In 1998, patients diagnosed with chronic myeloid leukemia (CML) had only about a 30% chance of surviving for 5 or more years – unless, that is, they were enrolled in the early clinical trials of imatinib (Gleevec), the first monoclonal antibody targeted against a tyrosine kinase.

Now, though, imatinib and its successor tyrosine kinase inhibitors (TKIs) are mainstays of treatment for CML and other hematologic and soft-tissue malignancies. A multicenter study published in 2011 looking at clinical outcomes among patients with CML treated with imatinib showed that among those who remained in complete cytologic remission 2 years after starting on the drug, survival was not statistically different from that of the general population.

More recently, investigators in the EURO-SKI (European Stop Tyrosine Kinase Inhibitor) study showed that while many patients with CML are maintained on TKIs indefinitely, it may be safe for some to stop or interrupt therapy with little fear of relapse or refractory disease recurrence if relapse does occur.

At the European Hematology Association 2016 annual congress, in Copenhagen, Denmark, Johan Richter, MD, PhD, professor in the division of molecular medicine and gene therapy at Lund University in Sweden, reported during the presidential session that among 750 patients with CML treated with a TKI who had been in remission for at least 1 year, nearly two-thirds (62%) of patients were able to maintain a treatment response 6 months after stopping the drug, and 56% retained responses 1 year after stopping TKI therapy.

The evidence suggests that patients with CML in deep molecular remission (MR4.0 or better according to European LeukemiaNet molecular response criteria) may be good candidates for interrupting TKI therapy, Richter said.

EURO-SKI Details

EURO-SKI investigators enrolled 868 adults with chronic-phase CML at 61 sites in 11 countries. The patients were required to have had at least 3 years of TKI therapy and to have been in deep molecular remission for at least 1 year before study entry. Patients for whom TKI therapy had previously failed were not eligible for the study.

A total of 750 patients had sufficient follow-up data — defined as a minimum of 6 months — for the analysis presented at the meeting. Of this group, 94% had been treated with imatinib as first-line therapy, 4% had received first-line nilotinib (Tasigna), and 2% had received first-line dasatinib (Sprycel). In total, 115 patients had switched to a second-line agent due to not being able to tolerate the first-line drug — 58 from intolerance to dasatinib, seven from intolerance to imatinib, and 49 for intolerance to nilotinib (data on one patient switched to another agent were missing).

The median duration of deep molecular remission before stopping a TKI was 4.7 years. The median time from diagnosis was 7.7 years, and the median duration of therapy was 7.6 years.

For the primary endpoint of molecular relapse-free survival, 62% of patients remained in remission for at least 6 months after stopping the TKI, 56% remained in remission at 12 months, 52% remained at 24 months, and 49% were still in deep molecular remission at 36 months.

The median time to restarting therapy for patients who resumed taking their TKI was 4.1 months.

Prognostic Factors Examined

Neither age, gender, depth of molecular response, nor standard CML risk scores were associated with remission status after stopping imatinib.

To determine a cutoff point beyond which it may be safe to stop a TKI, the investigators used a minimal P-value approach, and found a cutoff of approximately 6 years of imatinib therapy. This cutoff was based on a molecular relapse-free survival at 6 months of 65.5% for patients who remained on imatinib for more than 5.8 years, versus 42.6% for those who had been on imatinib for 5.8 years or less.

As of the most recent follow-up, more than 80% of patients who had a loss of their deep molecular remissions after stopping a TKI regained remission after re-starting therapy, Richter reported, and patients who were sensitive to TKIs retained their sensitivity after stopping and restarting therapy.