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Expert Opinion on the Treatment of Refractory Chronic Phase Chronic Myeloid Leukaemia

European Oncology & Haematology, 2017;13(1):17–23 DOI:


The development and clinical availability of second-generation tyrosine kinase inhibitors (TKIs) for the treatment of patients who discontinue imatinib therapy has further improved the outlook for patients with chronic phase chronic myeloid leukaemia (CP-CML). There is, however, uncertainty surrounding how best to treat patients after failing second-generation TKIs. A three-section questionnaire was devised by chronic myeloid leukaemia experts to address questions surrounding this issue. Responses were received from 14 out of 34 experts (41.2%). Generally, a reasonable consensus was found among the responses for most issues. There was a complete consensus that ponatinib was suitable for all patients carrying the T315I mutation regardless of the molecular response to prior treatment. There was also complete consensus that allografting is appropriate in any patient who has had blast crises and is back in a second chronic phase. More recommendations for third-line treatment of CP-CML patients are necessary.
Keywords: Chronic phase chronic myeloid leukaemia, tyrosine kinase inhibitors, allogeneic haematopoietic stem cell transplantation
Disclosure: Tim Hughes has recevied research funding and honoraria from Novartis, BMS and Ariad. Giuseppe Saglio has received consulting fees from Novartis, BMS, Incyte, Ariad and Pfizer.

Compliance with Ethics: All procedures were followed in accordance with the responsible committee on human experimentation and with the Helsinki Declaration of 1975 and subsequent revisions, and informed consent was received from the patient involved in this case study; or This study involves a review of the literature and did not involve any studies with human or animal subjects. performed by any of the authors.

Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Received: October 08, 2016 Accepted: January 25, 2017
Correspondence: Tim Hughes, SAHMRI, North Terrace, Adelaide SA 5000 Australia, PO Box 11060, Adelaide SA 5001. E:
Support: The publication of this article was supported by Ariad. The views and opinions expressed are those of the authors and do not necessarily reflect those of Ariad. The authors provided Ariad with the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion.

The treatment of patients with chronic phase chronic myeloid leukaemia (CP-CML) has changed dramatically with the advent of the first BCR-ABL tyrosine kinase inhibitor (TKI) imatinib (Gleevec®, Novartis Pharmaceutical Corporation, New Jersey, US) in the 1990s.1,2 Multiple studies demonstrated the efficacy and acceptable tolerability of imatinib 400 mg daily.3,4 Despite the good cytogenetic and molecular response rates, some patients show primary resistance (refractoriness) or relapse after an initial response (secondary or acquired resistance).5,6 Adverse events occurred mainly within the first 2 years of treatment initiation and symptoms appeared to be mild or moderate in most instances, but with other treatment options available even low-grade toxicities are less acceptable and lead to discontinuation. Definitions of haematological, cytogenetic and molecular response have been previously described.7 Resistance in this setting has been defined as treatment with imatinib ≥600 mg/d (for ≥3 months) with disease progression (≥50% increase in white blood cells), or no haematological response after 4 weeks, or patients receiving <600 mg/d with mutations at any of the following ABL amino acids: L248, G250, Q252, Y253, E255, T315, F317, H396.7 Dasatinib (Sprycel®; Bristol-Myers Squibb, New Jersey, US) and nilotinib (Tasigna®; Novartis, New Jersey, US), two second-generation TKIs initially launched for use as second-line therapies in 2006/2007, were approved for first line use in 2010. Treatment with dasatinib or nilotinib in recommended doses of 100 mg daily or 400 mg twice daily resulted in significantly higher cytogenetic and molecular response rates compared to imatinib 400 mg daily but there was no progression-free survival (PFS) or overall survival (OS) benefit. With the success of TKIs the earlier gold standard of allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is reserved for later-line patients failing to achieve adequate responses.

Second-line treatment
In second-line, dasatinib and nilotinib have been recommended for treatment of CP-CML patients with resistance/intolerance to imatinib. In addition, bosutinib (Bosulif®; Pfizer, New York, US) received a conditional marketing authorisation in 2013 that is valid throughout the European Union (see Table 1),8–10 for the treatment of adult chronic myeloid leukaemia (CML) patients in all phases.11,12 Despite some good responses to second-line TKI therapy, approximately half of patients treated with dasatinib 100 mg daily or nilotinib 400 mg twice daily develop resistance or intolerance8,13,14 and discontinue therapy.

Third-line treatment
Patients who fail to respond to second-line therapy generally receive third-line therapy with another TKI,10,15–20 and identifying patients most likely to benefit from third-line TKI therapy represents an important unmet need. A cohort of 26 patients with CP-CML who had failed imatinib and a second-line TKI was analysed to identify prognostic factors for response and outcomes.21 For the achievement of complete cytogenetic responses on third-line therapy, prior cytogenetic response with imatinib or a second-line therapy were the only independent predictors. For OS, younger age and the demonstration of a cytogenetic response on second-line therapy were the only independent predictors. The authors highlighted the need to be able to select more accurately

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Keywords: Chronic phase chronic myeloid leukaemia, tyrosine kinase inhibitors, allogeneic haematopoietic stem cell transplantation