Rapid reduction in BCR‐ABL1 transcript predicts deep molecular response in dasatinib‐treated chronic‐phase chronic myeloid leukaemia patients

Abstract

Objectives We conducted a phase‐II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic‐phase chronic myeloid leukaemia (CML‐CP) in Japan (IMIDAS PART 2 study). Methods Seventy‐nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post‐treatment influences of various factors. The BCR‐ABL1 international scale (IS), halving time (HT) and reduction rate of BCR‐ABL1 transcript within the initial 1 or 3 months of therapy (RR‐BCR‐ABL11m,3m) were the post‐treatment factors investigated to predict the molecular response. Results The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non‐haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post‐treatment factors at 3 months predicted DMR by univariate analysis. However, RR‐BCR‐ABL13m was the only significant landmark for predicting DMR by multivariate analysis. Conclusions Primary treatment of CML‐CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR‐BCR‐ABL13m was found to be a more useful predictor of DMR than HT‐BCR‐ABL1 and BCR‐ABL1 IS.

Leukemia: Reduction Ratio and Halving Time of BCR: : ABL1 IS Transcript Levels

“…Although various TKI treatments are currently available, the early detection of patients who may require alternative treatments remains an important issue. Recent studies have reported that the rate of decline in the BCR::ABL1 IS transcript level may be a better predictor of treatment response [ 6 , 7 , 8 , 9 , 14 , 15 ].…”

“…The baseline level is important for the calculation of BCR::ABL1 kinetics, such as HT and RR at 3 months. A decrease in transcript levels observed before and after TKI treatment may be predictive of EMR and has been shown to have prognostic value in recent years [ 3 , 4 , 6 , 7 ]. Our study found that in patients with imatinib-treated CP-CML, the HT cut-off was 24 days and the RR cut-off was 0.04 for achieving MMR at 12 months.…”

“…This has led to a need for developing assessment methods that reflect individual differences in response to therapy. Thus, the halving time (HT) and reduction ratio (RR) of BCR::ABL1 IS transcript levels have recently received much attention as prognostic markers of imatinib response and outcome in patients with CML [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ].…”

Handling challenging questions in the management of chronic myeloid leukemia: when is it safe to stop tyrosine kinase inhibitors?

“…14,15 Furthermore, several studies found that EMR was an early predictor of DMR, regardless of first-line TKI type and CP-CML risk score. 14,15,18,19 In ENESTnd, cumulative incidences of MR4.5 by 5 years in patients with ,1%, between 1% and 10%, and .10% BCR-ABL1 IS at 3 months were 70%, 51.7%, and 8.3%, respectively, with nilotinib 300 mg twice daily and 67.4%, 33.8%, and 15.9%, respectively, with imatinib. 18 In a large singlecenter study, Sasaki et al 20 found that best fit average real time quantitative polymerase chain reaction values for sustained MR4.5 for $2 years at any time during first-line TKI treatment were 0.051% IS at 3 months, 0.019% IS at 6 months, 0.007% IS at 9 months, and 0.003% IS at 12 months.…”

Handling challenging questions in the management of chronic myeloid leukemia: when is it safe to stop tyrosine kinase inhibitors?

“…14,15 Furthermore, several studies found that EMR was an early predictor of DMR, regardless of first-line TKI type and CP-CML risk score. 14,15,18,19 In ENESTnd, cumulative incidences of MR4.5 by 5 years in patients with <1%, between 1% and 10%, and >10% BCR-ABL1 IS at 3 months were 70%, 51.7%, and 8.3%, respectively, with nilotinib 300 mg twice daily and 67.4%, 33.8%, and 15.9%, respectively, with imatinib. 18 In a large single-center study, Sasaki et al 20 found that best fit average real time quantitative polymerase chain reaction values for sustained MR4.5 for ≥2 years at any time during first-line TKI treatment were 0.051% IS at 3 months, 0.019% IS at 6 months, 0.007% IS at 9 months, and 0.003% IS at 12 months.…”