Management of chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) comprises about 20% of all cases of leukaemia in the western world. The annual incidence of about 1 per 1 of the population is remarkably constant worldwide. The majority of patients present with symptoms related to anaemia, splenomegaly or bleeding, but increasingly the diagnosis is made before the onset of symptoms leucocytosis is recognized as a result of a routine blood test performed for totally unrelated reasons. The majority of patients with CML have a Philadelphia (Ph') chromosome in all or almost all their myeloid cells at the time of diagnosis. The Philadelphia chromosome, 22q-, is the result of a reciprocal translocation of genetic material between a no. 9 and a no. 22 chromosome, usually designated t(9;22)(q34;q 11). The precise position of the breakpoint on chromosome 9 is rather variable from patient to patient but the breakpoint on chromosome 22 seems to be localised within a relatively short (5 .8 kilobase) sequence of DNA that has been termed the 'breakpoint cluster region' (bcr). A protooncogene, c-abl, which bears homology with the transforming sequence of the Abelson strain of Moloney murine leukaemia virus, is normally localised to the long arm of chromosome 9. In CML the distal end of the long arm of chromosome 9, including the c-abl oncogene, is translocated to chromosome22and thedistalendofthelong armof chromosome22, includingaportion of the3 ' endof the bcr gene, is translocated to chromosome 9; as a consequence a new hybrid gene consisting of the 5 ' end of the bcrgeneand thec-abloncogeneis formed on the 22qchromosome. This hybrid gene is responsible for the production of novel mRNAs of 8 and 9 kb in length and these in turn are associated with the production of a unique abl-related protein of molecular mass 210 kD. Unlike its normal counterpart, which has a molecular mass of about 145 kD, the P210 has tyrosine kinase activity, a function characteristic of the transforming sequences of some oncogenic retroviruses. These molecular changes appear specific for CML (see refs 1-4 for more detailed reviews of this subject). When diagnosed, the disease is usually in the chronic or stable phase without any major excess of blast cells in the blood or marrow. The median duration of this chronic phase (CP) is about 45 months but the range is wide. Death, when it occurs, is usually due to the insidious or rapid onset of blastic transformation (BT), at which point immature blast cells predominate in the marrow and blood. In recent years clinicians have come to recognize in some patients a phase of the disease intermediate between stable C P and overt BT. The precise definition of this socalled accelerated phase is not generally agreed but, in the absence of overt blastic transformation, the presence of fever, weight loss, increasing splenomegaly or increasing leucocytosis in