ABSTRACT
Patients with chronic myeloid leukemia (CML) have been served well by clinical and laboratory research, particularly over the past two decades, and the unraveling of some of the molecular mechanisms which underlie the indolent or chronic phase (CP) of the disease has paved the way to defining potential specific targets for treatment. Patients with CML have in their leukemia cells a chromosomal translocation [t(9;22)] giving rise to the Philadelphia (Ph) chromosome (22q − ), that results in a fusion gene, BCR-ABL1 . 1-4 This gene encodes a BCR-ABL oncoprotein with enhanced tyrosine kinase activity, which is generally considered to be the ‘initiating event ’ in the leukemia, though there remains some debate as to whether it really is the initial molecular event in all cases. 5,6
The incidence of CML is about 1.0 – 2.0 per 100 000 of population per annum and is remarkably constant worldwide, at least in parts where national cancer registries have been maintained. In the Western world it represents approximately 15 % of all adult leukemias and <5 % of all childhood leukemias but the percentage is probably higher in the East, for example India, where chronic lymphocytic leukemia is very rare. The median age of onset is about 50 years and there is slight male excess. There appear to be no obvious predisposing factors other than following exposure to high doses of irradiation, as occurred in survivors of Hiroshima and Nagasaki atomic bombs in 1945. 7 Even then, the actual risk of
developing CML was only marginally increased. A small number of families with a high incidence of the disease have been reported. One convincing case has been reported of CML recurring in cells of donor origin following related allogeneic stem cell transplantation. 8
CML is a remarkably heterogeneous disease. Before the introduction of imatinib mesylate it typically ran a biphasic or triphasic course. It was usually diagnosed in CP and this lasted typically 3 – 6 years; the leukemia then spontaneously progressed to blast transformation. About 70 – 80 % of patients had a myeloid blast transformation, and they usually survived between 2 and 6 months; patients entering a lymphoid blast transformation had a slightly better survival. About half of the patients in the CP transformed directly into blast transformation and the remainder did so following a period of accelerated phase. 9
The advent of imatinib mesylate, the first ABL tyrosine kinase inhibitor, has radically changed this natural history for the majority of patients who receive this drug as initial therapy, especially if they remain in complete cytogenetic response beyond the 4th year of therapy. 10,11 The recent 6-year follow-up of the phase III prospective trial (IRIS) which compared imatinib mesylate with the previous best non-transplant therapy, interferon alfa (IFNα) and cytarabine, showed that no patient in complete cytogenetic response
continuing beyond the 4th and 5th year of treatment had subsequently entered the advanced phase 12 ( Table 4.1 ). At the time of this landmark analysis, about 60 % of the original cohort randomized to receive imatinib mesylate remained in complete cytogenetic response. Most, if not all, of this cohort were in early CP. Patients presenting in late CP appear to fare less well; the Italian collaborative group (GIMEMA) recently demonstrated a complete cytogenetic response rate of 50 – 60 % in a prospective analysis of 277 late CP patients. 13
For patients subjected to an allogeneic stem cell transplant, the vast majority remain in a complete cytogenetic and molecular remission for 10 years or more. Some of these patients do become intermittently positive for BCR-ABL transcripts, albeit at low levels, but the rare patient with a persisting high transcript level is at a high risk of relapse. 14,15 A very small minority appear to relapse directly into the advanced phases of the disease.
