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

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 control 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 consistently 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 mathematical framework to investigate the influence of different dosing regimens 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 monitoring 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 therapy with TKIs. We emphasize the clinical potential of this approach to reduce treatment-related side-effects and treatment costs.

Discontinuation of imatinib in children with chronic myeloid leukaemia in sustained deep molecular remission: results of the STOP IMAPED study

“…Further studies are needed to determine whether rates of sustained DMR after discontinuing 2nd generation TKIs in paediatric CML patients are similar to adults (Saussele et al , , Ross et al , ). Another option for further research could include stepwise reduction in TKI therapy, as recent papers on adult patients highlight that a stepwise reduction in TKI therapy results in higher treatment‐free remission rates (Abruzzese, ; Clark et al , ; Fassoni et al , ). So far, no experience on this approach in paediatric patients has been published.…”

To cure or not to cure: consequences of immunological interactions in CML treatment

“…An alternative treatment strategy includes TKI-dose reduction by 50 % before treatment cessation, which has been recently studied the DESTINY trial [Clark et al, 2017]. Additionally, we discussed the potential of TKI dose reduction in the context of long-term maintenance treatment [Fassoni et al, 2018]. In both cases, the dose reduction is expected to cause a perturbation on the dynamics of CML, which can be captured and quantified by the patient-specific response in the BCR-ABL1/ABL1 ratios following dose reduction.…”

Exploiting the “survival of the likeliest” to enable evolution-guided drug design

“…To do this, we first identified a simple, clinically-parameterized model of CML treatment that incorporates hematopoietic stem cell division and differentiation 49 . To adapt the system to our question, we added our 19 resistance variants of interest to the model ( Figure 4A).…”