MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.
Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.
The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).
"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.
Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.
Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR4 relapsed, compared with 39% in MR4.5 and 39% in MR5.
"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.
As no statistical test was performed and this was an interim analysis, MR4.5 or MR5 cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.
The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).
Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.
A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR4 before stopping, and which prognostic factors influence molecular relapse-free survival, she said.
EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.
Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.
MR4 status also had to be confirmed in an MR4-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)
Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.
A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.
First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.
The median duration of TKI therapy was 8 years and median MR4 duration before stopping TKI therapy was 5 years.
Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.
A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.
The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.
Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.
The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.
Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.