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      The Role of Early Molecular Response in the Management of Chronic Phase CML

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          Abstract

          Purpose of Review

          Although tyrosine kinase inhibitors (TKIs) spectacularly improve the disease burden and the overall survival of chronic myeloid leukemia patients, early identification of a subset of poor TKI responders has been recognized as a critical goal to prevent disease progression in these patients. We herein review the past and recent evidence on the impact of early response.

          Recent Findings

          In the recent years, the achievement of an early molecular response (EMR, defined as 3-month BCR-ABL1 transcript <10% IS) has emerged as a useful tool to identify poor-risk patients. Although several groups have reported the importance of such milestone, clinical intervention based on it remains controversial partly due to its low specificity to predict progression, which may be partially improved by using the rate of decline in BCR-ABL1 transcript level (halving time or velocity of ratio reduction).

          Summary

          Standardization of halving time or velocity of ratio reduction will likely help establishing more stringent recommendation and modify current clinical practices.

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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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              Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial.

              Jorge Cortés, Giuseppe Saglio, Hagop Kantarjian … (2016)
              We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib.
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                Author and article information

                Contributors
                Hugues de Lavallade: h.delavallade@nhs.net
                Journal
                Journal ID (nlm-ta): Curr Hematol Malig Rep
                Journal ID (iso-abbrev): Curr Hematol Malig Rep
                Title: Current Hematologic Malignancy Reports
                Publisher: Springer US (New York )
                ISSN (Print): 1558-8211
                ISSN (Electronic): 1558-822X
                Publication date (Electronic): 12 April 2017
                Publication date PMC-release: 12 April 2017
                Publication date (Print): 2017
                Volume: 12
                Issue: 2
                Pages: 79-84
                Affiliations
                [1 ]ISNI 0000 0004 0489 4320, GRID grid.429705.d, Department of Haematological Medicine, , King’s College Hospital NHS Foundation Trust, ; London, UK
                [2 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Haematology Department, , King’s College London, ; London, UK
                [3 ]ISNI 0000 0004 0391 9020, GRID grid.46699.34, Laboratory for Molecular Haemato-Oncology, , King’s College Hospital NHS Foundation Trust/King’s College London, ; London, UK
                Article
                Publisher ID: 375
                DOI: 10.1007/s11899-017-0375-0
                PMC ID: 5410202
                PubMed ID: 28405921
                SO-VID: 8268f4d3-4ce9-4e9a-9bdf-b216c1ee2ed0
                Copyright © © The Author(s) 2017
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Funding
                Funded by: King's College London
                Categories
                Subject: Chronic Myeloid Leukemias (J Pinilla-Ibarz, Section Editor)
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media New York 2017

                ScienceOpen disciplines: Hematology
                Keywords: tyrosine kinase inhibitors,cml,chronic myeloid leukemias,early molecular response
                Data availability:
                ScienceOpen disciplines: Hematology
                Keywords: tyrosine kinase inhibitors, cml, chronic myeloid leukemias, early molecular response

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