New CML Data Post Signs on Route to Treatment-Free Remission

Theodore Bosworth


February 10, 2017

The Trajectory of Response

MMR at 12 months is a milestone toward the ultimate goal of DMR, which may take years. Dr Branford cited one study in which the median time to MR4 after MMR was 3 years and the median time to MR4.5 was 5 years. DMR is important not only because it provides a barrier to the clonal evolution that is fundamental to disease progression, but also because it appears to be a prerequisite for treatment-free remission—which, in at least some cases, may signify cure of CML.

However, with current techniques of measuring BCR-ABL1 transcript levels, DMR remains a relative rather than absolute value. In the stop-therapy trials, a substantial proportion of patients in DMR relapse. According to Dr Branford, it is unknown whether there is a BCR-ABL1 transcript level below which patients are protected from relapse or whether other factors, such as relative immune function, also determine which patients in DMR who discontinue therapy will remain in remission and which will experience relapse. So far, the treatment cessation studies indicate that a longer period in DMR status provides greater relative protection against relapse when treatment is discontinued, but there are exceptions.

In new data from the European Stop TKI (EURO-SKI) trial presented at the 2016 ASH meeting, the overall molecular recurrence-free survival (MRFS) in more than 700 patients with CML who discontinued the TKI imatinib after a sustained period in DMR was 62%.[1] However, MRFS fell to 42.6% among those in DMR for 5.8 years or less. This was significantly different (P < .001) from the 65.5% MRFS rate among those treated for more than 5.8 years. Other studies have demonstrated a similar correlation between longer DMR and reduced risk for relapse. In EURO-SKI, each additional year of DMR was associated with a 16% increase in the likelihood of relapse-free survival.

However, data generated from other studies, including one presented at the 2016 ASH meeting,[2] suggest that there may be no period of treatment associated with absolute protection from relapse. In a study in which 87 patients discontinued nilotinib therapy after at least 2 years in MR4.5, 53 patents (58.9%) were MRFS after 1.3 years of follow-up—but in this study, there was no correlation between MRFS and duration of MR4.5 before treatment discontinuation. One of the patients who experienced relapse had been in MR4.5 for 10 years before TKI discontinuation.

In another study, patients with CML in DMR were enrolled in a cessation study that involved 2 years of dasatinib consolidation.[3] Dasatinib is a second-generation TKI that is considered more potent than the first-generation imatinib and was selected with the expectation that it could provide a deeper DMR. Of the 54 patients who remained in DMR for 2 years and discontinued dasatinib, 34 (62%) remained molecular recurrence–free after a median of 16.2 months of follow-up. As established in the study protocol, all patients who had relapse were restarted on dasatinib, and all regained DMR. Lymphocyte profile analysis suggested that specific patterns at the end of consolidation predicted a greater likelihood of remaining molecular recurrence–free, but these were considered preliminary findings to be explored in larger studies.

The differences in immune reconstitution suggested by the dasatinib discontinuation study support the hypothesis that factors other than the depth and duration of DMR influence the likelihood of MRFS. The fact that enhanced-sensitivity PCR analyses have not so far provided any increased discriminating power for predicting sustained MRFS is relevant to this hypothesis.

In patients who experience relapse, clinical studies have repeatedly demonstrated that DMR is rapidly regained when TKIs are restarted. These studies have also demonstrated repeatedly that the risk for relapse is greatest within the first 6 months of TKI discontinuation. For patients who have remained in DMR for 12 months after treatment discontinuation, the rate of relapse has been low. Although restarting therapy generally restores DMR, Dr Branford emphasized that close monitoring of BCR-ABL1 transcript levels during the first year of discontinuation is critical. The accepted criterion for restarting TKI therapy is loss of MMR.

The follow-up of patients who have achieved MRFS remains limited, but the data so far encourage the conclusion that some substantial proportion of patients with sustained DMR on TKI can eventually discontinue TKI therapy without disease recurrence. On the basis of the data so far, the ability to achieve MRFS may depend on not only a sustained DMR over several years of treatment, but also a rapid initial response at the time treatment is initiated. Dr Branford suggested that there is now a broad consensus that milestones of early response should be pursued for this purpose.

Disclosure: Dr Branford reports financial relationships with Ariad, Bristol-Myers Squibb, Cepheid, Novartis, and Qiagen.


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