Contributions
Abstract: PB1942
Type: Publication Only
Background
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.
Aims
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.
Conclusion
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.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Dose intensity, Prediction, Tyrosine kinase inhibitor
Abstract: PB1942
Type: Publication Only
Background
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.
Aims
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.
Conclusion
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.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): Chronic myeloid leukemia, Dose intensity, Prediction, Tyrosine kinase inhibitor