Introduction

For chronic myeloid leukemia (CML) patients who achieve deep and durable molecular remission, the feasibility of discontinuing tyrosine kinase inhibitors (TKIs) has been established, challenging the notion of lifelong dependency on TKIs. Achieving treatment-free remission (TFR) without affecting overall survival (OS) is a key objective in current CML treatment. Recently, the Journal of Clinical Oncology (JCO) published the three-year follow-up results of the EURO-SKI study, providing a final analysis of prognostic factors related to TFR. Here, we present a summary of the findings from this comprehensive study.

Background

CML is a model for targeted cancer therapy, particularly with the advent of TKIs targeting the BCR::ABL1 fusion gene, which has significantly improved patient prognosis and quality of life. Discontinuing TKIs to achieve TFR has become a new goal in CML treatment. Studies indicate that approximately 40-55% of CML patients with an excellent treatment response can discontinue TKIs after achieving deep molecular remission (DMR). However, prognostic indicators for TFR have not been fully established. The EURO-SKI study, a comprehensive registry clinical trial on TKI discontinuation, aimed to elucidate prognostic factors for TFR. This article presents the final analysis results from the three-year follow-up of the EURO-SKI study.

Patients and Methods

The study included adult chronic phase CML (CML-CP) patients who had received TKI treatment for at least three years and achieved DMR (BCR-ABLIS ≤0.01%). The primary endpoints were the major molecular response (MMR) rates at six and 36 months after discontinuing TKIs, measured as molecular relapse-free survival (MRecFS).

Results

Between May 30, 2012, and December 3, 2014, 728 CML-CP patients were enrolled in the study. After TKI treatment, results showed that 61% of CML patients maintained MMR six months after stopping TKIs (six-month MRecFS of 61%). The secondary endpoint showed that the 36-month MRecFS was 46%, and the three-year overall survival (OS) was 98%.

Re-establishing DMR After Restarting TKIs

Among patients who lost MMR within six months of stopping TKIs, 28%, 71%, and 85% regained MR4 at three, six, and 12 months, respectively, after restarting TKIs. For those who lost MMR after six months of stopping TKIs, 52%, 96%, and 98% achieved MR4 at three, six, and 12 months, respectively, after restarting TKIs.

Factors Influencing MRecFS at Six Months

Among 355 CML patients with the e14a2 or e14a2+e13a2 transcript, the six-month MRecFS was 63%. In contrast, for 106 patients with only the e13a2 transcript, the six-month MRecFS was 47% (OR=1.892, 95% CI: 38%~57%; P=0.0043).

Factors Influencing MMR Maintenance from Six to 36 Months

Of the 348 patients who maintained MMR or better at six months after stopping TKIs, 33 could not be evaluated at 36 months. Among the remaining 315 patients, 76% maintained MMR (36-month MRecFS of 76%). The duration of TKI treatment was a significant factor for maintaining MMR between six and 36 months. Additionally, disease characteristics at diagnosis, peripheral blood blast percentage, and platelet count were independent factors influencing MMR.

Prognostic Factors for TKI Discontinuation Over the 36-Month Study Period

Over the 36-month study period, the duration of TKI treatment, the duration of DMR before stopping TKIs, peripheral blood blast percentage at diagnosis, and transcript type were closely related to maintaining MMR. Compared to patients with the e13a2 transcript, those with the e14a2 (+e13a2) transcript were more likely to maintain MMR at 36 months after stopping TKIs (P=0.0051).

Discussion

Previous studies have shown that stopping TKIs in CML patients is safe and feasible when adhering to discontinuation criteria and standardized molecular monitoring. The final results of the EURO-SKI study indicate that the six-month MRecFS was 61% and the 36-month MRecFS was 46%, both higher than the pre-set values. Preliminary analysis identified the duration of TKI treatment and the duration of DMR before stopping TKIs as the two main factors predicting MMR at six months after stopping TKIs. These factors significantly contributed to maintaining MMR after stopping TKIs, with each additional year of TKI treatment and DMR maintenance before stopping increasing the six-month MMR by approximately 3%. Additionally, the e14a2 transcript was a favorable factor for maintaining MMR, confirmed in the STIM2 validation cohort. Compared to patients with the e13a2 transcript, those with the e14a2 transcript had a higher three-year TFR.

Approximately 80% of molecular relapses occurred within six months of stopping TKIs, accompanied by an increase in BCR::ABL1 levels, distinct from the characteristics of relapses occurring after six months. For relapses between six and 36 months, the duration of TKI treatment was the most critical factor for maintaining MMR after stopping treatment, rather than the duration of DMR. The EURO-SKI study also identified peripheral blood blast percentage, platelet count, and disease characteristics at diagnosis as independent factors for maintaining MMR between six and 36 months. These factors are components of the Sokal score and have been identified as prognostic factors in studies such as STIM1.

In summary, the EURO-SKI study identified four prognostic factors over the three-year trial period and successfully validated them in the STIM2 study: the duration of TKI treatment, the duration of DMR before stopping treatment, the peripheral blood blast percentage at diagnosis, and transcript type.

References:

Mahon FX, Pfirrmann M, Dulucq S, et al. European Stop Tyrosine Kinase Inhibitor Trial (EURO-SKI) in Chronic Myeloid Leukemia: Final Analysis and Novel Prognostic Factors for Treatment-Free Remission. J Clin Oncol. 2024 Mar 12:JCO2301647. doi: 10.1200/JCO.23.01647. Epub ahead of print. PMID: 38471049.