Discontinuation of tyrosine kinase inhibitor therapy in chronic
myeloid leukaemia (EURO-SKI): a prespecified interim analysis
of a prospective, multicentre, non-randomised, trial

J 2018

Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial

SAUSSELE, S., J. RICHTER, J. GUILHOT, F.X. GRUBER, H. HJORTH-HANSEN et. al.

Basic information

Original name

Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial

Authors

SAUSSELE, S. (276 Germany), J. RICHTER (752 Sweden), J. GUILHOT (250 France), F.X. GRUBER (578 Norway), H. HJORTH-HANSEN (578 Norway), A. ALMEIDA (620 Portugal), J.J.W.M. JANSSEN (528 Netherlands), Jiří MAYER (203 Czech Republic, belonging to the institution), P. KOSKENVESA (246 Finland), P. PANAYIOTIDIS (300 Greece), U. OLSSON-STROMBERG (752 Sweden), J. MARTINEZ-LOPEZ (724 Spain), P. ROUSSELOT (250 France), H. VESTERGAARD (208 Denmark), H. EHRENCRONA (752 Sweden), V. KAIRISTO (246 Finland), K.M. POLAKOVA (203 Czech Republic), M.C. MULLER (276 Germany), S. MUSTJOKI (246 Finland), M.G. BERGER (250 France), A. FABARIUS (276 Germany), W.K. HOFMANN (276 Germany), A. HOCHHAUS (276 Germany), M. PFIRRMANN (276 Germany) and F.X. MAHON (250 France, guarantor)

Edition

Lancet Oncology, New York, Elsevier Science INC, 2018, 1470-2045

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 35.386

RIV identification code

RIV/00216224:14110/18:00103231

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/S1470-2045(18)30192-X

UT WoS

000434153000041

Keywords in English

Tyrosine kinase inhibitors

Abstract

V originále

Background Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. Methods In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0.1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. Findings Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1.14 [95% CI 1.05-1.23]; p=0.0010) and longer deep molecular response durations (1.13 [1.04-1.23]; p=0.0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1.13 [0.98-1.29]; p=0.08). TKI discontinuation was associated with substantial cost savings (an estimated (sic)22 million). No serious adverse events were reported. Interpretation Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure. Copyright (c) 2018 Elsevier Ltd. All rights reserved.

Citovat

SAUSSELE, S., J. RICHTER, J. GUILHOT, F.X. GRUBER, H. HJORTH-HANSEN, A. ALMEIDA, J.J.W.M. JANSSEN, Jiří MAYER, P. KOSKENVESA, P. PANAYIOTIDIS, U. OLSSON-STROMBERG, J. MARTINEZ-LOPEZ, P. ROUSSELOT, H. VESTERGAARD, H. EHRENCRONA, V. KAIRISTO, K.M. POLAKOVA, M.C. MULLER, S. MUSTJOKI, M.G. BERGER, A. FABARIUS, W.K. HOFMANN, A. HOCHHAUS, M. PFIRRMANN and F.X. MAHON. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncology. New York: Elsevier Science INC, 2018, vol. 19, No 6, p. 747-757. ISSN 1470-2045. Available from: https://dx.doi.org/10.1016/S1470-2045(18)30192-X.

@article{1423286,
   author = {Saussele, S. and Richter, J. and Guilhot, J. and Gruber, F.X. and HjorthandHansen, H. and Almeida, A. and Janssen, J.J.W.M. and Mayer, Jiří and Koskenvesa, P. and Panayiotidis, P. and OlssonandStromberg, U. and MartinezandLopez, J. and Rousselot, P. and Vestergaard, H. and Ehrencrona, H. and Kairisto, V. and Polakova, K.M. and Muller, M.C. and Mustjoki, S. and Berger, M.G. and Fabarius, A. and Hofmann, W.K. and Hochhaus, A. and Pfirrmann, M. and Mahon, F.X.},
   article_location = {New York},
   article_number = {6},
   doi = {http://dx.doi.org/10.1016/S1470-2045(18)30192-X},
   keywords = {Tyrosine kinase inhibitors},
   language = {eng},
   issn = {1470-2045},
   journal = {Lancet Oncology},
   title = {Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial},
   volume = {19},
   year = {2018}
}

TY  - JOUR
ID  - 1423286
AU  - Saussele, S. - Richter, J. - Guilhot, J. - Gruber, F.X. - Hjorth-Hansen, H. - Almeida, A. - Janssen, J.J.W.M. - Mayer, Jiří - Koskenvesa, P. - Panayiotidis, P. - Olsson-Stromberg, U. - Martinez-Lopez, J. - Rousselot, P. - Vestergaard, H. - Ehrencrona, H. - Kairisto, V. - Polakova, K.M. - Muller, M.C. - Mustjoki, S. - Berger, M.G. - Fabarius, A. - Hofmann, W.K. - Hochhaus, A. - Pfirrmann, M. - Mahon, F.X.
PY  - 2018
TI  - Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial
JF  - Lancet Oncology
VL  - 19
IS  - 6
SP  - 747-757
EP  - 747-757
PB  - Elsevier Science INC
SN  - 14702045
KW  - Tyrosine kinase inhibitors
N2  - Background Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. Methods In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0.1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. Findings Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1.14 [95% CI 1.05-1.23]; p=0.0010) and longer deep molecular response durations (1.13 [1.04-1.23]; p=0.0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1.13 [0.98-1.29]; p=0.08). TKI discontinuation was associated with substantial cost savings (an estimated (sic)22 million). No serious adverse events were reported. Interpretation Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure. Copyright (c) 2018 Elsevier Ltd. All rights reserved.
ER  -

SAUSSELE, S., J. RICHTER, J. GUILHOT, F.X. GRUBER, H. HJORTH-HANSEN, A. ALMEIDA, J.J.W.M. JANSSEN, Jiří MAYER, P. KOSKENVESA, P. PANAYIOTIDIS, U. OLSSON-STROMBERG, J. MARTINEZ-LOPEZ, P. ROUSSELOT, H. VESTERGAARD, H. EHRENCRONA, V. KAIRISTO, K.M. POLAKOVA, M.C. MULLER, S. MUSTJOKI, M.G. BERGER, A. FABARIUS, W.K. HOFMANN, A. HOCHHAUS, M. PFIRRMANN and F.X. MAHON. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. \textit{Lancet Oncology}. New York: Elsevier Science INC, 2018, vol.~19, No~6, p.~747-757. ISSN~1470-2045. Available from: https://dx.doi.org/10.1016/S1470-2045(18)30192-X.

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