Aim. To provide case reports on the course and treatment of aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). Materials & Methods. This paper reports the histories of adult patients with ASM (n = 4) and MCL (n = 2) treated with cytoreduction predominantly at the City Clinical Hospital No. 31 (Saint Petersburg). The patients were 36–61 years of age (median 50 years); there were 4 women and 2 men. Results. All patients showed stable response to cladribine (n = 3), imatinib (n = 2), and combined lenalidomide, elotuzumab, and dexamethasone treatment with subsequent allogeneic hematopoietic stem cell transplantation (n = 1). With a median follow-up of 124 months (range 55–186 months), 1 out of 2 MCL patients died due to the concomitant hypereosinophilic syndrome progression and secondary infectious complication. Conclusion. Cladribine therapy in 2 ASM patients and imatinib therapy in 2 MCL patients yielded stable long-term response with good quality of life being maintained. More comparative studies are required for efficacy assessment and optimum sequencing of chemotherapeutic drugs.