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Chronic Myeloid Leukemia
Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: a simulation study based on phase III trial data
Artur C. Fassoni,1,2 Christoph Baldow,2 Ingo Roeder2,3* and Ingmar Glauche2*
*IR and IG contributed equally to this work.
ABSTRACT
Continuing tyrosine kinase inhibitor (TKI)-mediated targeting of the BCR-ABL1 oncoprotein is the standard therapy for chronic myeloid leukemia (CML) and allows for a sustained disease con- trol in the majority of patients. While therapy cessation for patients appeared as a safe option for about half of those patients with optimal response, no systematic assessment of long-term TKI dose de-escalation has been made. We use a mathematical model to analyze and consistent- ly describe biphasic treatment responses from TKI-treated patients from two independent clinical phase III trials. Scale estimates reveal that drug efficiency determines the initial response while the long-term behavior is limited by the rare activation of leukemic stem cells. We use this math- ematical framework to investigate the influence of different dosing regi- mens on the treatment outcome. We provide strong evidence to suggest that TKI dose de-escalation (at least 50%) does not lead to a reduction of long-term treatment efficiency for most patients, who have already achieved sustained remission, and maintains the secondary decline of BCR-ABL1 levels. We demonstrate that continuous BCR-ABL1 monitor- ing provides patient-specific predictions of an optimal reduced dose without decreasing the anti-leukemic effect on residual leukemic stem cells. Our results are consistent with the interim results of the DESTINY trial and provide clinically testable predictions. Our results suggest that dose-halving should be considered as a long-term treatment option for CML patients with good response under continuing maintenance thera- py with TKIs. We emphasize the clinical potential of this approach to reduce treatment-related side-effects and treatment costs.
Introduction
In tyrosine kinase inhibitors (TKI)-treated chronic myeloid leukemia (CML), the proportion of BCR-ABL1 mRNA is used to monitor the individual treatment response.1-3 Most patients show a typical bi-phasic response with a steep, initial decline (slope a), followed by a slower, secondary decline (slope β) of BCR-ABL1 levels.4-6 Whereas the initial decline is attributed to the eradication of proliferating leukemic cells (LC), the secondary decline has been suggested to result from a slower eradication of quiescent leukemic stem cells (LSCs).5-7 About two-thirds of the patients achieve major molecular remission (MMR), i.e. a reduction of three logs from the baseline (MR3), while one-third of these even achieve deep molecu- lar remission (DMR, i.e. MR4.5) within five years of treatment.3,6,8
Recently, TKI cessation and, thus, treatment-free remission has been established as an important therapeutic goal.9,10 However, about 50% of the patients with good response experience a molecular relapse after stopping TKI, pointing towards per- sisting residual LCs that cannot be controlled by patient-specific immunological mechanisms. As these mechanisms underlying the currently unpredictable individ- ual molecular relapse risk remain controversial, complementary approaches to
Ferrata Storti Foundation
1Instituto de Matemática e Computação, Universidade Federal de Itajubá, Brazil; 2Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany and 3National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany
Haematologica 2018 Volume 103(11):1825-1834
Correspondence:
ingmar.glauche@tu-dresden.de
Received: March 29, 2018. Accepted: June 26, 2018. Pre-published: June 28, 2018.
doi:10.3324/haematol.2018.194522
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/11/1825
©2018 Ferrata Storti Foundation
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