Chronic Myeloid Leukemia (CML): historical perspective, pathophysiology, and treatment advances

Chronic myeloid leukemia (CML) was the first leukemia to be described in medical literature and remains one of the most well-studied hematologic malignancies. This review traces the historical evolution of CML research, from its first clinical recognition in the mid-19th century to modern molecular diagnostics and targeted therapy. Key milestones include the discovery of the Philadelphia chromosome in 1960, identification of the BCR::ABL1 fusion gene in the 1980s, and the subsequent development of tyrosine kinase inhibitors (TKIs). The introduction of imatinib in the early 2000s revolutionized CML treatment, transforming a fatal disease into a chronic condition with near-normal life expectancy for most patients. Second- and third-generation TKIs have since been introduced to overcome drug resistance and target specific BCR::ABL1 mutations, such as T315I. Recently, research has focused on mechanisms of TKI resistance, novel signaling pathways, and strategies to achieve treatment-free remission (TFR). Emerging therapies such as vamotinib, KF1601, and combination regimens are being explored. Furthermore, new insights into non-kinase functions of BCR::ABL1 and the role of microRNAs in resistance open additional therapeutic avenues. This review provides a concise overview of CML from a historical and molecular perspective, highlighting diagnostic advances, evolving response criteria, and future directions in treatment.