Article
Mathematical modelling reveals the potential for considerable dose reductions in tyrosine kinase inhibitor treated chronic myeloid leukemia
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Published: | August 27, 2018 |
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Introduction: The availability of tyrosine kinase inhibitors (TKIs) has revolutionized Chronic Myeloid Leukemia (CML) therapy. However, permanent control of the disease requires continuing and potentially life-long TKI therapy. While TKI cessation appeared as a safe option for about half of the optimally responding patients, a systematic assessment of the long-term effects of TKI dose de-escalation is missing. It is our aim to theoretically study quantitative effects of TKI dose de-escalation as a potential alternative treatment option for patients with good treatment response.
Methods: We use a mathematical model (applying ordinary differential equations) to analyze and consistently describe response data of TKI-treated CML patients from independent clinical trials. The model describes CML as a clonal competition process of normal and leukemic cells that is modulated by the TKI effect. It allows us to estimate patient-specific parameters that describe cell cycle activation and de-activation of leukemic stem/progenitor cells as well as the TKI-induced kill of leukemic cells.
Results: Our analysis reveals that the TKI-induced long-term decline in CML tumor load is limited by the activation of quiescent leukemic stem cells. Based on this finding we suggest dose de-escalation schedules in which the treatment intensity can be substantially reduced without altering the long-term leukemic stem cell response. We also suggest a step-wise dose alteration to identify optimal, patient-specific TKI doses.
Discussion: Our analysis provides strong theoretical evidence that TKI dose de-escalation does not lead to a reduction of long-term treatment efficiency in most patients. We demonstrate that continuous BCR-ABL1 monitoring allows to provide patient- specific predictions of an optimal (reduced) TKI-dose that does not decrease the anti-leukemic effect on residual leukemic stem cells. We make the predictions that dose halving might be safe for the majority of patients and that a longer treatment with a reduced dose is more efficient than the same cumulative dose applied in a shorter period. The model results are consistent with the interim analysis of the DESTINY trial, which studies dosage-halving in CML patients in sustained remission, and it provides clinically testable predictions. Our results reveal a currently unutilized clinical potential of dose de-escalation in long-term CML treatment to reduce treatment-related side effects and therapy costs.
The authors declare that they have no competing interests.
The authors declare that an ethics committee vote is not required.
Notes: EHA Meeting 2018, Stockholm (submitted)