PURPOSE: Imatinib induces a durable response in most patients with Philadelphia 
chromosome-positive chronic myeloid leukemia, but it is currently unclear 
whether imatinib reduces the leukemic stem cell (LSC) burden, which may be an 
important step toward enabling safe discontinuation of therapy. In this article, 
we use mathematical models of BCR-ABL levels to make inferences on the dynamics 
of LSCs.
EXPERIMENTAL DESIGN: Patients with at least 1 BCR-ABL transcript measurement on 
imatinib were included (N = 477). Maximum likelihood methods were used to test 3 
potential hypotheses of the dynamics of BCR-ABL transcripts on imatinib therapy: 
(i) monoexponential, in which there is little, if any, decline in BCR-ABL 
transcripts; (ii) biexponential, in which patients have a rapid initial decrease 
in BCR-ABL transcripts followed by a more gradual response; and (iii) 
triexponential, in which patients first exhibit a biphasic decline but then have 
a third phase when BCR-ABL transcripts increase rapidly.
RESULTS: We found that most patients treated with imatinib exhibit a biphasic 
decrease in BCR-ABL transcript levels, with a rapid decrease during the first 
few months of treatment, followed by a more gradual decrease that often 
continues over many years.
CONCLUSIONS: We show that the only hypothesis consistent with current data on 
progenitor cell turnover and with the long-term, gradual decrease in the BCR-ABL 
levels seen in most patients is that these patients exhibit a continual, gradual 
reduction of the LSCs. This observation may explain the ability to discontinue 
imatinib therapy without relapse in some cases.