Initial treatment considerations for advSM variants. Therapeutic options for patients with newly diagnosed ASM, SM-AHN, and MCL are shown. We always encourage participation in clinical trials. Midostaurin is Food and Drug Administration and European Medicines Agency approved for all 3 advSM subtypes, irrespective of KIT mutation status. For patients with SM-AHN, a determination must first be made regarding whether treatment is needed and which component requires more immediate therapy (in the text). Cladribine and [pegylated]–interferon-α with or without prednisone have been used on an off-label basis for all 3 advSM variants; cladribine is preferred in patients requiring rapid debulking of disease, whereas interferons are preferred in slow progressors. Imatinib is approved for the rare ASM patients who are KIT D816V mutation negative or whose KIT mutation status is unknown. For patients with eosinophilia, rule out FIP1L1-PDGFRA positivity, because such neoplasms are very sensitive to imatinib. Allogeneic hematopoietic stem cell transplantation (HSCT) may be considered as initial therapy for ASM or SM-AHN. We do not recommend transplantation as frontline treatment of MCL, but it may be considered for individuals achieving substantial clinical benefit with midostaurin, cladribine, or a clinical trial drug. We also do not recommend multiagent chemotherapy as initial treatment of MCL given the activity of these other agents. Corticosteroids may be used on a short-term basis for rapidly progressive SM-related organ damage.