The top portion of the figure illustrates a hypothetical patient diagnosed with chronic phase CML and commenced on TKI therapy. The patient had a warning response to TKI, based on the 2013 European LeukemiaNet criteria due to of failure to achieve a major molecular response⁹  (BCR-ABL1 ≤0.1%) by 12 months. Although the patient’s response plateaued for several months, there was a subsequent progressive increase in BCR-ABL1 consistent with overt treatment failure. The lower portion of the figure illustrates the clone sizes at various stages of therapy. At the time of the warning response, a KD mutation emerged with an allele frequency of ∼3%, but because this was not detectable by SS, the same therapy was continued until the resistant clone expanded enough to be eventually detectable by SS. Earlier intervention would likely have prevented overt treatment failure by initiating an appropriate therapy switch when the new low-level KD mutation was detected.