Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial

Abstract

Background: Tyrosine kinase inhibitors (TKI) have dramatically improved survival in chronic myeloid leukemia (CML) with a high proportion of patients reaching deep molecular responses (DMR). The effectiveness of stopping TKI treatment is a key question regarding the management of CML. Actually, in several studies, it has been proven that a substantial part of patients in DMR can safely and successfully stop TKI therapy. However, the exact preconditions for stopping CML treatments are not yet defined. This is the aim of the European stop TKI (EURO-SKI) trial (ClinicalTrials.gov numbers: NCT01596114). Methods: Chronic phase CML patients without prior TKI failure, treated with either imatinib, nilotinib or dasatinib, in DMR (BCR-ABL <0.01% on the international scale, MR4) for the duration of at least one year were proposed to stop TKI treatment. Molecular recurrence (MR) was defined by the loss of the major molecular response (MMR, BCR-ABL <0.1% IS) at any one point. We estimated molecular recurrence-free survival (MRFS) with the Kaplan-Meier method. The potential prognostic values for MR were tested by univariate and multivariable analyses and the cut-off was identified with the minimal p-value approach. Results: From June 2012 to December 2014, 821 CP CML patients were included in 11 European countries belonging to the European Leukemia Net (ELN). 750 patients had assessable molecular data (European standardization according to Cross et al, Leukemia 2012) for the estimation of MRFS. Of these patients, 348 lost MMR and 5 died in remission ; MRFS was 62% (95% confidence interval (CI): 59% - 67%) at 6 months (m), 56% (CI: 52% - 59%) at 12 m and 52% (CI: 48% - 56%) at 24 m on an "Intention to Treat Basis ". At the time of evaluation most patients regained DMR, and importantly, no progression to advanced disease phase was noted. A prognostic modelling was performed based on 448 patients treated with imatinib. Univariate analysis showed no significant association between age, gender, depth of molecular response (MR4.5 vs. no MR4.5) or any variable part of the Sokal, EURO, EUTOS, or ELTS scores and MMR status at 6 months after treatment stop. Treatment duration with imatinib and MR4duration prior to the stop were significantly (p<0.001) correlated with MMR status at 6 months. The odds ratio for treatment duration was 1.16 (95%-CI: 1.08-1.25), meaning that one additional year of treatment increases the odds to stay in MMR at 6 months by 16%. Molecular relapse-free survival at 6 months was 65.5% for imatinib treatment > 5.8 years and 42.6% for treatment ≤ 5.8 years. This cut-off was identified with the minimal p-value approach. A true pharmaco-economic study will be necessary but taking into account the number of months without treatment in 603 patients, Imatinib front line (with a median observation time of 24 m for patients still off treatment) and the cost of imatinib in each of the 11 European countries (range: 1.734-3.370 Euro per month) the total estimated savings amounted to 27.85 million Euro. Conclusion: Using standardized molecular monitoring, stopping TKI therapy in a very large cohort of CML-patients appears feasible and safe and high MRFS rates are achievable. Longer duration of imatinib-therapy (optimal ≥ 5.8 years) prior to TKI-stop is associated with a higher probability of MRFS. Taking into account the long follow-up without molecular relapse in the historical studies such as STIM1 (Etienne et al; JCO 2016) the "operational" cure of CML with oral TKI is an up-to-date issue. Disclosures Mahon: NOVARTIS PHARMA: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; PFIZER: Honoraria; ARIAD: Honoraria. Richter:Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Almeida:BMS: Speakers Bureau; Shire: Speakers Bureau; Alexion: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Berger:NOVARTIS PHARMA: Honoraria. Machova Polakova:Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Saussele:NOVARTIS PHARMA: Consultancy, Honoraria; BMS: Honoraria.

Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring

“…Similar results were observed in the EURO‐SKI trial, the largest study to date of TKI discontinuation in CML . In this study of 821 patients with CML treated with frontline imatinib, nilotinib or dasatinib, who had achieved at least MR4, and who subsequently stopped TKI therapy, the molecular recurrence‐free survival at 2 years was 52%.…”

Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia

“…6 Recently, the ongoing European Stop Tyrosine Kinase Inhibitor (EURO-SKI) trial explored less deep MR levels as thresholds for discontinuing imatinib, dasatinib, or nilotinib, enrolling patients who maintained MR4 for at least 1 year only. 13 In the STIM and TWISTER trials, the definitions for molecular relapse after TKI discontinuation were quite stringent. 5,13 In the STIM study, a 1-log increase in BCR-ABL1 transcripts between 2 consecutive assessments defined a molecular relapse and triggered imatinib resumption.…”

“…5,13 In the STIM study, a 1-log increase in BCR-ABL1 transcripts between 2 consecutive assessments defined a molecular relapse and triggered imatinib resumption. 13 In the TWISTER study, detectable BCR-ABL1 transcripts at any level in 2 consecutive assessments were considered as a molecular relapse and a trigger for restarting imatinib. 4,[7][8][9][10][11]13 Then, the loss of a major molecular response (MMR) was proposed as a more reliable and safe molecular definition for relapse and treatment-free remission (TFR) was preferred over molecular relapse-free survival as the primary endpoint in most TKI-cessation studies.…”

“…3,5 It has also been reported that the Sokal risk score and DMR duration are factors in success, and the role of different DMR levels also is under investigation in EURO-SKI. 13 In case of a molecular relapse, patients must rapidly resume TKI therapy, and no major efficacy issues have been reported. Currently, whether such relapsing patients may hope for re-attempting TFR is uncertain.…”

Early results of lower dose dasatinib (50 mg daily) as frontline therapy for newly diagnosed chronic‐phase chronic myeloid leukemia

“…In the European Stop Tyrosine Kinase Inhibitor (EURO-SKI) study, the largest study to date of TKI discontinuation in CML, among 821 patients with CML treated with frontline imatinib, nilotinib, or dasatinib who had achieved at least MR4.0 and had subsequently stopped TKI therapy, the molecular recurrencefree survival rate at 2 years was 52%. 20 In a multivariate analysis, a duration of MR4.0 of 3 or more years was the only significant factor for a persistent deep molecular response after therapy was stopped. Additional factors include a duration of TKI therapy of 6 or more years.…”