The concept of treatment-free remission in chronic myeloid leukemia

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Abstract

The advent of tyrosine kinase inhibitors (TKI) into the management of patients with chronic myeloid leukemia (CML) has profoundly improved prognosis. Survival of responders is approaching that of the general population but lifelong treatment is still recommended. In several trials, TKI treatment has been stopped successfully in approximately half of the patients with deep molecular response. This has prompted the development of a new concept in the evaluation of CML patients known as ‘treatment-free remission'. The future in CML treatment will be to define criteria for the safe and most promising discontinuation of TKI on one hand, and, on the other, to increase the number of patients available for such an attempt. Until safe criteria have been defined, discontinuation of therapy is still experimental and should be restricted to clinical trials or registries. This review will provide an overview of current knowledge as well as an outlook on future challenges.

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European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.

Michele Baccarani, Michael Deininger, Gianantonio Rosti … (2013)

Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

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Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial.

François-Xavier Mahon, Delphine Rea, Joëlle Guilhot … (2010)

Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib. In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR-ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with ClinicalTrials.gov, number NCT00478985. 100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1-30), and 69 patients had at least 12 months follow-up (median 24 months, range 13-30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29-52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR-ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge. Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors. Copyright © 2010 Elsevier Ltd. All rights reserved.

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Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial

A Hochhaus, G Saglio, T. Hughes … (2016)

In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54% 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR4.5; BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

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Author and article information

Journal

Journal ID (nlm-ta): Leukemia

Journal ID (iso-abbrev): Leukemia

Title: Leukemia

Publisher: Nature Publishing Group

ISSN (Print): 0887-6924

ISSN (Electronic): 1476-5551

Publication date (Print): August 2016

Publication date (Electronic preprint): 02 May 2016

Publication date (Electronic): 03 June 2016

Volume: 30

Issue: 8

Pages: 1638-1647

Affiliations

[1 ]III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg , Mannheim, Germany

[2 ]Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital , Lund, Sweden

[3 ]Klinik für Innere Medizin II, Hämatologie/Onkologie, Universitätsklinikum Jena , Jena, Germany

[4 ]Bergonié Cancer Institute, INSERM Unit 916, University of Bordeaux , Bordeaux, France

Author notes

[* ]III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg , Pettenkoferstrasse 22, 68169 Mannheim, Germany. E-mail: susanne.saussele@ 123456medma.uni-heidelberg.de

Article

Publisher Item ID: leu2016115

DOI: 10.1038/leu.2016.115

PMC ID: 4980559

PubMed ID: 27133824

SO-VID: fcdac04c-0272-4ff9-88a4-a6a45257fc11

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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

History

Date received : 22 February 2016

Date revision received : 22 March 2016

Date accepted : 30 March 2016

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The concept of treatment-free remission in chronic myeloid leukemia

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Most cited references 53

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.

Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial.

Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial

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