European Stop Tyrosine Kinase Inhibitor Study

Chronic Myeloid Leukemia Clinical Trial

— EURO-SKI  

Official title:

Multicenter Trial Estimating the Persistence of Molecular Remission in Chronic Myeloid Leukemia After Stopping TKI

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01596114
• Other study ID #: ELN-001
• Secondary ID: 2011-000440-22
• Status: Completed
• Phase: Phase 3
• Start date: May 30, 2012
• Est. completion date: December 31, 2019

Study information

• Verified date: October 2021
• Source: European LeukemiaNet
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The EURO-SKI is a multicenter open label, uncontrolled trial estimating the persistence of molecular remission in Chronic Myeloid Leukemia (CML) patients after stopping Tyrosine Kinase Inhibitor (TKI). Main goal is the assessment of the duration of major molecular response (MMR) or better after stopping TKI therapy. Secondary goals include: - Identification of clinical and biological factors affecting the persistence of complete molecular remission after stopping TKI (e.g. level of Complete molecular remission (CMR), risk score, duration of TKI treatment, type of TKI pretreatment) - Evaluation of quality of life (QoL) in patients stopping TKI - Evaluation of medico-economic impact of stopping TKI - Estimating the number of patients in CMR who are eligible for stopping TKI therapy by setting up a screening log - Time to recovery of CMR There will be no randomised comparison. Based on the experience of the STIM trial (Mahon et al., Lancet Onc 2010) we expect an overall six-month molecular-relapse-free survival probability of at least 40%. An interim analysis will be performed after a pilot phase where 200 patients have been observed for at least six months. Formally, it is planned to test the null hypothesis H0: Six-month molecular relapse-free survival probability P ≤ 40% against the alternative hypothesis H1: Six-month molecular-relapse-free survival probability P > 40%. Eligible are adult CML patients in chronic phase on TKI treatment in CMR for at least one year (> 4 log reduction of BCR-ABL transcripts on IS, TKI treatment for at least 3 years, confirmed by a PCR within a standardized CMR laboratory). Clinical and biological monitoring will be performed during 3 years: Associated scientific projects are performed. Recruitment period: 2 years; follow up: 3 years. Planned patient recruitment in main phase: n=500

Recruitment information / eligibility

• Status: Completed
• Enrollment: 868
• Est. completion date: December 31, 2019
• Est. primary completion date: December 3, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• CML in CP under treatment with TKI in first line or in second line because of toxicity to first line TKI or with TKI in combination
• Duration of TKI treatment before enrolment at least 3 years
• At least complete molecular remission MR4
• Before inclusion confirmation of CMR4 through a EUTOS-CMR laboratory
• Baseline data and documentation on treatment before study entry available
• Both sexes but fertile women only if using effective contraceptive
• Health insurance coverage
• 18 years or older

Exclusion Criteria:

• Under 18 years old
• Hospitalized patients without ability to give informed consent
• Adults under law protection or without ability to consent
• Previous or planned allogeneic stem cell transplantation

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Other:
• Stopping treatment with TKI
stopping until loss of MMR

Locations

Country	Name	City	State
Czechia	Fakultní nemocnice	Brno
Czechia	Fakultní nemocnice Hradec Králové	Hradec Kralove
Czechia	University Hospital Olomouc	Olomouc
Czechia	University Hospital Plzen	Plzen
Czechia	Fakultni nemocnice Kralovske Vinohrady	Prague
Czechia	Ústav hematologie a krevní transfuze	Prague
Denmark	Odense University Hospital	Odense
Finland	Helsinki University Central Hospital	Helsinki
France	CHU d'Angers	Angers
France	Institut Bergonié	Bordeaux
France	Université Victor Segalen	Bordeaux
France	Hôpital André Mignot	Chesnay cedex
France	Chu Estaing	Clermont Ferrand
France	Hôpital Claude Huriez	Lille
France	Hôpital Édouard Herriot	Lyon
France	Institut Paoli-Calmettes (IPC)	Marseille
France	Centre Hospitalier Universitaire (CHU) de Nantes	Nantes
France	Hôpital de l'Archet	Nice
France	Hôpital Saint-Louis	Paris cedex 10
France	Hôpital Necker-Enfants Malades	Paris Cedex 15
France	Hopital de la Milétrie, Centre Hospitalier Universitaire (CHU) de Poitiers	Poitiers
France	Hôpital Pontchaillou	Rennes
France	Hôpital Purpan	Toulouse
France	CHU de Tours	Tours
France	Hôpital de Brabois	Vandoeuvre-lès-Nancy
Germany	Uniklinik RWTH	Aachen
Germany	Universitätsklinikum	Bonn
Germany	Klinikum	Chemnitz
Germany	Universitätsklinikum	Jena
Germany	Klinikum Kempten-Oberallgäu	Kempten
Germany	Universitätsmedizin Mannheim, Universität Heidelberg	Mannheim
Germany	Universitätsklinikum Giessen und Marburg GmbH	Marburg
Germany	MVZ Klinikum Straubing GmbH	Straubing
Greece	University of Athens, Society of Hematology	Athens
Netherlands	VU Academic Medical Center	Amsterdam
Netherlands	Albert Schweitzer Hospital	Dordrecht
Norway	Oslo universitetssykehus HF Rikshospitalet	Oslo
Norway	Stavanger University Hospital	Stavanger
Norway	University Hospital of Northern Norway	Tromsø
Norway	Norwegian University of Science and Technology	Trondheim
Portugal	Instituto Português de Oncologia Francisco Gentil	Lisboa
Sweden	Karoliniska Univ hospital Huddinge	Huddinge
Sweden	Univ hospital Linköping	Linköping
Sweden	Sunderby hospital	Luleå
Sweden	Lunds Universitet	Lund
Sweden	Univ hospital Örebro	Örebro
Sweden	Karoliniska Univ sjh Solna	Stockholm
Sweden	Länssj Sundsvall	Sundsvall
Sweden	Norrlands Univ hospital	Umeå
Sweden	Uppsala University hospital	Uppsala

Sponsors (1)

Lead Sponsor	Collaborator
European LeukemiaNet

Countries where clinical trial is conducted

Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Netherlands,  Norway,  Portugal,  Sweden, 

References & Publications (7)

Bouillon AS, Ventura Ferreira MS, Awad SA, Richter J, Hochhaus A, Kunzmann V, Dengler J, Janssen J, Ossenkoppele G, Westerweel PE, Te Boekhorst PAW, Mahon FX, Hjorth-Hansen H, Isfort S, Fioretos T, Hummel S, Schemionek M, Wilop S, Koschmieder S, Saußele S, Mustjoki S, Beier F, Brümmendorf TH. Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia. Blood Adv. 2018 Jul 10;2(13):1572-1579. doi: 10.1182/bloodadvances.2018017772. — View Citation

Ilander M, Olsson-Strömberg U, Schlums H, Guilhot J, Brück O, Lähteenmäki H, Kasanen T, Koskenvesa P, Söderlund S, Höglund M, Markevärn B, Själander A, Lotfi K, Dreimane A, Lübking A, Holm E, Björeman M, Lehmann S, Stenke L, Ohm L, Gedde-Dahl T, Majeed W, — View Citation

Richter J, Lübking A, Söderlund S, Lotfi K, Markevärn B, Själander A, Stenke L, Deneberg S, Ahlstrand E, Myhr-Eriksson K, Panayiotidis P, Gedde-Dahl T, Žácková D, Mayer J, Olsson-Strömberg U, Mahon FX, Saussele S, Hjorth-Hansen H, Koskenvesa P. Molecular status 36 months after TKI discontinuation in CML is highly predictive for subsequent loss of MMR-final report from AFTER-SKI. Leukemia. 2021 Aug;35(8):2416-2418. doi: 10.1038/s41375-021-01173-w. Epub 2021 Feb 15. — View Citation

Rinaldetti S, Pfirrmann M, Manz K, Guilhot J, Dietz C, Panagiotidis P, Spiess B, Seifarth W, Fabarius A, Müller M, Pagoni M, Dimou M, Dengler J, Waller CF, Brümmendorf TH, Herbst R, Burchert A, Janßen C, Goebeler ME, Jost PJ, Hanzel S, Schafhausen P, Pran — View Citation

Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, Janssen JJWM, Mayer J, Koskenvesa P, Panayiotidis P, Olsson-Strömberg U, Martinez-Lopez J, Rousselot P, Vestergaard H, Ehrencrona H, Kairisto V, Machová Poláková K, Müller MC, Mustjo — View Citation

Schütz C, Inselmann S, Saussele S, Dietz CT, Mu Ller MC, Eigendorff E, Brendel CA, Metzelder SK, Bru Mmendorf TH, Waller C, Dengler J, Goebeler ME, Herbst R, Freunek G, Hanzel S, Illmer T, Wang Y, Lange T, Finkernagel F, Hehlmann R, Huber M, Neubauer A, Hochhaus A, Guilhot J, Xavier Mahon F, Pfirrmann M, Burchert A. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Leukemia. 2017 Apr;31(4):829-836. doi: 10.1038/leu.2017.9. Epub 2017 Jan 11. Erratum in: Leukemia. 2018 Jan 30;:. — View Citation

Söderlund S, Persson I, Ilander M, Guilhot J, Hjorth-Hansen H, Koskenvesa P, Richter J, Saussele S, Mustjoki S, Olsson-Strömberg U. Plasma proteomics of biomarkers for inflammation or cancer cannot predict relapse in chronic myeloid leukaemia patients stopping tyrosine kinase inhibitor therapy. Leuk Res. 2020 Mar;90:106310. doi: 10.1016/j.leukres.2020.106310. Epub 2020 Jan 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	molecular relapse-free survival	Evaluation of molecular relapse-free survival after stopping TKI (survival without molecular relapse defined by BCR-ABL1 > 0.1% on the IS at one time point (loss of major molecular response, MMR))	3 years
Secondary	Overall and progression-free survival	Overall and progression-free survival and the probabilities of a restart of TKI without prior molecular relapse	3 years
Secondary	Treatment costs	Saved treatment costs / country from the time off TKI therapy considering also the more frequent PCR monitoring	3 years
Secondary	QoL	Patient reported QoL and symptom burden over time	3 years
Secondary	Time to recovery	Analysing the time to recovery of CMR4 after loss of MMR	3 years