Milan, Italy—More than 60% of patients with chronic myeloid leukemia (CML) were free of relapse 6 months after stopping tyrosine kinase inhibitor (TKI) therapy that led to deep molecular remission, according to the interim results from an ongoing trial reported by Susanne Saussele, MD, of Universitätsmedizin Mannheim, Germany, at the 2014 European Hematology Association meeting.
A majority of the 200 patients from 47 European centers remained relapse free at 12 months. The 6-month data allowed investigators to reject the null hypothesis of a relapse-free survival (RFS) rate of 40% (P <.001) and to continue enrollment to an accrual goal of 700 patients.
The results also showed that the depth of molecular response (MR) achieved before the withdrawal of TKIs affects RFS.
“With less strict inclusion and relapse criteria than was used in [previous trials], stopping is safe, and we can continue with the trial,” said Dr Saussele.
These results are consistent with previous studies, showing that select patients with CML can stop long-term TKI therapy after achieving deep MR, she added. TKI therapy has improved the survival of patients with CML, and more patients achieve durable deep MRs (ie, MR4).
The effectiveness of TKIs has given patients and clinicians a reasonable expectancy of improved survival and cure, said Dr Saussele. A critical first step toward cure is to increase the proportion of patients who achieve durable deep molecular remission after the withdrawal of treatment.
Previous studies showed that 40% to 65% of patients maintained deep MR for up to 36 months after TKI therapy discontinuation. However, the trials used stringent definitions of deep remission. In addition, some of the trials had a relatively small sample size.
Other key objectives of the study were to determine the minimal duration of TKI therapy required before withdrawal, the minimal duration of MR4 before stopping, and prognostic factors for RFS.
Eligible patients had completed at least 3 years of TKI therapy and had maintained MR4 for at least 1 year. Patients with previous or planned allogeneic stem-cell transplantation because of TKI therapy failure were excluded. After a screening phase to confirm MR4, patients stopped the TKI therapy and began follow-up for 3 years. They had MR status evaluated by polymerase chain reaction every 4 to 6 weeks during the first year after discontinuation and then every 3 months.
The trial’s primary end point is duration of deep molecular remission after stopping TKI therapy (defined by the loss of major MR). The null hypothesis is a molecular RFS of 40% at 6 months.
The median duration of TKI therapy was approximately 8 years, and the duration of MR4 before discontinuation was 5 years. All but 6 patients received imatinib as first-line TKI therapy. Of the 24 patients who received second-line TKI therapy, dasatinib was the choice in 16 cases.
Overall, 86 patients relapsed, including 77 patients in the first 6 months after stopping TKI therapy. Subsequently, 13 patients who relapsed regained MR4 status.
RFS was 87% at 3 months, 61% at 6 months, 58% at 9 months, and 55% at 12 months.
Of 197 evaluable patients, 74 attained MR4, 79 attained MR4.5, and 44 attained MR5. Subsequently, 37 patients in MR4 relapsed, as did 31 in MR4.5, and 17 in MR5.
“In the setting of standardized molecular testing within a stopping trial in CML, it seems that the level of molecular remission has an impact on relapse-free survival,” said Dr Saussele.
A total of 57 adverse events (all grades) occurred in 31 patients, including 3 patients who had a total of 9 grade 3/4 adverse events.
