TKIs and Molecular Response in CML: the EURO-SKI Study

On the second day of the 56th Annual Meeting of the American Society of Hematology (ASH), held December 6-9 in San Francisco, several European research groups discussed findings from trials conducted in patients suffering from chronic myelogenous leukemia (CML) to prevent disease progression to advanced stages. The session was called “Chronic myeloid leukemia: outcomes with TKI therapy.”

Francois-Xavier Mahon, MD, PhD, Bordeaux Hospital, INSERM 1035, Bordeaux, France, shared the results from the European Leukemia Net Stop TKI (EURO-SKI) study during the session; the trial used tyrosine kinase inhibitors (TKIs) in CML to define prognostic markers to increase the rate of patients in durable deep molecular response (MR) after stopping TKI. The study, according to Mahon, also aimed to evaluate harmonized methods of molecular monitoring, assess patient quality of life, and calculate saved treatment costs per country.

The study deemed adult CML patients in chronic phase CML on TKI treatment in confirmed deep MR (MR4, BCR-ABL <0.01%) for at least 1 year and under TKI treatment for at least 3 years, as eligible. Primary endpoint of the trial was the assessment of the duration of MR (defined by continuous MMR) after stopping TKI.

Mahon showed that 648 patients from 11 countries were enrolled and included in the trial. Of the eligible 200 pts, 41.5% were female. Median age at diagnosis was 53.3 years. In assessable patients, 8.7% and 18.2 % were high-risk according to EUTOS and Sokal Scores. One hundred and three patients were treated prior to initiating TKI therapy, mostly with hydroxyurea or interferon. First-line TKI was imatinib in 97% of patients, dasatinib in 1.5% of patients, and nilotinib in 1.5% of patients. Twenty-four patients switched to second-line TKI therapy due to intolerance, 16 to dasatinib, 2 to imatinib, and 6 to nilotinib. TKI treatment duration was less than 5 years in 16%, 5 to 8 years in 36% and more than 8 years in 48% of patients. Median duration of TKI treatment was 8 years and median duration of MR⁴ before TKI cessation was 5.4 years. MR4 duration was less than 2 years in 8%, 2 to 5 years in 37%, 5 to 8 years in 39% and more than 8 years in 16% of patients.

Of the 200 patients, disease recurrence was observed in 77 patients within 6 months and 12 patients showed recurrence after 6 months. Of the 89 patients who lost MMR, 76 regained MMR and 70 returned to MR⁴, said Mahon. Their analysis showed that longer duration with TKI and a longer MR⁴ were inversely proportional to the relapses observed. Of the patients treated with TKI for less than 8 years, 47% showed relapse, while in patients who received a TKI for greater than 8 years, only 27% showed a relapse. Similarly, for MR⁴ less than 5 years, 45% of patients showed a relapse, while for MR⁴ greater than 5 years, only 30% of patients presented with a disease relapse.

However, “No significant difference was observed for relapse within 6 months based on depth of molecular response at discontinuation (MR⁴ vs MR^4.5 vs MR⁵),” said Mahon. He clarified though that the molecular data from this study is still under evaluation.

Providing a cost analysis, Mahon suggested that accounting for the price of imatinib in various European countries and the number of days when imatinib treatment was not administered, the total savings could be about €7 million or greater. “However, further studies to accurately assess the pharmacoeconomic impact of TKIs would be necessary,” said Mahon.

He concluded that employing standardized molecular testing for patient selection within a TKI cessation trial in CML would improve the possibility of staying in treatment-free remission. The EURO-SKI trial, he said, will further elucidate the prognostic impact of the duration of TKI therapy before cessation.