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Editorials
phase CML where more than half of the deaths are not related to CML.2 However, the bottom line at a time of generic imatinib is that a starting dose of 800 or 600 mg/d reduced to 400 mg/d in subjects achieving a stable MMR is probably a safe and effective therapeutic strategy.
The report of Michel et al. recalls an interesting obser- vation made several years ago in the OpTKima study. There, some older subjects receiving imatinib 400 mg/d, but who stopped therapy every 3rd month maintained a MMR and sometimes even improved the depth of molec- ular response.12 However, unlike the uniformly stable MMRs reported by Michel et al., approximately 25% of subjects in the OpTKima study lost their MMR. The stud- ies differ, of course, in the fact that, in the OpTKima study, subjects completely stopped imatinib while in the CML-Study IV subjects had an imatinib dose reduction.
What do these data suggest? A reasonable conclusion is that the best strategy is to optimize initial imatinib dose based on the rapidity, depth and stability of a sub- ject’s molecular response rather than using the same dose and schedule for everyone. Alternatively, some subjects who could benefit by starting off directly on a 2nd genera- tion TKI,13 could be moved to lower (and less toxic) dosages of the same drug once they achieved a good molecular response, or eventually, in specific cases, switch to imatinib for maintenance. Studies testing the feasibility and the value of this approach are needed and, indeed, some are already ongoing or planned.14
The regulatory approved dose of imatinib and other TKIs often evolves from results of phase I safety studies designed to determine the maximum tolerated dose (MTD) followed by phase II and III studies of efficacy.15 This developmental scheme assumes the MTD is the maximally effective dose (MED). But is this assumption correct? In the case of CML, the MED is the dose associ- ated with maximal inhibition of P210BCRABL1 that is also safe, especially when given over a long period of time. Given these considerations, it is easy to see why the MTD and MED might differ for a TKI.15
Another issue is why different subjects respond differ- ently to the same dose of a TKI like imatinib. Many fac- tors could explain this heterogeneity but the most obvi- ous is BCRABL1 mutations.16 Other variables include pharmaco-kinetic and pharmaco-dynamic variables relat- ed to TKI absorption and metabolism, susceptibility to AEs, and compliance.17 Also, some subjects in chronic phase CML have subclones with additional mutations in genes other than BCR-ABL1 reflecting the genomic insta- bility typical of CML.18 These subclones are not detected by routine diagnostic procedures and may be important in determining response to TKI-therapy and likelihood of CML progression, obviously confounded outcomes. In this context, it is important to remember that there is a substantial interval between when BCRABL1 is acquired to when CML is diagnosed, leaving ample time for clonal evolution. For example, in the atom bomb survivors, who likely acquired BCRABL1 when the atom bomb exploded, median latency to CML diagnosis was 10 years with a possible range of from <2 to >30 years.19
How can we best reconcile the goal of reducing the risk and severity of AEs with the need to control or eradicate undetected CML subclones that may require a higher TKI
dose, different TKIs, or both? One strategy might be to start with what might be called an ‘induction phase’ with a high-dose of a 2nd or even a 3rd generation TKI, or high- dose imatinib, followed by switching to a lower dose in a ‘maintenance phase’ in responders. It might also be rea- sonable to begin with a 2nd or 3rd generation TKI and then switch to imatinib.
The next question is when to transition from the ‘induction’ to the ‘maintenance’ phase. The decision could be based on surrogate end points such as MMR or MR4, but it is also important to remember that end points like MMR or MR4 are predictive rather than prognostic surrogate end points.20
Which TKI is best? Should we reduce the approved dose of newer TKIs or switch to imatinib 400 mg/d? This could depend on the therapeutic goal and this may differ in different subjects. Is it to improve EFS, PFS or survival, achieve TFR, decrease AEs and costs, increase compli- ance, something else, or a combination of different goals? When the therapeutic goal is TFR, the rapidity of achiev- ing a deep molecular response (DMR) and its stability and duration are crucial.21 As such, a more intensive initial therapy strategy may be preferable. However, this may not be the goal in other subjects in whom survival is the goal and where less ‘induction’ therapy may be appropri- ate.
Another way to consider revising TKI therapeutic strat- egy is to make treatment decisions based on time-to- event end points with the possibility of continually revis- ing strategy according to outcomes using statistical tech- niques such as Markov or Bayesian adaptive models.22 This can be considered an extension of current European LeukemiaNet recommendations,23 while also considering additional variables, such as TKI, dose, schedule, thera- peutic goal, AEs, pharmaco-kinetic and pharmaco- dynamics, and others, such as the kinetics of decline of BCRABL1 transcripts. It is even conceivable that one might consider potency of suppression of P210BCRABL1 kinase activity in different subjects, and even activity in CML leukemia stem cells.
The bottom line is that it is time to re-think our strategy of using TKIs to treat CML. We suggest testing an indi- vidualized, precision-based approach that considers dis- ease, patient and therapeutic goal heterogeneities, and modifying therapy according to the rate, depth, duration and stability of molecular response while acknowledging poor correlations with EFS, PFS and survival. Much work remains to clarify these issues, and this needs to be tested in randomized trials.
References
1. Hochhaus A, Larson RA, Guilhot F, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017;376(10):917-927.
2. Hehlmann R, Lauseker M, Saußele S, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017;31(11):2398-2406.
3. Michel C, Burchert A, Hochhaus A, et al. Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV. Haematologica. 2018 Dec 4. [Epub ahead of print]
4. Baccarani M, Rosti G, Castagnetti F, et al. Comparison of imatinib
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