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

Deininger2, Gianantonio Rosti3, Andreas Hochhaus4, Simona Soverini3, Jane F. Apperley5, Francisco Cervantes6, Richard E. Clark7, Jorge E. Cortes8, François Guilhot9, Henrik Hjorth-Hansen10, Timothy P. Hughes11, Hagop M. Kantarjian8, Dong-Wook Kim12, Richard A. Larson13, Jeffrey H. Lipton14, François-Xavier Mahon15, Giovanni Martinelli3, Jiri Mayer16, Martin C. Müller17, Dietger Niederwieser18, Fabrizio Pane19, Jerald P. Radich20, Philippe Rousselot21, Giuseppe Saglio22, Susanne Saußele17, Charles Schiffer23, Richard Silver24, Bengt Simonsson25, Juan-Luis Steegmann26, John M. Goldman27, and Rüdiger Hehlmann17

Abstract

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."

Some snips from this article:

"In the definition of response, a controversial point is the value of early molecular response, particularly after 3 months of treatment. A BCR-ABL1 transcripts level >10% was reported to be prognostically significant in several studies.93⇓⇓⇓⇓⇓⇓⇓⇓⇓-103 However, the conclusion of the panel is that a single measurement of BCR-ABL transcripts level is not sufficient to define as failure necessitating a change of treatment, whereas 2 tests (at 3 and 6 months) and supplementary tests in between provide more support for the decision to change the treatment. Failures must be distinguished as either primary (failure to achieve a given response at a given time) or secondary (loss of response) (Table 5)."

"It is recommended that in practice outside of clinical trials, the first-line treatment of CP CML can be any of the 3 TKIs that have been approved for this indication and are available nearly worldwide, namely imatinib (400 mg once daily), nilotinib (300 mg twice daily), and dasatinib (100 mg once daily). These 3 TKIs can also be used in second or subsequent lines, at the standard or at a higher dose (400 mg twice daily for imatinib, 400 mg twice daily for nilotinib, and 70 mg twice daily or 140 mg once daily for dasatinib). Bosutinib (500 mg once daily) has been approved by the FDA and EMA for patients resistant or intolerant to prior therapy. Ponatinib (45 mg once daily) has also been approved by the FDA for patients resistant or intolerant to prior TKI therapy. Also approved, for patients in whom prior TKI therapy fails, are radotinib, which is available in Korea,110 and omacetaxine, which is a non-TKI drug approved by the US FDA.111,112

Busulfan is not recommended. Hydroxyurea can be used for a short time before initiating a TKI, until the diagnosis of CML has been confirmed. rIFNɑ alone is recommended only in the rare circumstances in which a TKI cannot be used. The combinations of TKIs and rIFNɑ are potentially useful but still investigational.113 Cytotoxic chemotherapy is never recommended in CP but may be useful to control BP and to prepare BP patients for alloSCT.

Treatment recommendations for CP are proposed in Table 7. These recommendations are based on a critical evaluation of efficacy, but it is acknowledged and recommended that the choice of the TKI must take into account tolerability and safety, as well as patient characteristics, particularly age and comorbidities, which may be predictive of particular toxicities with the different TKIs. In all cases of “warning,” research and investigational studies are warranted and should be encouraged to improve treatment results."

"The quality of life is also affected by the very fact that living together with a potentially fatal disease—CML is a cancer, after all—has emotional and social consequences affecting family and career planning and is accompanied by a variable level of uncertainty and fear. It was not surprising that both physical and mental health were reported to be better and closer to normal in the older than in the younger patients, because younger have more and different expectations, not only of a normal life, but also of a life free from leukemia and from treatment.141 Currently, the major goal of therapy is survival, but it is acknowledged that living without treatment and without detectable leukemia will be a major issue for clinical investigation, requiring the achievement of a deeper molecular response."

http://bloodjournal.hematologylibrary.org/content/122/6/872.full