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, <1% at 6 months, and ≤0.1% from 12 months onward define optimal response, whereas >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.
The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available firstline). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase
inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome.
In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable
and manageable, but they are increasingly important as therapy is potentially
lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet
panel for CML management recommendations presents an exhaustive and critical summary
of AEs emerging during CML treatment, to assist their understanding, management and
prevention. There are five major conclusions. First, the main purpose of CML
treatment is the antileukemic effect. Suboptimal management of AEs must not
compromise this first objective. Second, most patients will have AEs, usually early,
mostly mild to moderate, and which will resolve spontaneously or are easily
controlled by simple means. Third, reduction or interruption of treatment must only
be done if optimal management of the AE cannot be accomplished in other ways, and
frequent monitoring is needed to detect resolution of the AE as early as possible.
Fourth, attention must be given to comorbidities and drug interactions, and to new
events unrelated to TKIs that are inevitable during such a prolonged treatment.
Fifth, some TKI-related AEs have emerged which were not predicted or detected in
earlier studies, maybe because of suboptimal attention to or absence from the
preclinical data. Overall, imatinib has demonstrated a good long-term safety profile,
though recent findings suggest underestimation of symptom severity by physicians.
Second and third generation TKIs have shown higher response rates, but have been
associated with unexpected problems, some of which could be irreversible. We hope
these recommendations will help to minimise adverse events, and we believe that an
optimal management of them will be rewarded by better TKI compliance and thus better
CML outcomes, together with better quality of life.
A new prognostic scoring system for estimating survival of patients with CML treated with interferon alfa has been developed and validated through use of a large dataset.
Key Points
In a 3-year follow-up of the DASatinib versus Imatinib Study In treatment-Naive CML patients trial, first-line dasatinib resulted in faster and deeper responses compared with imatinib. Deeper responses at 3, 6, and 12 months were associated with better 3-year progression-free survival and overall survival.
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