Stopping TKIs Proven Safe in Chronic Phase CML

Johan Richter, MD, PhD

Tyrosine kinase inhibitors (TKI) can safely be halted in select patients with chronic phase chronic myeloid leukemia (CML) following a maintained deep molecular remission, according to findings from the large EURO-SKI trial presented at the 2016 European Hematology Association (EHA) Congress.

After a median follow-up of 10 months, 62% of patients were still in major molecular remission (MMR) 6 months after TKI-stop, 56% were still in remission after 12 months, and 51% were still in remission after 24 months. Most patients in the trial were previously receiving the TKI imatinib (Gleevec).

Based on this, as well as previous trial data, researchers have determined an ideal time frame for physicians to consider stopping TKIs for patients with chronic phase CML, said Johan Richter, MD, PhD, the EURO-SKI investigator who presented the data at EHA.

“We have identified a cutoff suitable for stopping imatinib therapy, which is around 6 years,” said Richter, professor, division of Molecular Medicine and Gene Therapy at Lund University in Sweden. “With a minimal P value approach, about 6 years of therapy would be optimal therapy prior to incorporating a stop attempt. This is only done in patients who are first-line TKIs or second-line TKIs because of toxicities to first-line. There are no patients that have shown any resistance to TKIs before stopping and I think that is of importance.”

The study included 868 patients from 11 countries and 61 sites with chronic phase CML. After some patients were excluded or withdrew, 772 patients were eligible, including 46.6% who were female. Median age at diagnosis was 51.9 years (range, 11.2-85.5), and median age at stop was 60.3 years (range, 19.5-89.9). One patient decided not to stop therapy after inclusion.

Treatment with TKI-therapy was required for a minimum of 3 years prior to entering the study with a deep molecular remission (MR4) experienced for at least one year prior to entering study. MR4 was reached after a median time of 21 months.

Before going off TKIs, patients were screened for ≥6 weeks and had to give informed consent. If MR4 was validated, therapy was stopped and patients were monitored every four weeks for 6 months, followed by every 6 weeks until year 2 when they began to be followed every 3 months.

The time from a diagnosis of CML to first day of stopping TKI ranged from 36 to 270 months, with a median time of 92.7 months. Median duration of MR4 prior to TKI stop was 56.3 months (range, 12.6-159.8).

Ninety-four percent of patients in the trial had previously received imatinib. Four percent had received nilotinib (Tasigna) and 2% had received dasatinib (Sprycel) prior to the trial.

After a median follow-up of 10 months, 331 of the 717 patients with assessable molecular data, lost MMR, 4 died in remission, and 381 are still in MMR at last follow-up (range, 1-36 months). This resulted in 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).

Success was consistent across a variety of patient profiles, said Richter.

“We tried to correlate this to gender, age, or risk score but none showed significant association with success of stopping of TKI-therapy,” he said. “However, longer duration of TKI-therapy and longer duration of molecular response prior to TKI-stop correlated to a higher probability of successful stopping of TKI-therapy.”

Previously, most patients receiving TKIs maintained the treatment for the duration of their life. These findings suggest that this may not be necessary for all patients, said Richter. While smaller clinical trials have previously shown that imatinib can be stopped in sustained deep molecular response, the EURO-SKI trial was the first to show success on a large scale.

“With inclusion and relapse criteria less strict than in many previous TKI cessation trials, and with decentralized but standardized disease-monitoring, stopping of TKI therapy in a large cohort of CML-patients with very good therapy response was feasible and safe,” said Richter.

Stopping TKIs, which do come with toxicities, may have a significant impact on quality of life for patients, said Richter. There may also be a financial benefit for patients, as well as the health care system as whole, although this will need to be analyzed in more detail, he said.

At this time, patients have only been followed for three years, so more follow-up is needed before anything can be said definitively. While more research is needed, the EURO-SKI trial has provided key information, says Richter.

“I don’t think we will ever reach zero chance of recurrence after stopping, but I do think we can now give better numbers and a better basis of information to our patients,” he said.

Richter J, Mahon F-X, 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. Presented at: 21st Congress of the European Hematology Association; Copenhagen, Denmark; June 9-12, 2016. Abstract S145.

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“If at any time they had a relapse, defined as loss of MMR, then they were restarted on therapy,” said Richter. “So far it has been shown that all patients that do relapse are again sensitive when they are put back on the TKI therapy. There is no real evidence for any escape of the disease in this setting.”