hematology and oncology
Chronic Myeloid Leukemia (CML)
Pathophysiology of CML
The Philadelphia (Ph) chromosome is present in 90 to 95% of cases of chronic myeloid leukemia. The Ph chromosome is the product of a reciprocal translocation between chromosomes 9 and chromosome 22, t(9;22). During this translocation, a piece of chromosome 9 containing the oncogene ABL is translocated to chromosome 22 and fused to theBCRgene. The chimeric fusion geneBCR-ABLis responsible for production of the oncoprotein bcr-abl tyrosine kinase. The bcr-abl oncoprotein has uncontrolled tyrosine kinase activity, which deregulates cellular proliferation, decreases adherence of leukemia cells to the bone marrow stroma, and protects leukemic cells from normal programmed cell death (apoptosis). CML ensues when an abnormal pluripotent hematopoietic progenitor cell initiates excessive production of all myeloid lineage cells, primarily in the bone marrow but also in extramedullary sites (eg, spleen, liver). Although granulocyte production predominates, the neoplastic clone includes red blood cells, megakaryocytes, monocytes, and even some T cells and B cells. Normal stem cells are retained and can emerge after drug suppression of the CML clone. Untreated, CML undergoes 3 phases: Chronic phase:An initial indolent period that may last 5 to 6 years Accelerated phase:Treatment failure, worsening anemia, progressive thrombocytopenia or thrombocytosis, persistent or worsening splenomegaly, clonal evolution, increasing blood basophils, and increasing marrow or blood blasts (up to 19%) Blast phase:Accumulation of blasts in extramedullary sites (eg, bone, central nervous system, lymph nodes, skin); blasts in blood or marrow increase to ≥ 20% The blast phase leads to fulminant complications resembling those of acute leukemia, including sepsis and bleeding. Some patients progress directly from the chronic to the blast phase. 