Final analysis of EURO-SKI: primary endpoints met in chronic myeloid leukaemia

EURO-SKI evaluated the duration of treatment-free molecular remission and survival after cessation of treatment with tyrosine kinase inhibitors (TKIs) in the largest patient population studied to date. Three-year results of the EURO-SKI trial showed that approximately half of the participants with chronic myeloid leukaemia (CML) were in treatment-free remission.

Treatment cessation has become a realistic therapy goal since the introduction of TKIs for the treatment of CML, with treatment-free remission being achievable in up to 55% of patients with deep molecular response (DMR). However, little is known about prognostic indicators of sustained treatment-free remission. Thus, the multicentre, open-label, uncontrolled EURO-SKI study (NCT01596114), aimed to define prognostic markers besides other goals. Prof. Susanne Saußele (Heidelberg University, Germany) presented the final analysis after 3 years of follow-up [1].

EURO-SKI enrolled 728 adult CML patients on TKI treatment (≥3 years) and in confirmed DMR (≥1 year). The median age was 51 years, and 46.8% were women. First and secondary primary endpoints were molecular recurrence-free survival (MRecFS) at 6 and 36 months. Molecular recurrence was defined as BCR-ABL1 >0.1% (major molecular response [MMR] loss) at 1 time point. Patients were followed for 3 years after stop of TKI treatment. Median duration of TKI therapy was 7.5 years (3.1–22.6 years), with imatinib as first-line treatment in 93.7% of patients [2].

At 36 months, MRecFS was 48% (n=678; 95% CI 44–52) and molecular treatment-free survival (MRecTFS) was 46% (95% CI 43–50); 15 patients re-started TKI therapy without MMR loss. The cumulative incidence of MMR loss was 50% at 36 months (95% CI 46–54; see Figure). Of the 9 deaths, none were attributed to MMR relapse or CML.

Figure: Cumulative incidence of MMR loss after TKI treatment cessation [1]

CI, confidence intervals; MMR, major molecular response; TKI, tyrosine kinase inhibitor.

The first primary endpoint at 6-month was met: 434 out of 713 patients (61%; 95% CI 57–64) were in MMR or better, and the null hypothesis of ≤40% MMR maintenance at 6 months was rejected (P<0.0001). Similarly, the secondary primary endpoint of 36-month MRecFS was met: 309 out of 678 patients (46%; 95% CI 42–49) are still in MMR or better, and the null hypothesis of MMR maintenance at 36 months was rejected (P<0.0001). There were 17 patients who prematurely restarted TKI therapy and 33 patients with missing data.

Prof. Saußele also presented a preliminary analysis of prognostic factors. For MMR loss at 6 months, TKI treatment duration and DMR duration are the most important factors. For late MMR loss, TKI treatment duration before stop is the only relevant variable.

In summary, the primary endpoints of the EURO-SKI study were met and MRecFS probabilities were 62% and 46% after 6 and 36 months, respectively. First prognostic analyses support the importance of TKI treatment duration for early and late MMR loss, with further prognostic analyses to follow. The EURO-SKI study outlined important preconditions that can be employed as guidance for stopping criteria.

1. 
   
   1. Saußele S, et al. Final analysis of a pan European stop tyrosine kinase inhibitor trial in chronic myeloid leukemia: the EURO-SKI study. S152, EHA 2021 Virtual Congress, 9–17 June.
   2. Saußele S, et al. Lancet Oncol 2018;19(6):747-57.

 

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Posted on 5 August, 20215 August, 2021