Velocity of Early BCR-ABL Transcript Elimination As an Optimized Predictor of Deep Molecular Response in Chronic Myeloid Leukemia Patients in Chronic Phase on Treatment with Dasatinib

Background: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study; UMIN000006358). Several groups reported that some of CML patients who achieved stable deep molecular response (DMR) level or deeper could stop Tyrosine Kinase Inhibitor (TKI) and approximately 40% of these patients could keep therapy free survival by cessation of TKI. Discontinuation of TKI has emerged as a new goal of treatment in CML. Achievement of DMR is necessary for discontinuation of TKI. The aim of the present study was to analyze the prognostic significance of (i) BCR-ABL transcript International Scale (BCR-ABL IS) levels, (ii) the halving time and (iii) velocity of BCR-ABL transcript elimination using an optimized cutoff according to receiver operating characteristic (ROC) analysis.

Methods: Eighty newly diagnosed CML-CP patients were included in this study. Patients received dasatinib 100mg once daily. Treatment has continued until disease progression or unacceptable toxicity. Clinical efficacy and safety was partially reported in 55^th ASH Meeting. We sought to investigate the impacts of above 3 parameters within the initial 1 or 3 months of therapy. Halving time was calculated by the method, described by Branford et al. Velocity of BCR-ABL transcript elimination at 1 or 3 months (V-BCR-ABL_1m or _3m respectively) was calculated as BCR-ABL IS at 1 or 3 months (BCR-ABL IS_1m or _3m respectively) divided by that at diagnosis.

Results: One patient was withdrawal before administration of dasatinib. Seventy-nine patients administered dasatinib 100 mg once daily. The estimated MMR and DMR rates were 92.1 % (95%CI, 76.8-97.3 %) and 60.9% (95%CI; 42.3-73.4 %) by 12 months respectively. The patients who had already achieved DMR at 3 months were excluded from landmark analysis. The cut off values for prediction of DMR at 12 months were obtained by ROC analysis. Those of BCR-ABL IS_1m and BCR-ABL IS_3m were 11.7% and 0.284% respectively. Those of halving times on 0-1 month and 0-3months (halving time_1m and _3m) were 17.8 and 13.6 days respectively. Those of V-BCR-ABL_1m and V-BCR-ABL_3m were 0.321 and 0.018 respectively. The estimated DMR at 12 months, 95% CI and probability (P), obtained by Kaplan-Myer analysis, were shown in Figure 1. Odd' ratio, obtained by Chi-square test, was shown in Table 1. The patients with less than 0.321 at V-BCR-ABL_1m showed the highest DMR at 12 months (80%), the least probability (P=0.009) and the least odd' ratio (0.175). At 3 months, there were similar data in these parameters among BCR-ABL IS_3m, halving time_3m and V-BCR-ABL_3m. Figure 1 showed the cumulative DMR rate according to the cutoff values in V-BCR-ABL_1m and V-BCR-ABL_3m. V-BCR-ABL_1m 0.321 and V-BCR-ABL_3m 0.018 separated best.

Conclusion: These data strongly suggested that V-BCR-ABL_1m, _3m would be a significant landmark to predict DMR at 12 months as well as BCR-ABL IS_1m, _3m, halving time_1m, _3m. Among them, less than 0.321 in V-BCR-ABL_1m was identified as an optimized predictive cutoff value of DMR at 12 months.