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TKI discontinuation in CML clinical practice
the subsequent six months, and then every three months.21 Although we may think that a stringent moni- toring is protective, and indeed most of the relapses occurred during the first year, late relapses were not com- plicated by loss of complete hematologic remission or pro- gression to advanced phases, even if monitoring was less frequent.32 Given this, we must mention that Italian cen- ters rely on the Lab-net CML network, which ensures a standardized measurement of minimal residual disease, with a short turn-around time between sampling and reporting.
The history of CML has been revolutionized by the introduction of imatinib, and while this has resulted in an extraordinary improvement in survival, second generation TKI have refined our concept of CML. The achievement of higher rates of DMR in shorter periods of time switched the goal of CML treatment from survival to cure, to the point that TFR was included in the data sheet of nilotinib.33 However, for the moment, a definitive treat- ment discontinuation is not yet an option for everybody. All the studies have tried to define prognostic factors for a successful TFR in order to increase the number of patients who can experience a successful discontinuation. In our study, having a high Sokal risk score at diagnosis was pre- dictive for a worse outcome, in agreement with the STIM and the Korean studies.7,16 As in the ISAV trial,13 we showed that age might have a role in the maintenance of response, with an advantage for older patients. We retro- spectively observed that our population was almost entirely characterized by an optimal early response at three months; this could explain why TFR was compara- ble when discontinuation occurred in a first-line setting or during subsequent lines of therapy. Duration of treatment was reported as a prognostic factor in many studies.7,15,16,21 In our analysis, the duration of total treatment for patients who discontinued TKI in second line was significantly longer compared to patients who discontinued TKI in front-line (128 vs. 82 months). This could possibly account for the lower risk of relapses in patients who discontinued TKI in second line as shown in the univariate analysis. In fact, in the multivariate analyses, the line of treatment lost significance. In our study, the total duration of treatment had a positive influence particularly on patients treated with second generation TKI: we observed a 22% reduc- tion of the risk of resuming therapy per year of treatment.
In this study, we observed that patients who discontin- ued second generation TKI had a median duration of treat- ment with the last TKI of 50 months versus 96 months of treatment with imatinib (Table 1). The results are in line with those of several prospective studies, such as the ENEST Freedom, the ENEStop (median duration of treat- ment with nilotinib of 43 months and 53 months, respec- tively), and the EURO-SKI trials (median duration of treat- ment with imatinib of 91 months).20,21,25 Furthermore, the multivariate Cox proportional hazards regression model showed a better probability of TFR for patients treated with second generation TKI, with an estimated 57% rela- tive risk reduction in favor of the second generation TKI. Even considering the quite large confidence interval, the minimum risk reduction is still 9%. These data are in keeping with the superiority of second generation TKI in deeply and rapidly reducing the level of disease.
Importantly, almost all the patients who were retreated regained at least MMR, and 82% regained the DMR crite- ria for a second discontinuation attempt, which has been recently proven to be feasible.31 In fact, Legros et al. report- ed that 35% of patients who had a second discontinuation attempt (median total time of treatment of 103 months) remained free from relapse at three years.31 Those who have eventually restarted treatment had nonetheless taken advantage of a treatment 'holiday' without meaningful risks.
Conclusions
This multicenter observational study included a sub- stantial number of patients who were cared for in care institutes through clinical practice procedures, confirming that treatment discontinuation is safe and effective also outside controlled clinical trials. Taking into account all the evidence collected in the last ten years, we think that TKI discontinuation in patients in persistent DMR must be considered in routine clinical practice, as long as molec- ular monitoring is performed regularly in standardized laboratories, and in accordance with the criteria stated in the ESMO and NCCN recommendations.34,35
Acknowledgments
We thank the Associazione Italiana Leucemie (AIL) for the continuous support to doctors and patients.
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