BCR–ABL1 transcript doubling time as a predictor for treatment‐free remission failure after imatinib discontinuation in chronic myeloid leukaemia in chronic phase

Abstract

Summary The doubling time (DT) of the BCR–ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re‐growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR–ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high‐risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse‐free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate‐risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low‐risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high‐risk patients for treatment‐free remission failure with an imminent risk of molecular recurrence, and to define low‐risk patients who can be spared the frequent monitoring of monthly molecular tests.

Optimal timing of molecular monitoring after tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia

“…A recent paper from a Canadian group showed that a shorter BCR::ABL1 doubling time (DT), defined as 12.75 days at 2 months (DT at 1 month was not statistically significative) was associated with higher rate of TFR failure in a cohort of 131 CML patients treated with imatinib. 6 This data seems to reflect a faster kinetic of CML relapse after TKI discontinuation, as has been found already in 2012 by Branford et al in patients losing response during imatinib therapy, 7 and is in line with our finding of a significant raise in BCR::ABL1 transcript a 1 and 2 months after TKI stop.…”

Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis

“…Our observation that TFR failure occurs mainly within one year, but a few patients still experience distant relapse, albeit slow onset [24,45,46] , suggests that there is an urgent need for a cost-effective and user-friendly method for monitoring molecular response after discontinuation, as well as for more accurate predictors. Dennis Dong Hwan Kim's results suggest that BCR-ABL1 transcriptional doubling time can be used as a predictor of TFR failure in CML-CP patients after imatinib discontinuation, potentially avoiding the need for frequent monthly monitoring of molecular assays [53] .…”

Final report of TKI discontinuation trial with dasatinib for the second attempt of treatment‐free remission after failing the first attempt with imatinib: Treatment‐free Remission Accomplished by Dasatinib (TRAD) study

“…For the DT grouping after IM discontinuation, we have applied 12.75 days at 2 months as a cutoff to determine the risk group based on a previous report demonstrating a DT value of 12.75 at 2 months as the optimal cutoff defining the high-risk group for TFR failure. 40 The Cox proportional hazard ratio model was applied using mRFS following DA discontinuation as its endpoint. The final model for multivariable analysis was constructed using a stepwise selection procedure.…”