Tyrosine kinase inhibitors (TKI) are highly efficient drugs to combat Chronic Myeloid Leukemia (CML). While long-term drug administration is associated with side effects and high economic costs, current efforts focus on the discontinuation of TKI therapy for well-responding patients. The DESTINY trial showed that TKI dose reduction prior to cessation can lead to an increased number of patients achieving sustained treatment free remission (TFR). However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials.

Here, we apply an established mathematical model of CML therapy to investigate different TKI dose reduction schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success. Our analysis is based on a cohort of 72 patients from the DESTINY trial for which we obtained individual model fits.

Our systematic analysis confirms clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while highlighting that lower dose TKI treatment for the same duration is equally sufficient for many patients. Applying the model to an unstratified cohort of CML patients in deep remission our results suggest that a stepwise dose reduction prior to TKI cessation can increase the success rate of TFR, while substantially reducing the amount of administered TKI.

Our findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically testable strategies that are applicable to many CML patients.

Summary Discontinuation of tyrosine kinase inhibitor (TKI) treatment is emerging as the main therapy goal for patients suffering from Chronic Myeloid Leukemia, although it is not clear how dose reduction regimens can improve the achievement of treatment free remission (TFR). Our systematic analysis uses mathematical models of leukemia-immune interaction to show that a stepwise dose reduction prior to TKI cessation can potentially increase the success rate of TFR, while substantially reducing the amount of total administered TKI.

R.E. Clark is a consultant for Pfizer. I. Roeder reports receiving a commercial research grant from Bristol- Myers Squibb and has received speakers bureau honoraria from Bristol-Myers Squibb and Janssen-Cilag. I. Glauche reports receiving a commercial research grant from Bristol-Myers Squibb and from GlaxoSmithKline. No potential conflicts of interest were disclosed by the other authors.

NCT01804985

This work was supported by the German Federal Ministry of Research and Education (BMBF, grant number 031A315 MessAge) to I.G. and ERA-Net ERACo-SysMed JTC-2 project prediCt (Project No. 031L0136A) to I.R. E.K. was funded via a Jose Carreras-DGHO-Promotionsstipendium and the Graduate academy of TU Dresden.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The DESTINY trial ((27), NCT 01804985) was conducted in accordance with the Declaration of Helsinki and applicable regulatory requirements. The protocol was approved by the North West - Liverpool East Committee of the UK National Research Ethics Service.

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The data used in this study are available upon request from the corresponding author.