The EURO-SKI (European Stop Tyrosine Kinase Inhibitor [TKI]) study was established to define prognostic markers that increase probability of durable deep molecular response after stopping TKI therapy.1 This study will also help clinicians learn the optimal duration of both TKI treatment and molecular response ≥4 log (MR4) for patients with chronic phase (CP) chronic myeloid leukemia (CML).
EURO-SKI enrolled adult patients with CP CML on TKI treatment for at least 3 years and in MR4 for at least 1 year. Confirmation of MR4 was based on 3 consecutive polymerase chain reaction results during the 12 months prior to inclusion. Final confirmation was performed in a EUTOS standardized laboratory. Patients with a prior TKI failure were excluded.
The primary end point of the study was molecular relapse-free survival (RFS) after stopping TKI defined as survival without loss of major molecular remission (MMR) at 1 time point. Data presented include results for all patients with a minimum follow-up of 6 months. Another assessment after 3 years’ follow-up is planned.
From June 2012 to December 2014, 868 patients in CP CML from 11 countries were enrolled. Of the 760 eligible patients, 52% were male. Median age at diagnosis was 52 years (range, 11-86 years); median age at TKI stop was 60 years (range, 20-90 years). Median duration of TKI therapy was 7.6 years (range, 3-14 years). Median duration of MR4 before stop was 4.7 years (range, 1-13 years). Patients were most often pretreated with hydroxyurea prior to TKI therapy. First-line TKI therapy was imatinib (94%), nilotinib (5%), and dasatinib (2%). Patients who switched to a second TKI due to intolerance received dasatinib (51%), nilotinib (42%), and imatinib (7%).
A total of 750 patients were assessable for estimation of molecular RFS. Of these patients, 46% lost MMR, 1% died in remission, and 53% are still in MMR at last follow-up (range, 1-36 months; median, 10 months). This resulted in a molecular RFS of 62% (95% confidence interval [CI], 59%-67%) at 6 months, 56% (CI, 52%-59%) at 12 months, and 52% (CI, 48%-56%) at 24 months.
Univariate analyses in 448 patients with complete records confirmed a statistically significant influence for duration of TKI treatment and duration of MR4 on molecular RFS up to 6 months, as well as MMR status. Each additional year of imatinib therapy increased the odds of staying in MMR at 6 months by 16%. Each additional year in MR4 before TKI stop increased the odds of staying in MMR at 6 months by 16%. Neither sex nor variables included in the Sokal and EUTOS was significantly associated with MMR status at 6 months.
On the basis of available data from this ongoing study, longer duration of imatinib therapy prior to stop correlates with a higher probability of RFS. These data from EURO-SKI currently suggest that the optimal time frame of TKI use appears to be 5.8 years, but Dr Richter suggested individualized decision-making for clinicians and patients considering TKI stop.
