A clear and thorough overview of the current data available from the clinical studies of TKI discontinuation and/or dose reduction.
Sandy
This is quite an in-depth article so I have highlighted a few paragraphs that standout and may reassure many - particularly those who are newly diagnosed.
Dose reduction
For a large majority of patients who cannot achieve TFR, another approach to reduce side effects and costs and to maintain compliance would be to identify the lowest possible effective dose of TKI.58,59 Both dasatinib and nilotinib have demonstrated efficacy at doses lower than the FDA-approved dose. In a recently published phase II study from the MD Anderson Cancer Center,60 dasatinib was given at a dose of 50 mg daily, instead of the FDAapproved dose of 100 mg, to newly diagnosed patients. Of the 81 patients enrolled, 81% had achieved a MMR at 12 months according to the follow-up data at the time of the publication. This is higher than in the DASISION study, in which the MMR rate was 46% at 1 year with dasatinib.24 The 50 mg dose was better tolerated with a low cumulative incidence of pleural effusions of 6%.
The NiloRED study was an observational study evaluating dose reductions for patients on nilotinib61 Of the 67 evaluable patients, 68.6% were receiving nilotinib as firstline therapy and 31.4% as second-line treatment. The median duration of MMR was 25 months at the time of dose reduction. The nilotinib dose was reduced to 450 mg daily, 400 mg daily and 300 mg daily in 87%, 10% and 3% patients, respectively. Only two patients lost the MMR, although they regained MR4 later on without a dose increase.
The DESTINY trial, detailed earlier, provides a perfect example illustrating the safety of dose reduction.2 Of the 174 patients enrolled, 148, 16 and 10 were receiving imatinib, nilotinib and dasatinib, respectively. At study entry, the TKI dose was reduced to half the standard dose for 12 months: imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily. After 1 year, 19% of patients in the group with MMR had lost their MMR compared to 2% of those starting with deeper responses. After 1 year of half-dose therapy, patients who had not “relapsed” discontinued therapy as discussed earlier. It is unclear what would have happened if those patients had stayed on a lower dose and had not attempted treatment discontinuation. The INTERIM trial was another study that demonstrated the safety of imatinib dose reduction for patients in a complete cytogenetic remission (CCyR).62 In that study, imatinib was reduced to 1 month on/1 month off in 67 patients who were >65 years of age and had attained CCyR. Of those patients, 17% and 18% lost their CCyR and MMR, respectively. All patients who restarted higher dose therapy attained CCyR and MMR again.
In summary, these data demonstrate that, particularly for patients experiencing chronic symptoms, dose reduction can be an option for those on a stable dose of TKI with adequate response, including those who are not eligible for or do not want an attempt at treatment discontinuation, and those in whom previous TKI discontinuation failed. More frequent monitoring is advisable for the first 6 months after dose reduction to detect the unusual individual who rapidly loses response.
In this regard, Fassoni and colleagues, using data from large clinical trials, modeled the kinetics of transcript levels after a 50% reduction in dose in patients in stable MMR.58 Importantly, their model predicts a transient increase in BCR-ABL1 transcripts shortly after dose reduction which decreases to baseline or lower, without a return to the original dose. Thus, the model suggests that clinicians should not reflexively increase the dose should the transcript level increase, but rather that they should continue to observe the patient closely.59 Indeed, this phenomenon was noted in some patients in the NiloRed trial mentioned above.54 Additional prospective, systematic studies of dose reduction would be welcomed in the future.
Future directions
An attempt at treatment discontinuation should be considered the standard of care for patients with CML who have a sustained DMR. Realistically, only 40-50% of newly diagnosed patients with CML will achieve this threshold, and only half of those (~20% of all patients) will achieve a successful TFR. These estimates are extrapolated from the results of clinical trials and may overstate the actual number of patients treated in general practice who may achieve the required depth and duration of response and be eligible for a trial of TKI discontinuation. Many unanswered questions remain. How can we better identify patients who will achieve DMR and TFR? Should these patients be considered “cured” of their disease and what are the mechanisms by which the disease is controlled/ eliminated? A better understanding of these mechanisms might suggest new approaches to prevent relapse. How can more patients achieve a DMR in order to consider a trial to achieve TFR? The limitations of the currently available TKI have been defined but a new inhibitor, ABL001, which inhibits signaling by blocking the myristoyl pocket of the enzyme,63,64 has recently been developed and combinations with traditional TKI will be conducted in the hopes of achieving deeper responses as the pathway to higher rates of TFR.
Nonetheless, when the extraordinary results using imatinib first became available, there was little expectation that the responses would be so durable and that it might eventually be possible to avoid lifetime treatment. CML investigators should be proud of these remarkable accomplishments.