A precision medicine, adaptive trial scheme for diverse SM-AHN variants. Baseline morphologic evaluation, serum tryptase level, KIT D816V VAF, and NGS are used to characterize the burden of SM as well as the type and stage of AHN (if present). This information is also used to stratify patients into potential treatment arms with therapies based on the identification of druggable targets. CML, chronic myeloid leukemia; CNL, chronic neutrophilic leukemia; ESA, erythropoiesis-stimulating agent; ET, essential thrombocythemia; HMA, hypomethylating agent; LDAC, low-dose cytarabine; MDS EB-1 or EB-2, MDS with excess blasts-1 or excess blasts-2; MDS-RS, MDS with ring sideroblasts; MF, myelofibrosis; MPN-U, MPN unclassifiable; PEG-IFN, pegylated interferon; PV, polycythemia vera; TKI, tyrosine kinase inhibitor.