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A.C. Fassoni et al.
which sets a lower limit to the dose de-escalation, a linear dose-response relationship is generally accepted over a wide range of treatment-relevant doses above this thresh- old.25,26 Thus, we deduced an explicit expression for the patient-specific optimal favorable dose reduction fraction 𝑓𝑂𝑃𝑇 (Online Supplementary Text S8), given by
𝑓𝑂𝑃𝑇 =0.247, and corresponds to a long-term treatment effi- ciency of 98.4% compared to the standard dose. Therefore, for the ‘median patient’ in our analysis, a reduction to 24.7% of the original dose would lead to a marginal decrease of only 1.6% in the long-term treatment efficien- cy, given that a minimal required plasma concentration for TKI cytotoxicity is maintained.
Our model predicts transient increases in BCR-ABL1 lev- els of proliferating LSCs when applying different dose reductions after the first decline, i.e. once a substantial reduction in BCR-ABL1 levels had been achieved (Figure 2). However, for favorable reductions, BCR-ABL1 levels decrease again with the original long-term treatment effi- ciency (slope 𝛽) after a few months (Figure 2B and C). For the example of a ‘median patient’, dose reductions at month 36 of treatment will maintain MR3, while BCR-ABL1 levels are predicted to return to their original val- ues at de-escalation after about 20 months (in case of favor- able reduction with 𝑓=0.5) or 58 months (for the optimal favorable reduction with 𝑓=0.25). Importantly, the transient increase of proliferating LSCs and, therefore, of BCR-ABL1 levels in the PB, does not lead to either relevant differences in the overall response of quiescent LSCs or in the total
This optimal fraction 𝑓𝑂𝑃𝑇
minimal favorable dose which still maintains the original long-term reduction rate of both proliferating and quies- cent LSCs. Therefore, as long as the TKI dose is not reduced below this threshold, our model predicts no impaired long-term efficiency, while an over-reduction compromises the overall treatment success.
We conclude from equation (E5) that 𝑓𝑂𝑃𝑇 is a patient- specific, fixed quantity determined by the proliferation rate of LSCs, 𝑝𝑌, their activation rate 𝑝𝑋𝑌, as well as the toxicity of the TKI, 𝑞=𝑒𝑇𝐾𝐼−𝑝𝑌. For the median parameters of the available dataset, the optimal favorable reduction fraction is
corresponds to the
AB
CD
Figure 4. Model predictions on dose de-escalation and comparison with clinical data. (A) Comparison of DESTINY interim results with model simulations of 50% dose de-escalation applied to IRIS and CML-IV patient data (assuming the same protocol and patient selection criteria of DESTINY). We simulated dose de-escalation starting from the individually predicted remission level at the time of the last BCR-ABL1 measurement of each patient, and evaluated the fraction of patients above MR3 one year after de-escalation. Error bars indicate 90% confidence intervals. (B) Model estimates of the risk of losing MR3 within one year after de-escalation, depending on the patient’s individual predicted remission level just before de-escalation. Patients with remission level above MR3.5 are very likely to lose MR3 at least transiently. (C) Model simulation illustrating the transient relapse above MR3 three months after de-escalation (highlighted time interval). De-escalation of 50% was implemented for a hypothetical patient of the DESTINY trial one year after reaching MR3. The simulation of a continuing half-dose regimen predicts that after about nine months the BCR-ABL1 levels fall below MR3 and the response regains the original slope 𝛽. (D) Simulation results showing the predicted relative increase/decrease in the number of patients without molecular relapse two years after cessation. We use the standard treatment scenario (full-dose for one year) as the reference (corresponding to the dashed line at 0%) to compare it with: i) half-dose for one year (the DESTINY protocol; red), and ii) half-dose for two years (blue). Relapse is defined as loss of MR3.
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haematologica | 2018; 103(11)