Clonal Evolution and Cytogenetic Changes in Chronic Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder. The disease has a progressive natural course from an indolent chronic phase (CP) followed by an accelerated phase (AP) which usually ends into a very aggressive blast crisis (BC). It accounts for approximately 5-20% of all cases of leukemia and is more common in elder people with a median age of 65 years at the time of diagnosis. Approximately 85% of cases display a standard cytogenetically balanced translocation t(9;22)(q34;q11) known as Philadelphia chromosome (Ph). As a consequence of the reciprocal translocation, the BCR-ABL1 chimeric gene is generated which is critical for the pathogenesis of CML. The remaining 15% of patients either harbor variant translocations, involving other chromosomes, or cryptic fusions seemingly a normal karyotype. The t(9;22), the primary chromosomal abnormality, typically remains as the only abnormality along most of the CP. The progression of the disease is related with the clonal evolution and the acquisition of additional secondary cytogenetic abnormalities. The most common secondary changes during the clonal evolution, in nearly 90% of cases, are: +8, +Ph, i(17q), and +19, which have been referred as the “major route”. The “minor route” aberrations, includes other less frequent (<10%) observed changes: -Y, +21, -7, alterations of 3q, among others. In the last fifteen years, the management of CML has been revolutionized by the development of BCR-ABL tyrosine kinase inhibitors (TKIs). The imatinib mesylate (IM) was introduced as first line therapy in 2000 for most newly diagnosed CML patients. Afterwards, second generation TKIs (dasatinib and nilotinib) were approved for the treatment of imatinib-intolerant or resistant patients, and they were proposed as a first line treatment option in 2012. The great majority of patients receiving imatinib treatment remain in complete hematologic (98%) and cytogenetic response (87%) with a median follow-up time of >5 years. A small percentage (around 8%) develops additional cytogenetic changes in their Ph-positive cells during the course of treatment. These changes may be transient and disappear during the follow-up or when the treatment is modified including doseincrease or change to another TKIs, especially in those patients who initially achievied a complete cytogenetic response. The available data suggest that the cytogenetic evolution pattern in patients treated with TKI seems to follow the “major route” of evolution. In our experience, 5% of cases in follow up treatment develop clonal evolution. Due to the importance of cytogenetic studies to properly monitor CML patients, this chapter focuses on the cytogenetic profile of karyotypic evolution in the context of actual TKI treatment and its relationship with response, resistance and progression.