Survival for patients with chronic myeloid leukemia (CML) has improved dramatically with the use of tyrosine kinase inhibitors (TKIs), and a high percentage of these patients achieve deep molecular responses (MR). Several studies have demonstrated that TKI treatment can be successfully and safely stopped in a large number of patients with deep MR.
However, preconditions for discontinuing TKI therapy in patients with CML have not been established. The European Stop TKI (EURO-SKI) study sought to define prognostic markers that indicate deep MRI would be durable after stopping TKI therapy.
Study participants were adult patients with CML in chronic phase treated with TKIs for at least 3 years and in MR4 for at least 1 year. MR4 status was confirmed by 3 consecutive PCR results in the 12 months prior to inclusion in the study, with final confirmation of MR4 performed in a EUTOS standardized laboratory. Molecular relapse-free survival after stopping TKI therapy was defined as “survival without loss of major molecular remission (MMR) at one time point.”
From June 2012 to December 2014, 772 of 868 patients with CML in chronic phase (46.6% female) from 11 countries were eligible for the trial. Median age was 51.9 years at diagnosis and 60.3 years at TKI therapy stop. EUTOS identified 10% of patients as high-risk, and Sokal Score classified 18% of patients as high-risk.
Participants’ first-line treatment was imatinib (94%), dasatinib (2%), or nilotinib (4%). Due to intolerance, 115 patients switched to a second-line TKI: 58 switched to dasatinib, 7 to imatinib, and 49 to nilotinib. Information is missing for one patient.
Time from CML diagnosis to first day of discontinuing TKI was 36.7 months to 270.7 months (median, 92.7 months). Treatment duration was a median of 91 months (range, 36.3 to 170.3 months), and median MR4 duration prior to discontinuing TKI was 56.3 months (range, 12.6. to 159.8 months). Participants reached MR4 after a median 21.0 months (range, 3.0 to 140.0 months; only first-line patients).
Molecular data for estimation of molecular relapse-free survival was available for 717 patients. Median molecular follow-up is 10 months. Of these patients, MMR was lost in 331 patients, 4 patients died in remission, and at last follow-up, 381 patients remain in MMR (range 1 to 36 months).
These results illustrate a molecular relapse-free survival of 62% at 6 months (95% CI, 58% – 65%), 56% at 12 months (95% CI, 52% – 59%), and 51% at 24 months (95% CI, 47% – 55%). No significant association was seen between sex or any of the variables of the EUTOS and Sokal scores and MMR status at 6 months.
First univariate analyses demonstrate that duration of TKI treatment and MR4 prior to TKI therapy stop are prognostic variables for molecular relapse-free survival for up to 6 months. The EURO-SKI trial is expected to reveal additional prognostic factors for improved rates of durable MMR after TKI stop.
1. Richter J, Mahon FX, Guilhot J, et al. Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial. Presidential symposium at: EHA21; June 9-12, 2016; Copenhagen, Denmark. Abstract S145.