Diagnosis and management of mastocytosis: an emerging challenge in applied hematology

Mastocytosis is a unique and rare neoplasm defined by abnormal expansion and accumulation of clonal mast cells (MCs) in one or multiple organ systems. Most adult patients are diagnosed to have systemic mastocytosis (SM). Based on histological findings and disease-related organ damage, SM is classified into indolent SM (ISM), smoldering SM (SSM), SM with an associated hematologic non-MC-lineage disease (SM-AHNMD), aggressive SM (ASM), and MC leukemia (MCL). The clinical picture, course, and prognosis vary profoundly among these patients. Nonetheless, independent of the category of SM, neoplastic cells usually exhibit the KIT point-mutation D816V. However, in advanced SM, additional molecular defects are often detected and are considered to contribute to disease progression and drug resistance. These lesions include, among others, somatic mutations in TET2, SRSF2, ASXL1, CBL, RUNX1, and RAS. In SM-AHNMD, such mutations are often found in the "AHNMD component" of the disease. Clinical symptoms in mastocytosis result from (1) the release of proinflammatory and vasoactive mediators from MCs, and (2) SM-induced organ damage. Therapy of SM has to be adjusted to the individual patient and the SM category: in those with ISM and SSM, the goal is to control mediator secretion and/or mediator effects, to keep concomitant allergies under control, and to counteract osteoporosis, whereas in advanced SM (ASM, MCL, and SM-AHNMD) anti-neoplastic drugs are prescribed to suppress MC expansion and/or to keep AHNMD cells under control. Novel drugs directed against mutated KIT and/or other oncogenic kinase targets are tested currently in these patients. In rapidly progressing and drug-resistant cases, high-dose polychemotherapy and stem cell transplantation have to be considered.