Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells Journal Article


Authors: Tang, M.; Gonen, M.; Quintas-Cardama, A.; Cortes, J.; Kantarjian, H.; Field, C.; Hughes, T. P.; Branford, S.; Michor, F.
Article Title: Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells
Abstract: Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitors (TKIs) imatinib mesylate and nilotinib represents a successful application of molecularly targeted anticancer therapy. However, the effect of TKIs on leukemic stem cells remains incompletely understood. On the basis of a statistical modeling approach that used the 10-year imatinib mesylate treatment response of patients with CML and a patient cohort receiving first-line nilotinib therapy, we found that successful long-term therapy results in a triphasic exponential decline of BCR-ABL1 transcripts in many patients. Within our framework, the first slope of -0.052 ± 0.018 (imatinib mesylate) and -0.042 ± 0.015 (nilotinib) per day represents the turnover rate of leukemic differentiated cells, whereas the second slope of -0.0057 ± 0.0038 (imatinib mesylate) and -0.0019 ± 0.0013 (nilotinib) per day represents the turnover rate of leukemic progenitor cells. The third slope allows an inference of the behavior of immature leukemic cells, potentially stem cells. This third slope is negative in most patients, positive in others, and not observable in some patients. This variability in response may be because of insufficient follow-up, missing data, disease heterogeneity, inconsistent compliance to drug, or acquired resistance. Our approach suggests that long-term TKI therapy may reduce the abundance of leukemic stem cells in some patients. © 2011 by The American Society of Hematology.
Keywords: controlled study; treatment response; unclassified drug; human cell; major clinical study; follow up; imatinib; cell differentiation; chronic myeloid leukemia; mathematical model; stem cell; leukemia cell; long term care; bcr abl protein; nilotinib; molecularly targeted therapy; turnover time; bcr abl1 protein
Journal Title: Blood
Volume: 118
Issue: 6
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2011-08-11
Start Page: 1622
End Page: 1631
Language: English
DOI: 10.1182/blood-2011-02-339267
PROVIDER: scopus
PMCID: PMC3156048
PUBMED: 21653938
DOI/URL:
Notes: --- - "Export Date: 3 October 2011" - "CODEN: BLOOA" - "Source: Scopus"
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MSK Authors
  1. Mithat Gonen
    701 Gonen