Five-year interim analysis of multi-institutional collaborative study for estimating the persistence of treatment free remission in chronic myeloid leukemia after stopping tyrosine kinase inhibitor in Japan: J-SKI

Abstract Introduction: Tyrosine Kinase Inhibitors (TKIs) have substantially improved survival outcomes for patients with chronic myeloid leukemia in chronic phase (CML-CP). In clinical practice, however, TKI treatment has generally been considered a life-long commitment. Several clinical trials, including the largest prospective study, the EURO-SKI trial, have demonstrated that TKI therapy can be safely discontinued in approximately half of the patients who achieve and maintain a deep molecular response (DMR). Although a subset of Japanese patients treated with TKIs achieves sustained DMR and may be eligible for Treatment-Free Remission (TFR), the long-term durability of TFR in a real-world setting remains unclear. Furthermore, the clinical and biological factors predicting successful TKI discontinuation are not fully elucidated, and little is known about the outcomes of a second TFR attempt. Objectives: The primary objective of this study was to determine the long-term TFR rate after TKI discontinuation in a large, real-world cohort of Japanese patients. The primary endpoint was the TFR rate at 5 years. Secondary endpoints included treatment-free survival (TFS), progression-free survival, and the cumulative incidence of regaining major molecular response (MMR) after treatment resumption. Exploratory endpoints were the identification of predictive factors for successful TFR and the success rate of a second TFR attempt. Methods: J-SKI is a multicenter observational study comprising two cohorts: a prospective TFR cohort of patients who newly discontinued TKI therapy in routine practice according to the 2018 JSH guidelines, and a retrospective TFR cohort of patients who had previously discontinued TKIs and were subsequently followed prospectively. Patients with major BCR::ABL1 positive CML were enrolled from September 2019 to March 2025, with a data cut-off date of May 31, 2024. All participants provided written informed consent. Key exclusion criteria included the inability to provide clinical information per the study schedule or participation in another clinical study where data submission to this registry was not permitted. Results: Of 844 patients registered, 795 were eligible for time-to-event analysis (Prospective cohort, n=283; Retrospective cohort, n=512). At data cut-off, 302 patients were evaluable for the 60-month primary endpoint. The overall TFR rate at 60 months was 65.2% (95% CI: 59.6-70.6%). Of the patients who experienced molecular relapse and resumed TKI therapy, 87% (95% CI: 82-92%) subsequently regained MMR. No patients progressed to blast crisis. A multivariate Cox regression analysis identified a longer duration of MR4.5 as the sole independent predictor for successful TFR (HR: 0.875; 95% CI: 0.829–0.924; p < 0.0001), corresponding to a 12.5% relative reduction in the risk of molecular relapse for each additional year of MR4.5. Furthermore, sustained MR4.5 at 1 or 3 months after TKI discontinuation was significantly associated with superior TFS compared to loss of MR 4.5 (p<0.0001, Log-rank test). A second TFR attempt was performed in 32 patients who failed their first attempt, with a subsequent TFS rate of approximately 40%. Conclusion: This 5-year interim analysis of the J-SKI study demonstrates that TKI discontinuation is a safe and feasible strategy for Japanese patients with CML in a real-world setting. These data support TFR as an achievable therapeutic goal in routine clinical practice, provided that established discontinuation criteria are met. As the duration of DMR is a key independent predictor for TFR success, future strategies should focus on methods to achieve and maintain DMR early in the treatment course. Our findings also suggest that a second TFR attempt can be a viable option for select patients.