Abstract: S152

Type: Oral Presentation

Session title: Response, resistance and treatment-free remission in CML

Background
With the introduction of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukaemia (CML), treatment cessation has become a realistic therapy goal for some CML patients. Around 40-60% of patients with stable DMR [deep molecular response, corresponding to <0.01% BCR-ABL (IS)] can stop the TKI successfully, e.g. in accordance with the recommendations given by the European LeukemiaNet. In the interim analysis of the first 200 patients of the EURO-SKI (European stop TKI) trial, 62% were in major molecular response (MMR: <0.1% BCR-ABL1 IS) or better at 6 months. DMR duration prior to TKI stop was most predictive for maintenance of MMR. Here we present the final analysis of the EURO-SKI trial after 3 years of follow-up.

Aims
The EURO-SKI trial was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims are the evaluation of harmonized methods of molecular monitoring, and assessment of prognostic factors.

Methods
Adult CML patients in chronic phase CML on TKI treatment in confirmed DMR for at least one year (>4 log reduction on TKI therapy for >12 months confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. DMR confirmation was performed in standardized laboratories. Primary endpoint was maintenance of MMR after stopping TKI. According to protocol, a 36 months follow-up was planned. The null hypotheses were that MMR maintenance at 6 and 36 months was less or equal 40% and less or equal 35%, respectively.

Results
Between May 30, 2012 and December 03, 2014, 868 CP CML patients were pre-registered by 61 European centres from 11 countries. 140 pts were excluded (consent withdrawal n=1, protocol violation n=38, not eligible n=74 DMR not confirmed n=11, atypical or unknown transcript n=15, missing data n=1) resulting in 728 eligible patents.

Of the eligible 728 patients, 46.8% were female. Median age at diagnosis was 51 years (range, 11 to 85 years). Median duration of TKI treatment was 7.6 years (range, 3.0-14.1 years) and median duration of MR4 before TKI cessation was 4.7 years (range, 1.0-13.3 years).

Nine patients died without MMR loss (none CML related), 15 patients restarted TKI without prior MMR loss.

At 6 months 713 patients were available (without molecular test at 6 months n=6, TKI restart without relapse n=9). Since 434 patients (61%) [95% CI: 57–64] remained without relapse in the first 6 months, the null hypothesis could be rejected (p<0.0001).

At 36 months, 678 patients could be analysed (TKI restart without relapse n=17, no molecular test at 36 months n=33). 309 patients were in MMR or better corresponding to 46% [95% CI: 42–49]. The null hypothesis of 35% or lower was rejected (p<0·0001).

Molecular recurrence-free survival (MRecFS) at 36 months resulted in 48% (CI: 44-52%) and MRecTFS (molecular treatment-free survival) in 46% (CI 43-50%) (s. Fig 1).

No Blast crisis was documented.

Prognostic factors for early (up to 6 months) and late (> 6 months) MMR relapses will be updated and presented.

Conclusion
With this final analysis we confirm the MRecFS and MRecTFS rate at 6 months from the interim analysis. However, late relapses (15% between 6 and 36 months) occurred. Nevertheless, with 46%, almost half of the patients stayed at least in MRecTFS.

Keyword(s): Chronic myeloid leukemia, Molecular relapse, Prognostic factor, Treatment-free remission