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

Hughes4, Susan Branford4, and Franziska Michor1

+ Author Affiliations
1Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, MA;2Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY;3Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX; and4Department of Genetics and Molecular Pathology, SA Pathology, and University of Adelaide, Adelaide, Australia

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.

http://bloodjournal.hematologylibrary.org/content/118/6/1622.full