Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial
Authors: Mahon Francois-xavier , Richter Johan , Guilhot Joelle , Hjorth-Hansen Henrik , Almeida Antonio , Janssen Jeroen J.W.M. JWM , Mayer Jiri , Porkka Kimmo , Panayiotidis Panayiotis , Stromberg Ulla , Berger Marc G , Diamond Joanna , Ehrencrona Hans , Kairisto Veli , Machova Polakova Katerina , Mueller Martin C. , Mustjoki Satu , Hochhaus Andreas , Pfirrmann Markus , Saussele Susanne 
Published: October 2019

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.