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633 FINAL Analysis of a PAN European STOP Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Progress with response prediction and TKI discontinuation
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research
Monday, December 13, 2021: 11:00 AM

Francois-Xavier Mahon, MD, PhD1,2, Johan Richter, MD, PhD3*, Andreas Hochhaus, MD4, Panayiotis Panayiotidis, MD5, Antonio Medina de Almeida, MD, PhD6,7*, Jiri Mayer8*, Henrik Hjorth-Hansen, MD9,10, Jeroen Janssen11*, Satu Mustjoki, MD, PhD12, Joaquín Martínez-López13*, Hanne Vestergaard, MD14*, Hans Ehrencrona, MD, PhD15*, Veli Kairisto16*, Stephanie Dulucq, PharmD, PhD17,18*, Katerina Machova19,20*, Franck E. Nicolini, MD, PhD21,22, Wolf-Karsten Hofmann23*, Joelle Guilhot, PhD24, Susanne Saussele, MD 25,26 and Markus Pfirrmann, PhD27*

1Hematology Department, Institut Bergonié, Bordeaux, France
2Cancer Center of Bordeaux, Institut Bergonié, INSERM U1218, University of Bordeaux, Bordeaux, France
3Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
4Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany
5School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
6Centro de Investigação Interdisciplinar em Saúde, Universidade Católica Portuguesa de Lisboa, Lisbon, Portugal
7Hospital da Luz, Lisbon, Portugal
8University Hospital Brno, Czech Republic, Brno, CZE
9Norwegian University of Science and Technology, Trondhein, Norway
10Department of Hematology, St. Olavs University Hospital, Trondheim, Norway
11Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, Netherlands
12Helsinki Univ. Central Hosp., Biomedicum, Helsinki, Finland
13Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
14Department of Hematology, Odense University Hospital, Odense, Denmark
15Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden
16Department of Clinical Chemistry, Turku University Central Hospital, Turku, Finland
17Laboratory of Hematology, University Hospital of Bordeaux, Hôpital Haut Lévêque, Pessac, France
18Institut Bergonié, French group of CML (Fi-LMC), Bordeaux, France
19Institute of Hematology and Blood Transfusion, Prague, Czech Republic
20Institute of Pathological Physiology, Charles University, First Faculty of Medicine, Prague, Czech Republic
21Hematology department, Centre Leon Berard, Lyon, France
22Hématologie Clinique, Centre Léon Bérard, Lyon, France
23University Hospital, Mannheim, Germany
24French group of CML (Fi-LMC), Pessac, France
25III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany
26Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
27IBE, Ludwig-Maximilians-Universität, München, Germany

Background: With the dramatic success of tyrosine kinase inhibitors (TKI) to treat Chronic myeloid leukemia (CML), the life expectancy of CML patients is now close to that of the general population. In addition, treatment cessation is now a realistic goal for some CML patients. This was shown by several clinical trials such as the STIM study leading to the concept of TFR (treatment free remission). 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 recommendations from 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) at 6 months. DMR duration before 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 main objectives of The EURO-SKI trial were the evaluation of molecular recurrence-free survival (MRecFS) after Stopping TKI in a large Pan-european cohort of CML patients and definition of 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.

Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed DMR for at least one year (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 than 40% and less or equal than 35%, respectively.

Results: Between May 2012 and December 2014, 868 patients were pre-registered by 61 centers 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/unknown transcript n=15, missing data n=1) resulting in 728 eligible patents. Of these, 46.8% were female. Median age at diagnosis was 52 years (range, 11 to 85 years). Median duration of TKI treatment was 7.5 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 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 during the first 6 months, the null hypothesis was rejected (p<0.0001). At 36 months, 678 patients could be analyzed (TKI restart without relapse: n=17, no molecular test at 36 months: n=33). With 309 patients in MMR, corresponding to 46% [95% CI: 42–49], the null hypothesis of 35% or less was rejected (p<0.0001). MRecFS at 36 months resulted in 48% (CI: 44-52%) and molecular recurrence- and treatment-free survival (MRecTFS) in 46% (CI: 43-50%) (Fig 1). No blast crisis occurred.

Regarding prognostic factors, we confirmed that TKI treatment duration and DMR duration were still the most important factors to predict MMR loss at 6 months. For the late recurrence, i.e., between 6 and 36 months (57 patients), TKI treatment duration before stop was the only relevant variable in a preliminary univariate logistic analysis.

Summary/Conclusion: With this final analysis of the largest TFR trial, we confirm the MRecFS and MRecTFS rates at 6 months previously obtained from the interim analysis. However, late molecular recurrence (15% between 6 and 36 months) occurred and the underlying mechanisms need to be discussed. Nevertheless, 46% of the patients, were still in MRecTFS at 3 years.

Disclosures: Hochhaus: Pfizer: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hjorth-Hansen: AOP: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Mustjoki: Janpix: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

*signifies non-member of ASH