontaneously.
Systemic mastocytosis (SM) is a persistent disease in which a somatic c-kit mutation at
codon 816 is usually detectable in MCs and their progenitors. The
clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. The WHO discriminates five categories of SM: indolent SM (ISM), aggressive SM (ASM), SM with associated clonal hematological non-MC-lineage disease (AHNMD), and
mast cell leukemia (MCL). The c-kit mutation D816V is quite common and may be found in all SM-categories. In SM-AHNMD, additional genetic abnormalities have been reported, whereas no additional defects are yet known for ASM or MCL. Patients with ISM and CM are treated with "mediator-targeting" drugs, whereas patients with ASM or MCL are candidates for cytoreductive
therapy. The use of "Kit-targeting"
tyrosine kinase inhibitors such as
STI571 (
Imatinib,
Gleevec), has also been suggested. However, the D816V mutation of c-kit is associated with relative resistance against
STI571. Therefore, these patients require alternative targeted drugs or new
drug-combinations. In patients with SM-AHNMD, separate treatment plans for the SM-component and the AHNMD should be established. Examples include the use of
STI571 in patients with SM plus
hypereosinophilic syndrome (SM-HES) and the FIPL1/PDGFRA fusion gene target, or
chemotherapy for eradication of AML in patients with SM-AML.