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Early predictors of MR4.5 attainment and eligibility for TKI discontinuation in CML treated with second-generation
Takaaki Ono1, Takashi Okada2, Naoto Takahashi3
1Department of Transfusion and Cell Therapy, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Abstract:
Among patients with chronic myeloid leukemia (CML) aiming for tyrosine kinase inhibitor (TKI) discontinuation, second-generation TKIs (2G-TKIs) are used as one of the first-line therapy options because they induce faster and deeper molecular responses (MR) than imatinib. However, predictors of attaining and sustaining MR4.5 (BCR::ABL1 International Scale [IS] ≤0.0032%) during 2G-TKI therapy remain undefined. We analyzed 431 patients enrolled in the phase 3 Japan Adult Leukemia Study Group CML212 trial comparing nilotinib at 300 mg twice daily (n = 218) and dasatinib at 100 mg once daily (n = 213) as first-line therapy. The objective was to identify predictors of MR4.5 attainment and TKI discontinuation eligibility (TDE). Candidate variables assessed within 6 months included the European Treatment and Outcome Study (EUTOS) Long-Term Survival (ELTS) score; BCR::ABL1 IS at baseline, 3 months, and 6 months; and IS-derived halving times (HT), HT (0-3) and HT (3-6). TDE was defined as ≥3 years of TKI therapy with ≥2 consecutive years of sustained MR4.5. With a median follow-up of 3.0 years, the cumulative incidence of MR4.5 was 46.6%, and 36.3% of patients achieving MR4.5 met TDE criteria. In multivariable models, HT (0-3) (subdistribution hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.09-4.55) and the 6-month IS value (HR, 0.38; 95% CI, 0.31-0.47) were independent predictors of MR4.5 attainment, whereas only the 6-month IS value predicted TDE (odds ratio, 0.37; 95% CI, 0.24-0.56). This study demonstrates that MR at 6 months after TKI initiation has important clinical value in early stratification of MR4.5 attainment and TDE in patients receiving 2G-TKI therapy.
Insights
Predicting deep molecular response in chronic myeloid leukemia (CML) is key for tyrosine kinase inhibitor (TKI) discontinuation. Early molecular response at 6 months using second-generation TKIs (2G-TKIs) effectively predicts MR4.5 attainment and TKI discontinuation eligibility.
Area of Science:
- Hematology
- Oncology
- Clinical Pharmacology
Background:
- Second-generation tyrosine kinase inhibitors (2G-TKIs) offer improved molecular responses compared to imatinib in chronic myeloid leukemia (CML).
- Predictors for achieving and sustaining deep molecular response (MR4.5) and treatment discontinuation eligibility remain unclear for 2G-TKI therapy.
Purpose of the Study:
- To identify predictors of MR4.5 attainment and TKI discontinuation eligibility (TDE) in CML patients receiving first-line 2G-TKI therapy.
Main Methods:
- Analysis of 431 CML patients from the JALSG CML212 trial comparing nilotinib and dasatinib.
- Assessment of baseline, 3-month, and 6-month BCR::ABL1 International Scale (IS) levels, IS-derived halving times, and EUTOS long-term survival (ELTS) score.
- TDE defined as ≥3 years of TKI therapy with ≥2 consecutive years of sustained MR4.5.
Main Results:
- Cumulative incidence of MR4.5 was 46.6% with a median follow-up of 3.0 years.
- 36.3% of patients achieving MR4.5 met TDE criteria.
- Independent predictors for MR4.5 attainment included halving time from 0-3 months (HT(0-3)) and 6-month IS. The 6-month IS was the sole predictor for TDE.
Conclusions:
- Molecular response at 6 months post-TKI initiation is a crucial factor for early stratification of MR4.5 attainment and TDE in CML patients on 2G-TKIs.
- Early molecular profiling aids in optimizing treatment strategies and assessing discontinuation potential.
