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A.C. Fassoni et al.
Although our model does not yet reflect immunological effects, which are proposed to be important determinants of disease dynamics post TKI-cessation, we speculated about the relative impact of dose reductions with respect to treatment stop. Specifically, we simulated the DES- TINY cessation protocol for the IRIS and CML-IV patients in our data-set and evaluated the primary DESTINY end point, i.e. the proportion of patients who can de-escalate TKI dose by 50% for one year and then stop treatment completely for two years without losing MR3. Our simu- lations indicate higher rates of molecular relapse in com- parison to a structurally identical control group receiving full-dose before TKI stop (Figure 4D) if no additional immunological control mechanisms are considered. However, comparing dose reductions of different dura- tion, we predict a beneficial effect if patients remain at half-dose for longer before stopping TKI. We conclude that the same cumulative dose is more efficient if applied over a longer time period, thereby emphasizing that the full benefit of TKI dose de-escalation appears in the long term.
Discussion
Our study supports the concept that TKI dose reduction in maintenance therapy can be a safe option for many CML patients who have already achieved a sustained remission. In particular, we dissect the typical biphasic response pattern under continuing TKI treatment and con- clude that the TKI effect during the secondary treatment phase is limited by the rare activation of quiescent LSCs. Our simulations predict that the overall treatment effect is maintained for most patients, even if the TKI dose is reduced. Based on their initial treatment response under full dose, we identify patients who most likely benefit from a reduction scheme and present a strategy to esti- mate a patient-specific, optimal dose. Our results suggest a treatment strategy that could considerably reduce cumu- lative drug intake and, therefore, decrease drug-mediated side-effects. It might also increase compliance of patients to adhere to the prescribed treatment schedule. On the population level, the long overall survival times of continuously treated CML-patients add a distinct eco- nomical aspect to the outlined strategy, as the high treat- ment costs could be substantially reduced.
The proposed strategy is not restricted to a particular TKI. Although our model encompasses all TKI pharmaco- kinetic parameters and doses within a single parameter 𝑒𝑇𝐾𝐼, we have found that this simple model, using a rela- tive reduction compared to a standard dose of the respec- tive TKI, is equivalent to a more elaborate formulation explicitly considering the daily TKI intake (Online Supplementary Text S10 and Online Supplementary Figure S9). Although a linear dose-response relationship appears to be an appropriate model assumption,25,26 we emphasize that the potential for dose reductions might be limited by a necessary TKI plasma concentration to ensure drug activity. Based on in vitro data for imatinib,28 we estimate this limit to be in the order of 25% of the original dose (Online Supplementary Text S11). Furthermore, recent results from clinical trials15,29 indicate that a 50% dose reduction is therapeutically active.
Several clinical studies have addressed the potential of dose reductions in various settings. While Naqvi et al.
report good results from a cohort of newly diagnosed CP- CML patients treated with low-dose dasatinib (50 mg daily) first line,29 Russo et al. study the effect of a one- month-on/on-month-off imatinib regimen in elderly patients after at least two years of initial full-dose therapy.30 In the later study, one-third of the patients lost their previous remission levels. Based on our model, we speculate whether the extended treatment interruptions might have added to this outcome as no therapeutically active TKI concentrations were achieved during this time. Furthermore, we have seen that several clinical studies reported a clear advantage of more potent TKI to achieve molecular response earlier as compared to standard-dose imatinib.8,31,32 However, the corresponding advantage in long-term survival is less pronounced, and we suggest that it is not the drug potency but the rare activation of LSCs that marginalizes the survival benefit.
In order to test our predictions in a controlled clinical setting, we suggest an approach in which the dynamics of initial treatment response to standard therapy are suffi- ciently monitored to obtain reliable estimates of the rele- vant slopes for an informed treatment adaptation (mea- surements every 3-4 months within the first year and at least every six months thereafter). Only after a clinically relevant remission level (at least MR3) is reached can dose reductions (e.g. < 50% of the initial dose) be considered and these should be accompanied by a detailed follow-up monitoring of BCR-ABL1 levels to guarantee patient safety and also inform on the validity of our model approach. Further dose reductions might be considered as a second step towards approaching an optimally reduced dose that retains the therapeutic threshold.
Our modeling results predict a transient increase of the number of proliferating LCs after dose reduction. However, because this is only a transient and expected effect, we suggest that the clinical criteria for molecular relapse after dose de-escalation would benefit from con- sidering a follow-up period rather than focusing on fixed thresholds. Although the transient increase in proliferating LCs might increase the chance of acquiring secondary mutations, we reason that this is a marginal effect which needs to be compared with the benefits of reducing treat- ment-related side-effects. Indeed, assuming that the risk of acquiring a secondary mutation is proportional to the number of proliferating LSCs divisions, this risk increases by only 1.5% when half-dose is applied for three years (after an initial period of three years under standard dose) in comparison with the full-dose scenario (Online Supplementary Text S12 and Online Supplementary Figure S10). We acknowledge that our estimates are based on the assumptions that there are no direct dose-dependent resistance mechanisms. This is supported by the observa- tion that re-starting TKI treatment after relapse in cessa- tion studies proved overall successful and did not suggest a higher tendency for TKI resistances.33,34
Our current model does not consider any immunologi- cal effects or other more detailed competition mechanism between LCs and their environment. Therefore, our pre- dictions on the risk of molecular relapse after TKI cessa- tion are solely based on the fraction of LCs at the time of TKI stop and the proliferation rate estimated from CML latency times. This implies that a lower residual LSC num- ber ultimately results in a lower relapse risk. Because of this limitation, our model does not reflect potentially ben- eficial effects resulting from mildly increased abundance
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haematologica | 2018; 103(11)