Observational Study of CML Italian Patients Who Discontinued TKIs

Background: Different studies analysed the outcome of patients (pts) who discontinued tyrosine kinase inhibitors (TKIs) reporting a median treatment-free remission (TFR) rate of 55%. On these bases it is judged safe to discontinue treatment in experimental contexts.

Aims: Aim of our study was to evaluate TFR in the setting of Italian pts .

Material and Methods: We designed a retrospective observational study of Italian pts with chronic phase CML who discontinued TKI treatment in deep molecular response (DMR). All Hematological Centers who are part of the GIMEMA group were invited to participate to this retrospective study and 32 centers had cases and participated to the study.

Results: We collected a total of 293 pts. Median age was 59 years; 59%, 30% and 11% of pts were low, intermediate and high Sokal score respectively. 72% of pts were on treatment with imatinib, 28.% with either nilotinib (n=58), dasatinib (n=23) or bosutinib (n=1) at the time of discontinuation. 55% of pts discontinued in first line, 40% in second line, 5% in third line. Median duration of treatment with the last TKI was 77 months (mos, IQR 54;111) median time to deep molecular response (DMR, i.e. undetectable transcript or MR4/MR4.5/MR5) with the last TKI was 46 mos (IQR 30;73), median duration of DMR was 46 mos (IQR 31;74) before stop. Duration of treatment with TKIs and duration of DMR were shorter with 2nd gen TKIs than with imatinib (p<0.001). At 3 mos of last TKI most of the pts were in optimal response: 34% of pts were already in MR3, 25% in PCyR and/or had a transcript < 10%, 40% were in CCyR and/or had a transcript < 1%. Only 1% of the whole population had no response. Definition of response at discontinuation was: undetectable for 16%, MR4 for 35%, MR 4.5 for 31%, and MR5 for 18% of pts. Only 12% of the Italian pts discontinued in a prospective interventional study. In the other cases pts discontinued per clinical practice and reasons for stopping treatment were: toxicity for 20% of pts, pregnancy for 6% pts and shared decision between treating physician and patient upon pts request for 62% of cases. After a median follow-up of 34 mos (Min-Max 12-161) estimated TFR was 62% (95% CI 56;68). At 12 mos estimated TFR was 68% (95% CI 62;74) for imatinib, 73% (95% CI 64;83) for 2nd gen TKIs. There was no statistically significant difference (see CI) between TFR at 12 mos with imatinib and with 2^nd gen TKIs. Overall 115 pts (39%) restarted treatment. Reasons for restarting were: loss of MR4 for 19%, loss of MR3 for 69%, loss of CCyR for 9%, other reasons for 3% of pts. Overall median time to restart treatment was 6 mos (IQR 4;11). Although 75% of pts restarted treatment by the first year, last pt was reported to restart treatment after 105 mos. Median time from loss of response to restart-treatment was 1 mo (IQR 0;2). No progressions occurred. Nine deaths were reported but none of them was disease related. Pts who had to restart therapy were treated with imatinib (77), nilotinib (22), dasatinib (9), bosutinib (3) or ponatinib (1). Interestingly most of the pts who stopped imatinib restarted imatinib after relapse and most of the pts who were on 2nd gen TKIs stayed with 2nd gen TKIs. 24 pts who lost MR4 (including 4 who lost MMR) did not restart treatment and were still off therapy after a median time of 12 mos. Almost all the pts retreated regained at least MR3. 73 pts regained the MR criteria for a second discontinuation attempt. We assessed age, sex, Sokal score, type of transcript, previous IFN therapy, duration of TKI therapy, response at 3 mos, time to DMR, DMR duration, line of therapy at stop, depth of MR, reasons for stop as potential prognostic factors for TFR, but no statistically significant association were found, with the exception of age: a decreased risk of relapse in older vs younger pts

Conclusion: Although our study has the limitation of a retrospective study, our experience within the Italian population confirms that discontinuation of imatinib and 2nd gen TKIs is feasible and safe in the clinical practice.