The much anticipated interim results from the EURO-SKI study of discontinuation of tyrosine kinase inhibitor therapy for patients with chronic myeloid leukaemia were recently published in the The Lancet Oncology.
The study enrolled more than 700 patients with sustained deep molecular response. It was predicted from previous clinical trials that sustained treatment-free remission would be achieved in a substantial proportion of patients. This was indeed the case. It is known that patients are at the greatest risk of molecular relapse in the first 6 months after stopping. The molecular relapse-free survival was 61% at 6 months after stopping therapy and 50% at 24 months.
The first trials of treatment discontinuation of the tyrosine kinase inhibitor imatinib had more stringent study entry criteria as well as stricter treatment restart rules. In the French STIM and the Australian TWISTER studies, patients were required to have undetectable BCR–ABL1 for at least 2 years using strict PCR sensitivity criteria. However, the time frame for maintaining deep molecular response and the depth of response were relaxed for the EURO-SKI study. Patients were only required to have one year of deep molecular response, defined as BCR–ABL1 values ≤0.01% on the international scale.
The less stringent study entry criteria were critical for establishing predictive factors for the success of treatment cessation. The factor with the largest effect was the length of deep molecular response before stopping therapy. An approximate 3% increase in the probability of maintaining treatment-free remission at 6 months was achieved with every additional year of deep molecular response. This finding will guide future cessation studies and impact clinician decisions as treatment-free remission moves into the mainstream of clinical practice.
The interim report did not investigate whether deeper molecular responses at the time of cessation were associated with higher rates of treatment-free remission. This is another variable that influences decisions for the timing of treatment cessation for individual patients and perhaps will be addressed in future EURO-SKI publications.
One of the most important aspects of this study in terms of moving treatment-free remission into clinical practice was the demonstration that molecular monitoring after treatment cessation does not need to be restricted to highly specialized laboratories. Fifteen different labs across Europe that were standardized to the international reporting scale performed the molecular analysis. This is in contrast to other studies where molecular monitoring occurred in one or a few specialized laboratories. If treatment-free remission is to be broadly available in the community, it is essential that general testing labs can appropriately monitor at the required sensitivity and that this level is clinically relevant. The EURO-SKI study has demonstrated that this is certainly achievable.
There are a number of immediate important benefits and lessons from this trial. Most important is the impact for the hundreds of patients who have maintained treatment-free remission. For the patients who relapsed, there were no serious adverse events reported, such as transformation to an acute leukaemia. For these patients, other trials are underway to identify the factors associated with the best chance of treatment-free remission in subsequent attempts. Of course, the cost saving of treatment-free remission is enormous, with an estimated € 22 million saved on drug cost in the EURO-SKI trial. All patients, clinicians and lab staff involved in the study are to be congratulated for their participation and success.