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Simple Summary: The term mastocytosis denotes a heterogeneous group of rare disorders characterized by abnormal accumulation and activation of mast cells in various organs. Based on the WHO classification, mastocytosis can essentially be split into indolent and advanced systemic disease. Indolent mastocytosis is the most prevalent variant in adults. In our retrospective study, we aimed to analyze the clinical outcomes of patients with mastocytosis attending our center over the last 15 years. We found that most patients in our cohort suffered from the indolent variant of mastocytosis. Furthermore, we determined the overall prevalence of mastocytosis in our region to be one case per 10,000 adults. In addition, overall survival was significantly better in indolent mastocytosis patients compared to patients with advanced disease. Therefore, awareness of differences in the prognoses of patients with indolent and advanced mastocytosis is important. Systemic mastocytosis (SM) is a rare, clonal, clinically heterogeneous disorder of the mast cells (MCs), and mainly affects adults. The present study aims to describe the clinical and laboratory features as well as the outcomes of SM. A 15-year retrospective study was conducted on 195 consecutive SM patients (aged ≥ 18 years) diagnosed in 2006–2020 at the Multidisciplinary Mastocytosis Center at Karolinska University Hospital. Patients with indolent SM (ISM) represented the most common SM variant (88.2%). Furthermore, the frequencies of aggressive SM and SM with associated non-mast-cell hematological neoplasm were 4.1% and 7.7%, respectively. The prevalence of SM in the adult population of the Stockholm region was estimated to be 10.6/100,000 inhabitants, and the mean incidence of SM cases in the Stockholm region was 0.77/100,000 people per year. In this series, tryptase levels were below 20 ng/mL in 51 patients (26%). Osteoporosis was present in 21.9% of all cases. Interestingly, there was no progression from ISM to advanced SM variants in our study. Furthermore, overall survival was significantly better in ISM patients compared to advanced SM patients (p < 0.0001). Our data suggest that the early recognition and correct diagnosis of SM has prognostic significance. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced systemic mastocytosis (AdvSM) is a rare malignant disease with a poor prognosis due to the drug resistance of neoplastic mast cells. We found that drugs targeting the cell cycle regulators CDK4 and CDK6 profoundly suppress the growth and survival of neoplastic mast cells. Furthermore, these drugs can overcome resistance against KIT D816V-targeting drugs, including midostaurin, in neoplastic mast cells. Finally, the CDK4/CDK6 inhibitors applied induced apoptosis in CD34+/CD38− stem cells in AdvSM. Based on these results, we believe that CDK4/CDK6 inhibition may be a new and interesting therapeutic approach with curative potential for AdvSM. Whether combinations of KIT D816-targeting drugs and CDK4/CDK6 inhibitors can induce long-term remission in patients with AdvSM remains to be determined in clinical trials. In most patients with advanced systemic mastocytosis (AdvSM), neoplastic mast cells (MC) express KIT D816V. However, despite their disease-modifying potential, KIT D816V-targeting drugs, including midostaurin and avapritinib, may not produce long-term remissions in all patients. Cyclin-dependent kinase (CDK) 4 and CDK6 are promising targets in oncology. We found that shRNA-mediated knockdown of CDK4 and CDK6 results in growth arrest in the KIT D816V+ MC line HMC-1.2. The CDK4/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib suppressed the proliferation in primary neoplastic MC as well as in all HMC-1 and ROSA cell subclones that were examined. Abemaciclib was also found to block growth in the drug-resistant MC line MCPV-1, whereas no effects were seen with palbociclib and ribociclib. Anti-proliferative drug effects on MC were accompanied by cell cycle arrest. Furthermore, CDK4/CDK6 inhibitors were found to synergize with the KIT-targeting drugs midostaurin, avapritinib, and nintedanib in inducing growth inhibition and apoptosis in neoplastic MCs. Finally, we found that CDK4/CDK6 inhibitors induce apoptosis in CD34+/CD38− stem cells in AdvSM. Together, CDK4/CDK6 inhibition is a potent approach to suppress the growth of neoplastic cells in AdvSM. Whether CDK4/CDK6 inhibitors can improve clinical outcomes in patients with AdvSM remains to be determined in clinical trials. [ABSTRACT FROM AUTHOR]