Until recently, progress in the treatment of patients with Ph(+) acute lymphoblastic leukaemia (ALL) has been limited, and long-term survival, even with high-dose intensified
chemotherapy, is rare. Allogeneic
stem cell transplantation is potentially curative, but treatment-related mortality and rate of disease recurrence are substantial. With the advent of the ABL-selective
tyrosine kinase inhibitor STI571 (
imatinib mesylate,
Glivec), it has become apparent that the understanding of crucial leukaemogenic pathways at the molecular level can lead to the development of specific and selective agents. In recent clinical trials,
imatinib has demonstrated significant anti-leukaemic efficacy in patients with advanced Ph(+) ALL, in conjunction with a remarkably favourable safety profile. Clinical resistance to
imatinib develops rapidly, highlighting the limitations of using
imatinib as a single agent; however, the value of
imatinib as an
element of treatment has become apparent. Resistance mechanisms have already been identified that will enable the development of rational strategies to prevent or overcome resistance. On the basis of available clinical results, combinations of
imatinib with established anti-leukaemic agents, as well as with novel, molecularly targeted treatment modalities, will need to be evaluated in advanced Ph(+) ALL. Incorporation of
imatinib in the first-line treatment of de novo Ph(+) ALL and in the setting of
minimal residual disease is a promising therapeutic approach which is currently being studied in clinical trials. Better understanding of targeted
therapies, including strategies based on recruitment of host immune functions, as well as the prudent use of active
chemotherapy agents, may eventually improve the outlook for patients with Ph(+) ALL.