Importance of the Duration of TKI Treatment in Treatment-Free Remission of Chronic Phase Chronic Myeloid Leukemia: Results of D-Free Trial

▪ Background: Treatment-free remission (TFR) is a new treatment goal for patients with chronic myeloid leukemia in chronic phase (CML-CP) with a sustained deep molecular response (DMR) by treatment with tyrosine kinase inhibitors (TKI). Although several guidelines have proposed clinical factors for successful TFR, they are based primarily on evidence with imatinib. Since 2 nd-generation TKI (2G-TKI) achieves a molecular response faster than imatinib, it may lead to TFR in a shorter treatment period. The multicenter phase II study D-FREE (Japan Registry of Clinical Trials: jRCTs031180332) was conducted to clarify optimal conditions for TFR in newly diagnosed patients with CML-CP treated with the 2G-TKI dasatinib. Methods: Newly diagnosed CML-CP patients were enrolled and treated with dasatinib in the induction phase. When patients achieved MR4.5 (BCR-ABL1 IS ≤0.0032%) based on assessment every three months during the induction phase for up to two years, they immediately entered the consolidation phase, where dasatinib is administered for 12 months. Patients with sustained MR4.5 throughout the consolidation phase discontinued dasatinib in the stop phase. Dasatinib was re-administered at molecular relapse, defined as loss of a major molecular response (BCR-ABL1 IS > 0.1%) or confirmed loss of MR4 (BCR-ABL1 IS > 0.01% on two consecutive assessments). The primary endpoint was the proportion of patients in TFR who showed no molecular relapse and did not need to resume dasatinib 12 months after treatment discontinuation. Results: Between July 2016 and May 2019, 181 patients with newly diagnosed CP-CML were enrolled in 41 centers in Japan. Four patients were excluded after screening, and no further information was available for 4 patients. Overall, 173 patients received study treatment. The median patient age was 54 years (18-83 years). The rates of Sokal low-, intermediate-, and high-risk groups were 28.6, 52.4, and 19.0%, respectively. The rates of EUTOS low- and high-risk groups were 81.0 and 19.0%, respectively. Of the 123 patients who completed the induction phase, 60 (48.8%) achieved MR4.5 for up to two years (median: 7.7 months, range: 3.0-21.1 months) and entered the consolidation phase. Single and multivariate analyses showed that the achievement of MMR at 3 months, but not sex, Sokal risk score, Hasford risk score, EUTOS risk score, or age (