FIRST INTERIM ANALYSIS OF A PAN-EUROPEAN STOP TRIAL USING STANDARDIZED MOLECULAR CRITERIA: RESULTS OF THE EURO-SKI TRIAL

LB-6214

Background: The advent of tyrosine kinase inhibitors (TKI) has substantially improved survival of chronic myeloid leukemia (CML) with a high percentage of patients reaching deep molecular responses (MR; Hehlmann JCO 2014). There is a reasonable expectancy not only to further improve survival but to cure the disease. An important step to cure CML is to increase the rate of patients in durable deep MR (MR4 or deeper) after withdrawal of TKI. In several studies, it have been shown that in a substantial proportion of patients with deep MR, treatment can be safely and successfully stopped (Mahon 2010, Ross 2013).

Aims: The EURO-SKI study (European stop TKI study) was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims are the evaluation of harmonized methods of molecular monitoring, assessment of quality of life, and calculation of saved treatment costs per country.

Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed MR for at least one year (>4 log reduction on TKI therapy for >12 months confirmed by three consecutive PCR results) and under TKI treatment for at least 3 years were eligible. Final MR4 confirmation had to be performed in a standardized laboratory (n=6) according to the definition by Cross et al. (Leukemia 2012). Primary endpoint is the assessment of the duration of deep MR (defined by loss of MMR) after stopping TKI. Patients with previous or planned allogeneic stem cell transplantation or after a prior TKI failure were excluded. According to protocol, an interim analysis was planned after 200 patients with eligible molecular results at month 6 were available to test the null hypothesis that relapse-free survival at 6 months is less or equal 40%.

Results: From June 2012 to July 2013, 254 patients in chronic phase from 8 countries were registered. 54 were excluded (consent withdrawal n=1, protocol violation n=1, not eligible n=34, restart of TKI without relapse n=4, atypical or unknown transcript n=6, missing data n=8). Of the eligible 200 patients, 41.5% were female. Median age at diagnosis was 53.3 years (range 13.8 to 85.5). In assessable patients with spleen size recording 8.7%, 18.2 % and 0%  were high-risk according to EUTOS, Sokal and EURO-Score, respectively. 103 patients were pretreated prior to TKI therapy, mostly with hydroxyurea and/or interferon. First-line TKI was imatinib in 97%, dasatinib in 1.5% and nilotinib in 1.5% of the patients. Twenty-four patients switched to second-line TKI due to intolerance, 16 to dasatinib, 2 to imatinib, and 6 to nilotinib. Time from diagnosis of CML to first day of stopping TKI varied from 34.4 months to 232.9 months, median time was 95.4 months. Median duration of TKI treatment was 94.8 months (range 34.2 to 150.6 months) and median duration of MR4 before stopping TKI was 65.1 months ( range 11.1 to 140.7 months). For all patients MR4 could be confirmed through a MR4-standardized laboratory. Nineteen patients with detectable transcripts were in MR 4 (9.5%), 37 patients in MR4.5 (18.5%) and 18 in MR5 (9.0 %), respectively.  123 patients had undetectable transcripts, of them 49 patients were in MR4 (24.5%), 48 in MR4.5 (24%) and 25 in MR5 (12.5%); exact classification of 3 patients with confirmed MR4 is pending.

A pre-planned interim hypothesis testing was performed. Since 123 of the 200 patients (61.5%, 95% confidence interval: [54.4%; 68.3%]) remained without relapse the first 6 months, the null hypothesis could be discarded (p < 0.0001).

Summary/Conclusion: As compared to the "A-STIM" study (Rousselot et al. JCO 2014) this first European Leukemianet stop trial in CML confirms that loss of MMR can be used as a criterion for restarting therapy. In addition, it improves the chance to stay in treatment-free remission in the setting of standardized molecular testing. The EURO-SKI trial will further elucidate prognostic factors which allow a better selection of patients to improve the rate of durable deep MR after withdrawal of TKI.

Keywords: Chronic myeloid leukemia, Standardization, Treatment, Tyrosine kinase inhibitor

http://www.ehaweb.org/