What other strategies might be considered to improve therapeutic efficacy and prevent emergence of resistance? Cytotoxic drugs are likely to select for resistant cells by clearing the ground of more sensitive ones. In TP53-mutated CLL, this may involve use of novel targeted therapies (eg, Ibrutinib, ABT199) 8 which have been shown to have promising activity in this subset. It is therefore important to identify low-level molecular lesions that are known to predict for chemoresistance so that treatment can be tailored appropriately. Certain subclones are likely to gain a competitive advantage due to their “fitness” in relation to these selection pressures. “Selection” can thus be introduced artificially by the use of chemotherapeutic agents.
It is therefore unsurprising that failure of chemotherapy to completely eradicate CLL cells can result in expansion of minor, more resistant, and more dangerous subclones. If these subclones are vying for space and resources, the reduction of some clones may unbalance the status quo. If multiple subclones coexist, what drives any to become dominant? There are many reasons, including limited potential for expansion due to “competition” from other clones as well as the independent effect of the surrounding microenvironment.
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