SOHO State of the Art Updates and Next Questions | Atypical Chronic Myeloid Leukemia: Pathogenesis, Diagnostic Challenges and Therapeutic Strategies

Atypical chronic myeloid leukemia (aCML) is a rare and challenging clonal hematopoietic disorder within the myelodysplastic/myeloproliferative neoplasm (MDS/MPN) spectrum. Over the past two decades, substantial progress has been made in understanding the genetic mechanisms driving aCML, revealing a complex and heterogeneous mutational landscape. Key ancestral mutations, such as ASXL1 and ETNK1, have been identified, providing a foundation for the pathogenesis and for the possible emergence of secondary abnormalities, particularly in epigenetic regulation (eg, SETBP1), and in splicing process (eg, SRSF2). These molecular insights have been integrated into current diagnostic classifications, refining disease characterization and offering potential targets for precision therapies. Despite these advances, significant clinical challenges persist due to the disease's rarity and the lack of randomized clinical trials. Therapeutic strategies remain inadequately defined, with allogeneic stem cell transplantation being the only curative option. This review provides an overview of the molecular, clinical, and therapeutic information that may pave the way for essential advancements in the proper management of this disease.