NonBCR: ABL MPN: Diagnosis, Risk Stratification, and Management

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic disorders characterized by excessive myeloid proliferation. The classical BCR::ABL1-negative MPN subtypes include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The others are chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), and juvenile myelomonocytic leukemia (JMML). Recent advancements in molecular genetics and diagnostic techniques have refined the classification, risk stratification, and management of these disorders. The 2022 World Health Organization (WHO) and International Consensus Classification (ICC) updates emphasize the integration of clinical, morphological, and molecular criteria in MPN diagnosis. Molecular testing plays a pivotal role with JAK2, CALR, and MPL mutations serving as key diagnostic markers on one hand, while emerging non-driver mutations (e.g., ASXL1, SRSF2, U2AF1Q157) influencing prognosis on the other. Risk stratification has evolved with the development of novel prognostic models, such as the Mutation-Enhanced International Prognostic Scoring System (MIPSS70+ v2.0) and the Genetically Inspired Prognostic Scoring System (GIPSS) for PMF, which integrate genetic and clinical factors to refine outcome predictions. For ET and PV, thrombotic risk assessment remains crucial for therapeutic decision-making, with treatment strategies planned based on molecular and clinical risk factors. The primary goal of treatment in MPN is to prevent the thrombotic complications and symptom control and not to modify the outcome of the disease, except in some cases where allogenic BMT is resorted to cure the disease and prevent leukemic transformation. This chapter presents a case-based discussion of recent updates in diagnostic criteria, molecular profiling, risk stratification models, and treatment algorithms for BCR::ABL1-negative MPNs, highlighting their clinical implications and future directions. The integration of next-generation sequencing, emerging biomarkers, and targeted therapies holds promise for improved disease classification, prognostication, and personalized treatment approaches.