Results from the U.S. Life after Stopping TKIs (LAST) Study

Background: Several studies have demonstrated the safety of stopping tyrosine kinase inhibitors (TKIs) for patients with chronic myeloid leukemia (CML) with a sustained deep molecular response. The LAST study is an NIH-funded multi-institutional trial aiming to improve the evidence for clinical decision-making regarding TKI discontinuation in the United States.

Methods: LAST is a non-randomized, prospective, longitudinal study. The primary objectives of the study are to determine the proportion of patients who develop molecular recurrence after discontinuing TKIs and to compare patient-reported outcomes (PROs) before and after discontinuation. Molecular recurrence is defined as loss of MMR (> 0.1% BCR-ABL using the International Scale) once. Key inclusion criteria are age > 18, patient currently taking imatinib, dasatinib, nilotinib, or bosutinib, on TKI therapy for at least 3 years with a documented BCR-ABL transcript level < 0.01% by QR-PCR for at least 2 years per the patient's local lab, 2 screening PCRs with results BCR-ABL is < 0.01% in a central lab, and no previous TKI resistance. Patients with prior allogeneic stem cell transplantation are excluded. Monitoring is monthly for the first 6 months, then every 2 months for 18 months, then every 3 months until 36 months. In addition, blood samples for BCR-ABL transcript levels measured by digital PCR are collected at the same time points as for RQ-PCR.

Results: From December 2014 to December 2016, 208 patients were screened and 173 patients were enrolled from 14 sites in the US. The median age was 61 (range, 50-68) and 90 (52%) were females. Median duration of TKI prior to enrollment was 79 months (range, 51-117). At the time of enrollment, 60%, 23%, 15%, and 2% were on imatinib, nilotinib, dasatinib, and bosutinib respectively. With a median follow up of 12.3 months (range, 0.9-27) and a minimum follow up of 6 months for all patients remaining on study, 115 (66%) patients remain in a treatment-free remission (TFR). Of the 58 who restarted TKI, 46 patients restarted based on loss of MMR by central lab, and 12 restarted by patient choice. Of the 46 patients who restarted drug based on loss of MMR by central lab, 38 (82%) again achieved MMR by central lab, 3 withdrew consent before confirmation of MMR, 4 patients have had less than 6 months follow up, and one patient died (from causes unrelated to CML) before confirmation of MMR. PROs will be reported separately. Of note, 3 patients restarted TKI because of withdrawal syndrome. The proportion of patients who remained in TFR at 6 and 12 months is 73% (127/173) and 60% (76/127) respectively.

Conclusion: Our results add to the evidence that stopping TKIs in a select group of patients is safe and feasible with close monitoring. Updated results will be presented at the meeting.