EHA 2016
Stopping tyrosine kinase inhibitors in CML
Dr Johan Richter - Lund University, Sweden
I’m presenting on behalf of the EURO-SKI collaborators and EURO-SKI is Europe Stop Tyrosine Kinase Inhibitors in chronic myeloid leukaemia. The title, as you see here and this will be presented this afternoon in the Presidential Symposium, is ‘Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukaemia patients: results of the EURO-SKI trial.’ The background is that the introduction of imatinib, the first tyrosine kinase inhibitor has substantially improved survival in patients with chronic myeloid leukaemia in chronic phase. This was around right after the year 2000. TKI therapy has then in clinical practice been instituted in most patients but it has mostly been considered lifelong. However, there are some small clinical trials that have previously shown that imatinib can be stopped in sustained deep molecular response. Between 40-60% of these patients maintain the molecular response even after stopping.
So, the purpose of the current trial was to determine the proportion of patients remaining in molecular remission after stopping TKI therapy in the larger setting, in a larger decentralised setting, and also to determine the predictive factors that will be able for you to determine beforehand how long a patient should be treated and also how successful a discontinuation attempt will be in the individual patient.
In total 868 patients were registered in this trial in eleven European countries. They were chronic myeloid leukaemia patients in chronic phase and as a prerequisite before entering the trial they had to have had at least three years of TKI therapy and also have been in deep molecular remission, what we call MR4, corresponding to 0.01% BCR-ABL copies on the international scale. They had to be in MR4 for at least one year prior to study entry. Only patients who had not failed on any TKI therapy were included so not patients that had been on multiple lines of therapy.
This shows you the outline of the study and up here you see once again, to the left, TKI treatment for at least three years and MR4, a very good therapy response, for one year. Then they entered a screening phase after signing informed consent where MR4 was validated in one of six central labs. If this could be done, MR4 verified, therapy was then stopped and the patients followed every four weeks for six months, every six weeks thereafter. Then from year two or three they were followed every three months. If they had at any of these times during this follow up a relapse, defined as a loss of MMR, then they were restarted on therapy.
The results are that with a median follow up of ten months 62% of the patients still were in deep molecular remission after six months of therapy. At twelve months this number was 56%. We tried to correlate this to gender, age or risk score but neither one of those factors showed a significant association with the success of stopping of TKI therapy. However, longer duration of TKI therapy and longer duration of molecular response, MR4, prior to TKI stop correlated to a higher probability of successful stopping. The cut-off, we have identified a cut-off suitable for imatinib therapy, that is around six years. So with a minimal p-value approach about six years of therapy would be optimal for therapy prior to performing a stop attempt.
The conclusions are with inclusion and relapsed criteria less strict than in many previous TKI cessation trials and with decentralised but standardised disease monitoring, stopping TKI therapy in a large cohort of CML patients with a very good therapy response was feasible and safe. The impact on the quality of life for patients and the savings in treatment costs for the European healthcare systems will be analysed in more detail
