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

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dc.contributor.authorTang, M.
dc.contributor.authorGonen, M.
dc.contributor.authorQuintas-Cardama, A.
dc.contributor.authorCortes, J.
dc.contributor.authorKantarjian, H.
dc.contributor.authorField, C.
dc.contributor.authorHughes, T.
dc.contributor.authorBranford, S.
dc.contributor.authorMichor, F.
dc.date.issued2011
dc.description.abstractTreatment 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.
dc.description.statementofresponsibilityMin Tang, Mithat Gonen, Alfonso Quintas-Cardama, Jorge Cortes, Hagop Kantarjian, Chani Field, Timothy P. Hughes, Susan Branford, and Franziska Michor
dc.identifier.citationBlood, 2011; 118(6):1622-1631
dc.identifier.doi10.1182/blood-2011-02-339267
dc.identifier.issn0006-4971
dc.identifier.issn1528-0020
dc.identifier.orcidHughes, T. [0000-0002-0910-3730] [0000-0002-7990-4509]
dc.identifier.orcidBranford, S. [0000-0002-1964-3626] [0000-0002-5095-7981]
dc.identifier.urihttp://hdl.handle.net/2440/86381
dc.language.isoen
dc.publisherAmerican Society of Hematology
dc.rights© 2011 by The American Society of Hematology
dc.source.urihttps://doi.org/10.1182/blood-2011-02-339267
dc.subjectHumans
dc.subjectBenzamides
dc.subjectPiperazines
dc.subjectPyrimidines
dc.subjectFusion Proteins, bcr-abl
dc.subjectProtein Kinase Inhibitors
dc.subjectTreatment Outcome
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectTranscription, Genetic
dc.subjectAlgorithms
dc.subjectModels, Biological
dc.subjectTime Factors
dc.subjectNeoplastic Stem Cells
dc.subjectLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subjectMolecular Targeted Therapy
dc.subjectImatinib Mesylate
dc.titleDynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells
dc.typeJournal article
pubs.publication-statusPublished

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