Chronic Myelocytic Leukemia

CML is a myeloproliferative disorder in which the crucial pathophysiological event is the fusion of the bcr gene on chromosome 22 and the abl gene on chromosome 9.14 The molecular biological details and cell biological consequences of this rearrangement are discussed in Chapter 20. The diagnosis of CML is confirmed when bone marrow or peripheral blood cells are determined to have a Philadelphia chromosome (i.e., a translocation between the long arm of chromosome 9 and the short arm of chromosome 22) by either molecular or kary-otypic analysis. Although Philadelphia chromosome-negative CML was considered a distinct pathophysiological entity,59 if patients do not evidence such a translocation by any method, they do not have CML. Although the Philadelphia chromosome is considered diagnostic of CML, this translocation has also been noted in patients with disorders clinically consistent with essential thrombocytopenia or other MPDs.61,62 Very rarely patients who present with apparent AML may be found to have a Philadelphia translocation. It is very difficult to dis tinguish such patients from those who have had an occult chronic phase of CML in transformation. Cells from approximately 25 percent of adults and 5 percent of children with acute lymphoblastic leukemia have Philadelphia chromosome on cytogenetic analysis.62 However, molecular analysis reveals that the vast majority of children with Philadelphia-positive ALL and about half the adults with this entity have a different molecular form of the bcr-abl fusion protein than do those with CML (190 kd rather than the typical p210).63 Those ALL patients whose cells express the p210 bcr-abl fusion protein may have had an occult chronic phase that underwent a lym-phoid blast crisis.

The clinical course of CML can be divided into a chronic indolent stable phase, an accelerated phase, and a blastic cri-sis.32,64 Most patients with CML are diagnosed in the chronic or indolent phase,32,65 which is characterized by granulocytic hyperplasia, basophilic, and possibly eosinophilic infiltration in the bone marrow and concomitant elevation of the white count with a differential characterized by a left shift with bands, metamyelocytes, myelocytes, and promyelocytes, and occasional blasts including basophilia and eosinophilia. An elevated white blood cell (WBC) count may be ascribed to either chronic phase CML or a leukemoid reaction due to an inflammatory or infectious process. However, the leukocyte alkaline phosphatase (LAP) score may help to distinguish between these two entities. A low LAP score is found in over 90 percent of patients with CML, but should be elevated in those with a leukemoid reaction. In later phases of the disease, or after treatment, the LAP score may be elevated. Nonetheless, any patient with a persistent leukocytosis and a left-shifted differential should undergo cytogenetic or molecular analysis to exclude the presence of a bcr-abl fusion protein. Any patient whose marrow or blood cells are proven to harbor a t(9;22) by cytogenetic, fluorescent in situ hybridization (FISH), or molecular analysis (whether clinical disease features are typical of CML or any other MPD) should be considered a candidate for therapy known to be useful in CML, especially oral agents that inhibit the c-abl tyrosine kinase.

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