Emerging drugs in chronic myelogenous leukaemia

Abstract

Chronic myelogenous leukaemia (CML) is characterised by a t(9;22)(q34;q11) translocation, which produces a fusion BCR–ABL protein with constitutive tyrosine kinase activity that is central to the pathogenesis of CML representing an ideal target for therapeutic intervention. Targeting BCR–ABL by imatinib has revolutionised the clinical course of CML. All patients in early chronic phase treated with imatinib achieve a complete haematological response, with 80 – 90% achieving a complete cytogenetic response. However, BCR–ABL transcripts remain detectable in the great majority of them, and ~ 16% chronic phase CML patients are resistant to or relapse after imatinib treatment, mainly through pre-existing or acquired point mutations in the binding pocket. Thus, other targeted approaches are being developed to overcome imatinib resistance. These include two novel tyrosine kinase inhibitors (nilotinib and dasatinib) that are producing clinical responses in different clinical settings, while other similar compounds are under evaluation in preclinical studies. Furthermore, additive immunotherapeutic strategies are emerging to synergise with imatinib in the elimination of molecular residual disease. This paper reviews the current details regarding these approaches and their developments.

Keywords::

• BCR–ABL
• chronic myelogenous leukaemia
• drug resistance
• imatinib
• immunotherapy
• kinase inhibitor
• vaccine

Notes

Hsp: Heat-shock protein; mTOR: Mammalian target of rapamycin; siRNA: Small interfering RNA.