Quantitative prediction of long-term molecular response in TKI-treated CML \u2013 Lessons from an imatinib versus dasatinib comparison

Ingmar Glauche,Hendrik Liebscher,Philipp Schulze,Christoph Baldow,Ingo Roeder,Xiaoning Wang,Tino Rothe,Amit Roy,Matthias Kuhn

doi:10.1038/s41598-018-29923-4

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.

Highlights

Chronic myeloid leukemia (CML) is a disease characterized by the expression of the BCR-ABL fusion protein in virtually all malignant cells in the vast majority of patients[1]
Our statistical analysis of the dynamic treatment response of chronic phase (CP)-CML patients within the DASISION trial demonstrates differences in the average BCR-ABL dynamics between first-line imatinib and dasatinib treatment. Whereas both tyrosine kinase inhibitors (TKI) show qualitatively similar response dynamics, we demonstrate that dasatinib leads to a significantly faster molecular response
Our results suggest that there is a slight effect on the long-term BCR-ABL decline, the major advantage of dasatinib treatment is evident in the early phase of treatment

Summary

Introduction

Chronic myeloid leukemia (CML) is a disease characterized by the expression of the BCR-ABL fusion protein in virtually all malignant cells in the vast majority of patients[1]. The primary chronic phase (CP) of the disease eventually transforms into an accelerated phase followed by an acute blast crisis (BC), in which differentiation of functional blood cells is impaired and, physiological blood function is severely constrained, leading to the patient’s death if left untreated It is the molecular specificity of the BCR-ABL fusion gene that forms the basis of a highly efficient, targeted therapy by tyrosine kinase inhibitors (TKI). While the first decline may result from the rapid depletion of actively cycling BCR-ABL positive leukemic cells, the second decline most likely represents the slow elimination of quiescent residual leukemic stem cells (LSC), which are less susceptible to cell kill due to their comparatively low cell cycle activity[11,12] Following this line of argument, we support a dynamic description of the BCR-ABL response to characterize and predict long-term disease and treatment dynamics in individual patient, as previously suggested[11,12,13,14]

Methods

Results

Conclusion