A new goal in treating CML is treatment-free remission (TFR). What this means is that CML is so deeply suppressed with treatment that the person is able to stop the medication altogether and the leukemia doesn’t return. The physical advantages of TFR will be obvious to anyone taking one of the TKIs (tyrosine kinase inhibitors) to control their CML: no need to remember to take the medication every day; and no troublesome side effects with which to cope. The psychological benefits are likely more profound: TFR isn’t necessarily a cure, but it’s the next best thing. Whatever residual leukemia there is remains undetectable, so for all intents and purposes you are living leukemia-free.
How achievable is TFR?
The first hurdle is to meet the criteria to be considered for a TFR trial (stopping treatment on your own is never recommended – it must be done in the rigorous conditions of a study). The optimal criteria haven’t yet been established, but typically they require that you achieve a deep molecular response and sustain it for about two years.
A deep molecular response is usually a 4.5-log reduction or better. This is an indication of the “signal strength” that drives the proliferation of white blood cells that is the key feature of CML. The CML gene produces proteins that act as signals for blood cells to divide, and to keep on dividing. Log reductions refer to where the decimal is placed: a 1-log shifts 100% to 10%, a 2-log to 1%, a 3-log to 0.1% (i.e. one one-thousandth of what the signal strength used to be), and so on. So a 4.5-log reduction means that the signal is so faint that leukemia may no longer be a problem. Beyond 5-log, the signal can’t be reliably detected even with the highest-tech CSI-style testing.
Most people can achieve a 4.5-log reduction if they keep taking their medication every day, but this can take many years. For example, in the German CML-study IV, the cumulative rate of achieving a 4.5-log reduction was 54% for people taking Gleevec – but this was over a 9-year period (Hehlmann and colleagues. J Clin Oncol 2014;32:415-423). This level of disease suppression wasn’t merely a fast-track to stopping therapy. It had its own merits. Those who achieved a deep molecular response lived longer compared to those with a 2- or 3-log reduction (92% survival at 8 years compared to 83%).
Nine years is a long time to wait, but the time can be considerably shortened with one of the second-generation medications. For example, in the ENESTnd trial, a majority of people achieved a 4.5-log reduction within five years when they started treatment with Tasigna (53% vs. 31% with Gleevec) (Saglio and colleagues. N Engl J Med 2010;362:2251-2259). Similarly, in the DASISION trial, 42% of people starting on Sprycel achieved a 4.5-log reduction compared to 33% of people taking Gleevec (Cortes and colleagues. Blood 2014;124:152).
How well do people do after stopping treatment? A few studies have looked at this question now. In the TWISTER study, 47% of people had a stable TFR after two years off treatment (Ross and colleagues. Blood 2013;122:515-522). Leukemia cells were detectable in some, but their illness wasn’t progressing so they were able to stay off therapy. About 30% continued to have undetectable disease (Ross & Hughes. Br J Haematol 2014;166:3-11).
More recently, a small study followed people who stopped treatment after having undetectable leukemia for a least one year (Yhim and colleagues. Acta Haematol 2015; epublished November 5, 2015). The duration of undetectable disease was rather short (2 years if more common), but about 1 in 4 remained in TFR after five years.
So a good proportion of people who try stopping therapy will be able to stay off their medication for the foreseeable future. Those who stop but then have a relapse can regain control of their CML if they re-start a medication right away. Relapses – if they occur – typically happen within the first 6-9 months of stopping. This is why it’s so important to stop treatment in a clinical trial. You will need to be monitored closely to ensure that your CML remains under control, and to re-start treatment promptly if you suffer a relapse.