In the Pipeline: Emerging Therapy for CML

The development of BCR-ABL1 tyrosine kinase inhibitors (TKI) has revolutionized the treatment of CML. A major limitation of TKI therapy is the relative inability to eradicate quiescence CML leukemic stem cells (LSC) that persist in the bone marrow microenvironment (BMM), which limits the achievement of treatment-free remission (TFR) in patients who have discontinued TKIs. This chapter will discuss novel and combination therapeutic strategies in targeting abnormal HSCs and TKI resistance in CML patients, with an aim of inducing TFR through the eradication of the LSC population. These strategies include the following: (a) targeting of signaling pathways in CML stem cells, (b) targeting the interaction between LSCs and the bone marrow niche, (c) targeting cell cycle and apoptosis via p53 modulation, (d) targeting differences in epigenetic regulation between normal HSCs and LSCs, (e) targeting autophagy, and (f) immunotherapy.