Evolving Molecular Therapy for Chronic Myeloid Leukaemia--are We on Target?

Chronic myeloid leukaemia (CML) is a clonal disease of stem cell origin that develops when a single pluripotent haemopoietic stem cell acquires the Philadelphia (Ph) chromosome. The unique fusion gene product translated, p210 (Bcr-Abl), is a constitutively active tyrosine kinase that is specific to, and has a central role in the pathogenesis of, CML, making it an atractive target for drug therapy. Imatinib mesylate (IM) is one such therapy that also targets Abl, c-kit and PDGF-R tyrosine kinases. Although IM induces a much higher rate of complete cytogenetic remission (CCR), with improved tolerability and better progression free survival compared to other licensed therapies, resistance is a significant clinical problem. The most common mechanism of IM resistance is mutation of the Bcr-Abl kinase catalytic domain. In addition, molecular persistence in patients in CCR is most likely attributable to persisting Ph(+) stem cells that are insensitive to IM by unknown mechanisms and this is a major focus of current research interest. Current results from pre-clinical in vitro work on novel agents and combination strategies as well as clinical trials including immunotherapy approaches are reviewed. Despite the widespread use of molecularly targeted therapies and the development of new therapeutic drugs and strategies, it is our belief that there is a requirement for further research into and development of stem cell-directed therapies to overcome molecular persistence. It is likely that a combination of molecularly targeted therapies or treatment modalities will finally eliminate the quiescent stem cell population, leading to a "molecular cure" of CML.