gms | German Medical Science

Introduction: In chronic myeloid leukaemia (CML) most patients are treated successfully with tyrosine kinase inhibitors (TKI). However, as long-term drug administration is associated with side effects and high costs, there is considerable interest in the discontinuation of TKI treatment for well-responding patients. It has been speculated that the immune system plays a major role in the control of residual disease levels and influences whether a patient will remain in sustained treatment free remission (TFR) or not.

Methods: We have previously shown that mathematical models of CML that include an immunological component can accurately describe patient time courses after stopping treatment. Here, we apply our model to an extended data set of the DESTINY trial, which showed that dose reduction prior to cessation can increase the fraction of patients achieving sustained TFR.

Our approach uses molecular patient time-course data during and after TKI therapy to identify model parametrizations for each individual CML patient. These fits are then used as an in silico cohort for simulating various amended TFR schedules. Applying a re-sampling approach, we can derive estimates of recurrence times and fractions.

Results: We demonstrate that our model can be used to study how the cohort would behave under alternative TFR strategies, in which the timing and the amount of dose reduction are varied in a systematic manner. As a particular application, our simulations confirm clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while at the same time indicating that lower dose TKI treatment is sufficient for many patients. Our model results further indicate that stepwise dose reduction prior to TKI cessation may decrease side effects and overall treatment costs while maintaining the overall success rate of TFR.

Conclusion: Our findings illustrate how mathematical modelling approaches could guide the planning of experimental and clinical studies.

The authors declare that they have no competing interests.

The authors declare that an ethics committee vote is not required.

The contribution has already been published: Bonn Conference on Mathematical Life Sciences 2023 [1]