PF410 DOUBLING TIME AFTER FIRST ATTEMPT OF IMATINIB DISCONTINUATION IS HELPFUL TO IDENTIFY THE BEST CANDIDATE FOR THE SECOND ATTEMPT FOR TREATMENT-FREE REMISSION WITH DASATINIB: CANADIAN TRAD TRIAL

Abstract

Background: Canadian tyrosine kinase inhibitor (TKI) discontinuation trial is currently ongoing to answer the question if a 2nd generation TKI (2G-TKI), i.e. dasatinib (DA), should be used for retreatment for 2nd attempt of treatment-free remission (TFR2) after failing the first TFR attempt (TFR1) with imatinib (IM) discontinuation. Aims: In our previous report (ASH 2018), the estimated TFR2 rate was 21.5% at 6 months. Also, rapid relapsing pattern after IM discontinuation correlated with a higher failure after DA discontinuation. It prompted us to revisit evaluating the correlation of doubling time (DT) after TFR1 attempt with TFR2 rate. Methods: This prospective clinical trial (BMS CA180–543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. DA 100 mg once daily was started if loss of molecular response is confirmed. DA is discontinued 12 months after achieving > MR4 for a 2nd TFR attempt. The study was designed to reject our null hypothesis if > 28% of pts (15 out of 54 pts) remain in TFR2 after DA discontinuation. Doubling time (DT) has been calculated based on the BCR-ABL1 qPCR value taken monthly in the first 6 months after IM discontinuation. The baseline qPCR level prior to IM discontinuation was referenced. We decided to apply DT measured at 2 months after TFR1 attempt for further analysis based on the previous result (EHA 2018). Results: As of Feb 21, 2019, 42 (32.%) of 131 pts are still ongoing. Of the 57 pts who lost molecular response after TFR1 attempt, 55 pts (96%) received DA and reachieved molecular response. 28/55 pts (51%) receiving DA attained MR4.5 for 12 months or longer, and discontinued it for TFR2. 21/28 (75%) of these pts lost molecular response at 3.7 months after TFR2 attempt. TFR2 rate was 20.2% at 6 months (7.4–37.5%), thus not allowing to reject our null hypothesis. 7 pts are still on DA discontinuation phase without losing molecular response (range 27–607 days). In the risk factor analyses for TFR2, following variables were analyzed but did not show any association with TFR2: Sokal risk score (p = 0.599), total IM duration prior to TFR1 attempt (p = 0.09), MR4 duration with IM (p = 0.866), or time to MR4 achievement with IM (p = 0.09).However, shorter time to molecular relapse after TFR1 attempt (p = 0.001, HR 0.523 per month, [0.350–0.782]) and rapid molecular relapse after TFR1 attempt (HR 4.003 for MMR loss, [1.397–11.48]) were confirmed to correlate with TFR2 failure. Next, we have evaluated the DT at 2 months after TFR1 attempt. In the group with DT ≤zero (n = 7), TFR2 rate was 50.0% at 6 months. It was 16.7% in those with DT ≥ 14 days (n = 7), while it was 7.9% in those with DT <14 days (n = 15; p = 0.04). TFR2 rate at 6 months was significantly higher at 33.3% in low risk (i.e. those with DT ≤zero or ≥ 14 days, n = 14) vs 7.9% in the high risk (i.e. those with DT<14 days, n = 15; p = 0.01, HR 2.902, [1.199–7.026]). The TFR2 rate in the low risk group (i.e. 33.3%) is above our pre-determined criteria to reject our null hypothesis (i.e. 28%), suggesting that this group can be a good candidate for TFR2 attempt. Summary/Conclusion: 1) Our result suggests that switch to 2G-TKI after failing TFR1 attempt may not improve TFR2 rate. 2) However, seeing a DT at 2 months after TFR1 attempt seems helpful to identify the subgroup having more benefit from the switch to 2G-TKI for TFR2 attempt.