How can Chronic Myeloid Leukaemic drugs (Tyrosine kinase inhibitors, e.g. imatinib, etc.) that act by inhibiting bind of ATP to the active site of the BCR-ABL1 protein actually reduce the prevalence of the Philadelphia chromosome? (For example, optimal response to TKIs in 3 months would be Ph+ <35% and/or BCR-ABL1 <10%.) What I am actually asking is how a drug that targets the result of the oncogene (the BCR-ABL1 protein) can have an effect on the source (ie. genotype of the cells), as CML is a clonal haematopoietic stem cell disorder?
The key is that TKIs, such as Imatinib, are a therapy rather than a cure
Per Wikipedia, Imatinib acts as a competitive inhibitor of the otherwise constitutively-active BCR-ABL fusion protein, rather than the fusion gene. By binding the kinase domain, BCR-ABL is unable to phosphorylate downstream effectors that result in unchecked proliferation. As long as a patient continues to take Imatinib, BCR-ABL activity should be blocked.
In the past few years (i.e, long after imatinib's discovery) there has been a lot of research into exactly how hematopoetic stem cells, which reside in the marrow and create leukemic blasts, work. Most HSCs remain in a quiescent state, but it's not particularly well-known how frequently they turn over. Recent CML studies have shown that after ~5 years, a large portion of CML patients can safely taper the the drug. Presumably this is related to HSC turnover, but frankly as a leukemia molecular biologist rather than a physician, I'm not the best font of clinical knowledge.