Therapy for chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has made this a potentially curable disease.21 However, many challenges remain, including: i) defining the best TKI, dose and schedule; ii) how to reduce the frequency and severity of adverse events (AEs); iii) how to increase the number of subjects who can achieve therapy-free remission (TFR), and others. In this issue of Haematologica, using data from the German CML-Study IV,2 Michel et al.3 tackle two of these challenges: the best TKI dose and reducing AEs. They report that subjects randomized to receive high-dose imatinib, 800 mg/day (d), achieving a stable major molecular response (MMR, 0.1% of BCRABL1) can have their imatinib dose reduced to 400 mg/d without losing their response, with the additional benefits of reducing AEs and cost, and likely increasing compliance.
Several prior clinical trials tested whether high-dose imatinib, 800 mg/d, was more effective than the approved dose, 400 mg/d.64 The primary end point of most of these trials was the proportion of study subjects achieving a MMR at 1 year, a landmark associated with a very low risk of leukemia progression and death from CML-related causes.7 A secondary end point was the time to MMR achievement. The conclusion of most studies was that high-dose imatinib resulted in faster MMRs but later led to a similar proportion of MMRs after 1 or 2 years.64 However, high-dose imatinib was associated with increased rates of ≥ grade 3 AEs, worse compliance, and higher costs.64 Consequently, many study subjects assigned to high-dose imatinib reverted to 400 mg/d. Recently, a landmark analysis of data from the CML-Study IV reported that study subjects receiving an optimized high-dose of imatinib (median dose, 600 mg/d) achieved deeper and faster molecular responses (MMR, MR4 and MR4.5) compared with those receiving 400 mg/d, with no increase in ≥ grade-3 AEs.8 Importantly, the conventional and optimized strategies of giving imatinib resulted in similar event-free survival (EFS), progression-free survival (PFS), and overall survival (OS).2
There are several caveats to accepting these conclusions including biases associated with landmark analyses and discordances between molecular responses (surrogate end points) and clinically important end points such as EFS, PFS and OS.109 Such discordances are common to many, if not most, clinical trials and underscore the limitations of surrogate end points.11 This is not surprising in chronic 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 observation made several years ago in the OpTKima study. There, some older subjects receiving imatinib 400 mg/d, but who stopped therapy every 3 month maintained a MMR and sometimes even improved the depth of molecular 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 studies 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 subject’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 2 generation 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 associated 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 differently to the same dose of a TKI like imatinib. Many factors could explain this heterogeneity but the most obvious is BCRABL1 mutations.16 Other variables include pharmaco-kinetic and pharmaco-dynamic variables related 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 instability 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 2 or even a 3 generation TKI, or high-dose imatinib, followed by switching to a lower dose in a ‘maintenance phase’ in responders. It might also be reasonable to begin with a 2 or 3 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 compliance, something else, or a combination of different goals? When the therapeutic goal is TFR, the rapidity of achieving 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 appropriate.
Another way to consider revising TKI therapeutic strategy is to make treatment decisions based on time-to-event end points with the possibility of continually revising strategy according to outcomes using statistical techniques 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, therapeutic 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 individualized, precision-based approach that considers disease, 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.
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