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Another piece of the puzzle – optimal TKI selection before treatment discontinuation in CML

The incredible advances made in the field of CML management during the last 20 years are currently in the phase of bringing as much patients as possible to treatment concepts allowing TKI discontinuation and potential cure (1, 2). Cure is clinically reflected by continuous treatment discontinuation without subsequent disease relapse. Data from the French STIM (3) and the Australasian TWISTER (4) studies are encouraging; however, only less than 20% of patients in the imatinib era indeed finally fulfil the requirements for treatment discontinuation. Therefore, the introduction of the 2ndgeneration TKIs is an important step to allow in the future a higher percentage of patients to discontinue therapy and to be potentially cured. Thus, data from randomized trials showing the superiority of 2nd-generation TKIs vs. imatinib are still important as positive data help patients and physicians to tolerate the clinically more relevant side effects of 2nd generation TKIs for the achievement of continuous deep molecular remission. The here presented paper by the Nordic CML group (NCMLSG) helps us further to believe that starting with a 2nd-generation TKI is probably the optimal strategy to get as much patients as possible in deep molecular remission (5). Henrik Hjorth-Hansen and his Nordic co-workers performed an interesting randomized trial comparing dasatinib versus imatinib in the front-line setting in CP-CML. The study was rather small, but the adjunct research programme aiming at quantifying CML stem cell dynamics with respect to their prognostic relevance is highly innovative (6). The scientific programme demonstrated that at diagnosis, the proportion of leukaemic stem cells (LSC) markedly varied between different individuals but correlated with various clinical variables (i.e. LSC burden at diagnosis was associated with less therapy-related haematological toxicity and superior cytogenetic and molecular responses). Most importantly and in contrast to in vitro findings, TKI therapy very rapidly depleted most of the detectable LSC in vivo. The authors now show in this issue of the European Journal of Haematology that especially the molecular data of their NCMLSG study compare favourable to the DASISION trial (7) or another randomized US trial from G. Radich and co-workers (8). Of note, even though the Nordic population was even older and had a comparable distribution of risk scores, the Nordic molecular response rates were almost doubled as compared to the two mentioned reference studies. At 24 months, for example, 52% in the NCMLSG trial had MR as opposed to 17% of patients in the DASISION study. It remains elusive whether the Nordic patients have a higher level of compliance due to the excellent healthcare system, or whether there are specific genetic polymorphisms regulating different TKI sensitivities [e.g. MRD1 polymorphisms or expression levels (9, 10)] or whether these observations are just due to the smaller patient population and thus do not reflect biological and potentially modifiable variables. The data are, however, of importance, especially with respect to possible cessation scenarios, as it suggests that dasatinib is clearly superior to imatinib in the induction of deep molecular responses, which is a prerequisite for TKI discontinuation.