Treatment-Free Remission in Ponatinib-Treated CML Patients: The Italy-Tfr Experience

Background: In recent years, treatment-free remission (TFR) has become a new therapeutic goal and is considered feasible even by international expert guidelines, at least in patients (pts) with a stable deep molecular response (DMR). From the EPIC study, we learned that many pts achieve a DMR very early, regardless of Sokal risk (Lipton, Lancet Oncol 2016). The Optic study showed that early dose reduction is associated with a containment of cardiovascular (CV) risk while maintaining therapeutic efficacy. In the cohort of pts initially treated with 45 mg QD, the number of events remained around 10% (Cortes, Blood 2021). Recommendations for treatment discontinuation suggest that it should be considered only after one line of treatment or after a second line if first-line TKI was switched for intolerance. Since 2016, there are case reports in the literature of imatinib-resistant pts, treated with ponatinib in second or following lines due to intolerance or resistance to previous TKIs, with or without ABL1 mutations, who reduced the daily dosage from 45 to 15 mg, still achieving a DMR and then discontinued ponatinib due to toxicity, obtaining a persistent TFR (Wisniowski, Blood 2016; Engel, J Oncol Pract 2016; Cohen, Leuk Lymphoma 2020). Methods: Within the context of the Italy-TFR retrospective and prospective study (NCT04769947) which is ongoing and actually includes 467 pts, we collected the data of 19 pts who attempted TFR after ponatinib treatment. Results: Median age was 44 years at diagnosis, 60 years at ponatinib discontinuation. 8 pts were male (42%); Sokal score was available for 14 pts: 5, 3 and 6 pts were low, intermediate and high risk, respectively. ELTS score was available for 11 pts: 6 pts, 4 and 1 were low, intermediate and high risk, respectively. 6 pts were treated with ponatinib in second line, 9 in third line, 3 in forth line. First-line therapy was available for 16 pts and was imatinib for 11 pts, nilotinib for 2 pts, dasatinib for 3 pts. Median duration of front-line treatment was 16 months (mos, IQR 11-34). Data on second line therapy was available for 11/12 pts: 5 pts were treated with nilotinib, 6 with dasatinib. Median duration of second-line treatment was 47 mos (IQR 19-58). Third line therapy was dasatinib for all 3 pts, with a duration of 1, 18 and 139 mos. Reason for starting ponatinib was intolerance for 8 pts, resistance for the others. For 7/11 resistant pts response at ponatinib start was CHR for one pt, MR1 for 3 pts, MR2 fo