Twenty years of evolution of CML therapy: how the treatment goal is moving from disease to patient.

The introduction of imatinib in 2000 opened the era of tyrosine kinase inhibitors (TKIs) for CML therapy and has revolutionized the life expectancy of CML patients, which is now quite like the one of the healthy aged population. Over the last 20 years, both the TKI therapy itself and the objectives have undergone evolutions highlighted and discussed in this review. The main objective of the CML therapy in the first 10 years after TKI introduction was to abolish the disease progression from the chronic to the blastic phase and guarantee the long-term survival of the great majority of patients. In the second 10 years (from 2010 to the present), the main objective of CML therapy moved from survival, considered achieved as a goal, to treatment-free remission (TFR). Two phenomena emerged: no more than 50-60% of CML patients could be candidates for discontinuation and over 50% of them molecularly relapse. The increased cumulative incidence of specific TKI off-target side effects was such relevant to compel to discontinue or reduce the TKI administration in a significant proportion of patients and to avoid a specific TKI in particular settings of patients. Therefore, the treatment strategy must be adapted to each category of patients. What about the patients who do not get or fail the TFR? Should they be compelled to continue the TKIs at the maximum tolerated dose? Alternative strategies based on the principle of minimal effective dose have been tested with success and they are now re-evaluated with more attention, since they guarantee survival and probably a better quality of life, too. Moving from treating the disease to treating the patient is an important change of paradigm. We can say that we are entering a personalized CML therapy, which considers the patients' age, their comorbidities, tolerability, and specific objectives. In this scenario, the new techniques supporting the monitoring of the patients, such as the digital PCR, must be considered. In the present review, we present in deep this evolution and comment on the future perspectives of CML therapy.