Atypical chronic myeloid leukemia: From diagnosis to molecular features and therapeutic options

Atypical chronic myeloid leukemia (aCML) is a rare form of myelodysplastic (MDS)/myeloproliferative neoplasm (MPN) overlap disorder characterized by neutrophilic leukocytosis with circulating immature myeloid cells (IMC), frequent hepatosplenomegaly, and poor prognosis with high rates of leukemic transformation. In the 2022 World Health Organization (WHO) classification, aCML was therefore renamed to “MDS/MPN with neutrophilia.” Diagnostic criteria for aCML include leukocytosis ≥ 13 × 109/L, circulating IMC ≥ 10%, dysgranulopoiesis, and at least one cytopenia for MDS-thresholds (per International Consensus Classification [ICC]). Bone marrow is hypercellular due to granulocytic proliferation, associated with dysplasia in granulocytes ± other cell lines. Mutations can be used to support the diagnosis in both classifications, that is, SETBP1 and ASXL1 or SETBP1 and/or ETNK1. Absence of monocytosis, basophilia, or eosinophilia, <20% blasts, and exclusion of other MPN, MDS/MPN, and tyrosine kinase fusions are mandatory. Cytogenetic abnormalities are identified in roughly 20%–40% of aCML patients, along with a complex genomic context with high rates of recurrent somatic mutations in ASXL1, SETBP1, SRSF2, TET2, EZH2, and, less frequently, in NRAS/KRAS, CBL, CSF3R, JAK2, and ETNK1. Unfortunately, effective risk stratification systems for identifying prognostic subgroups of aCML patients are lacking, resulting in the absence of a standard of care for its management. The most used agents include hydroxyurea, interferon, hypomethylating agents, and JAK inhibitors, although none of them are disease-modifying. Allogeneic hematopoietic stem cell transplant remains the only potentially curative approach and should be considered in all eligible patients. Actionable mutations (CSF3R, NRAS/KRAS, and KIT) have also been identified, supporting the development of new agents targeting the involved pathways.