Despite the success of tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML), minimal residual disease persists, requiring indefinite treatment. Accumulated evidence has shown that leukemic stem cells (LSCs) in the bone marrow can survive TKI treatment via downstream BCR-ABL1-independent signaling pathways that are activated by soluble growth factors and interactions with the extracellular matrix in the bone marrow microenvironment. Research efforts have therefore turned to the identification and development of agents that target LSCs, and together with TKIs, have the potential to eradicate CML. A number of such agents are now under clinical investigation, and others are soon to enter early-phase studies. This review examines the pathways, molecular targets, and potential new therapeutics that, with TKIs, may provide an effective "one-two punch" to cure CML.
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