Chronic Myeloid Leukemia (CML)

  • Chronic Myeloid Leukemia (CML) represents a neoplastic proliferation of fairly mature, well-differentiated granulocytes. Virtually all CMLs are caused by a particular chromosomal translocation that generates a novel oncogene known as BCR-ABL. Initially, CML charts a fairly indolent course and can remain asymptomatic or present with mild, non-specific symptoms. However, over time proliferation of neoplastic cells accelerates and ultimately a neoplastic clone inevitably undergoes a "blast crisis" and transforms into an acute leukemia akin to AML.
  • Neoplastic cells in nearly 95% of patients with CML display the "Philadelphia Chromosome" which represents a translocation between Chromosome 9 and Chromosome 22, t(9;22), generating a fusion protein between the "Breakpoint Cluster Region" (BCR) gene and the Abel 1 Tyrosine Kinase (ABL1) gene. This fusion protein, known as BCR-ABL, displays unregulated tyrosine kinase activity that promotes proliferation of cells and thus their neoplastic transformation.
  • It is important to point out that the cells of CML appear to undergo fairly normal differentiation into relatively mature granulocyte subtypes. Therefore, the BCR-ABL gene likely acts to cause unregulated proliferation of a myeloid precursor but does not block its further differentiation. This stands in contrast to cells of acute leukemia in which differentiation appears stuck at the very early "blast" stage of maturation.
  • CML is characterized by a substantial peripheral leukocytosis composed of elevated numbers of mature granulocytes and their precursors known as "myelocytes". In most cases, neutrophils and predominate although less impressive elevations of basophils (basophilia) and eosinophils (eosinophilia) are also typically seen. Because CML cells tend to be well-differentiated, it is sometimes difficult to differentiate CML from a reactive leukemoid reaction that might be seen during an infection. Previously, a variety of special stains were used to distinguish between these two possibilities; however, with the advent of cytogenetic analysis to detect the Philadelphia Chromosome, these diagnostic tests are less commonly used.
Clinical Consequences
  • CML initially acts as an indolent neoplasia and can potentially remain asymptomatic for years. In many cases patients come to attention when a routine blood count reveals an unexplained leukocytosis. When symptoms do arise they are typically non-specific and include fatigue, malaise, and weight loss. Infiltration of the spleen can result in progressive splenomegaly that can yield a sensation of abdominal fullness and early satiety.
  • However, as neoplastic cells accumulate further mutations, CML cells begin to proliferate more aggressively and become more resistant to anti-neoplastics. Inevitably, a clone of cells will transform into an aggressive acute leukemia, characterized by a dramatic increase in circulating numbers of poorly-differentiated "blast" cells. This event, termed a "blast crisis" transforms the CML into a picture very similar to AML and is followed by a relatively rapid clinical decline.