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

Min Tang, Mithat Gonen, Alfonso Quintas-Cardama, Jorge Cortes, Hagop Kantarjian, Chani Field, Timothy P. Hughes, Susan Branford, Franziska Michor

Research output: Contribution to journalArticle

44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1622-1631
Number of pages10
JournalBlood
Volume118
Issue number6
DOIs
StatePublished - Aug 11 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Tang, M., Gonen, M., Quintas-Cardama, A., Cortes, J., Kantarjian, H., Field, C., Hughes, T. P., Branford, S., & Michor, F. (2011). Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells. Blood, 118(6), 1622-1631. https://doi.org/10.1182/blood-2011-02-339267