Quantitative prediction of long-term molecular response in TKI-treated CML - Lessons from an imatinib versus dasatinib comparison

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

Longitudinal monitoring of BCR-ABL transcript levels in peripheral blood of CML patients treated with tyrosine kinase inhibitors (TKI) revealed a typical biphasic response. Although second generation TKIs like dasatinib proved more efficient in achieving molecular remission compared to first generation TKI imatinib, it is unclear how individual responses differ between the drugs and whether mechanisms of drug action can be deduced from the dynamic data. We use time courses from the DASISION trial to address statistical differences in the dynamic response between first line imatinib vs. dasatinib treatment cohorts and we analyze differences between the cohorts by fitting an established mathematical model of functional CML treatment to individual time courses. On average, dasatinib-treated patients show a steeper initial response, while the long-term response only marginally differed between the treatments. Supplementing each patient time course with a corresponding confidence region, we illustrate the consequences of the uncertainty estimate for the underlying mechanisms of CML remission. Our model suggests that the observed BCR-ABL dynamics may result from different, underlying stem cell dynamics. These results illustrate that the perception and description of CML treatment response as a dynamic process on the level of individual patients is a prerequisite for reliable patient-specific response predictions and treatment optimizations.

Details

Original languageEnglish
Article number12330
JournalScientific reports
Volume8
Issue number1
Publication statusPublished - 17 Aug 2018
Peer-reviewedYes

External IDs

PubMedCentral PMC6098052
Scopus 85051704132
ORCID /0000-0002-2524-1199/work/142251513
ORCID /0000-0003-2868-5155/work/199962740
ORCID /0000-0002-6741-0608/work/199962865

Keywords

Keywords

  • Biomarkers, Tumor, Dasatinib/pharmacology, Fusion Proteins, bcr-abl/antagonists & inhibitors, Humans, Imatinib Mesylate/pharmacology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy, Models, Theoretical, Neoplastic Stem Cells/drug effects, Prognosis, Protein Kinase Inhibitors/pharmacology, Reproducibility of Results, Treatment Outcome