Comparison of Molecular Kinetics after the First and Second Imatinib Discontinuation: Results from the KID Study

Backgroud: Recent reports showing that imatinib (IM) discontinuation can be employed in patients who had enough IM therapy and undetectable molecular residual disease (UMRD) durations prior to IM discontinuation result in treatment-free remission (TFR) as a new therapeutic goal in chronic phase chronic myeloid leukemia (CP CML). Although 50-70% of patients experienced molecular relapse by several TFR studies, the most of patients resumed molecular responses (MR) following restart of IM. Through the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study), we have identified predictors for sustained UMRD and explored molecular kinetics after the first IM discontinuation. In patients regaining durable UMRD with IM resumption, we tried second IM discontinuation and compared molecular kinetics between the first IM stop and second IM stop.

Methods: CP CML patients who were treated with IM for more than 3 years and had undetectable levels of BCR-ABL1 transcripts determined by quantitative reverse transcriptase polymerase chain reaction (PCR) for at least 2 years were eligible for KID study and in cases of MMR loss after 2 consecutive assessments, IM treatment was re-introduced. After IM resumption for MMR loss, the molecular response was evaluated every month until MMR was re-achieved and every 3 months thereafter. The second stop was permitted in the patients who were in second UMRD for at least 2 years.

Results: By the data cut-off date of 31 July 2015, among 90 non-transplant UMRD patients with at least 12 months of follow-up, 37 patients lost MMR in 2 consecutive analyses and resumed IM. Among them, 9 patients (5 men and 4 women) with a median age of 54 years (range, 35-59 years) entered into a second IM discontinuation after maintaining UMRD at least 2 years. Prior to first discontinuation, the median duration of IM therapy was 76.8 months (range, 38.5-129.0 months) and the duration of sustained UMRD was 30.1 months (range, 24.4-64.5 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.9-20.8 months) and re-achieved UMRD at a median of 5.5 months (range, 1.8-9.4 months) after IM resumption.

After sustaining a second UMRD for a median of 25.7 months, IM therapy discontinued for a second time. After a median follow-up of 37.4 months (range, 19.7-58.5 months) after second IM discontinuation, 7/9 patients (78%) and 4/9 patients (44%) lost UMRD and MMR, respectively. Among three patients who lost UMRD but not MMR, one patient showed fluctuation of BCR-ABL1 transcript under the level of 0.1% on IS for 19.5 months and two patients has not yet been followed up after a first detection of UMRD loss. Four patients who experienced second relapse (MMR loss) after a median 2.9 months (range, 2.7-3.9 months), which was similar to those of the first IM discontinuation [median 3.75 (range, 1.9-3.9 months)]. The patients who lost MMR were retreated with IM for a median of 13.6 months (range, 0.8-18.6 months); three patients re-achieved MMR at 3.5, 5.5, and 11.5 months, respectively and one re-achieved UMRD at 7.2 months.

Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. But the molecular kinetics after second IM resumption needs longer follow-up with more patients. Further studies on the predictors to select patients for a trial of second TFR and novel strategies such as intermittent therapy will be warranted.