Chapter 14: Chronic Myeloid Leukaemia

Central to the pathogenesis of this condition is the Philadelphia chromosome, a unique genetic anomaly resulting from a reciprocal translocation between chromosomes nine and twenty-two. This event fuses the ABL1 oncogene with the BCR gene, creating a chimeric BCR-ABL1 gene that encodes a fusion protein that maintains constant tyrosine kinase signaling. This molecular driver forces the uncontrolled expansion of myeloid cells, leading to the clinical hallmarks of the disease, such as massive splenomegaly, hypermetabolic symptoms like weight loss and night sweats, and a markedly elevated white blood cell count characterized by a full spectrum of granulocytic precursors and increased basophils. Diagnostic protocols have been refined through the use of sensitive molecular assays, including fluorescence in situ hybridization (FISH) and quantitative reverse transcriptase PCR, which are essential for identifying the BCR-ABL1 transcript and monitoring the depth of therapeutic response. The management of CML has been fundamentally transformed by the development of targeted tyrosine kinase inhibitors (TKIs). The chapter outlines the mechanisms and clinical application of first-generation agents like imatinib and subsequent generations such as nilotinib, dasatinib, and bosutinib, which effectively block the ATP-binding site of the abnormal protein. It further discusses the management of treatment resistance, particularly mutations like T315I that require specialized inhibitors like ponatinib. While the chronic phase of the disease is highly manageable with a survival rate exceeding ninety percent, the text also details the risks of progression into an accelerated phase or a terminal blast crisis. In these advanced stages, where the disease may transform into an acute myeloid or lymphoid leukaemia, allogeneic stem cell transplantation remains the primary curative strategy for patients who do not achieve optimal milestones with pharmacological intervention.